[Federal Register Volume 81, Number 183 (Wednesday, September 21, 2016)]
[Rules and Regulations]
[Pages 64982-65157]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2016-22129]
[[Page 64981]]
Vol. 81
Wednesday,
No. 183
September 21, 2016
Part II
Department of Health and Human Services
-----------------------------------------------------------------------
42 CFR Part 11
Clinical Trials Registration and Results Information Submission; Final
Rule
Federal Register / Vol. 81 , No. 183 / Wednesday, September 21, 2016
/ Rules and Regulations
[[Page 64982]]
-----------------------------------------------------------------------
DEPARTMENT OF HEALTH AND HUMAN SERVICES
42 CFR Part 11
[Docket Number NIH-2011-0003]
RIN 0925-AA55
Clinical Trials Registration and Results Information Submission
AGENCY: National Institutes of Health, Department of Health and Human
Services.
ACTION: Final rule.
-----------------------------------------------------------------------
SUMMARY: This final rule details the requirements for submitting
registration and summary results information, including adverse event
information, for specified clinical trials of drug products (including
biological products) and device products and for pediatric postmarket
surveillances of a device product to ClinicalTrials.gov, the clinical
trial registry and results data bank operated by the National Library
of Medicine (NLM) of the National Institutes of Health (NIH). This rule
provides for the expanded registry and results data bank specified in
Title VIII of the Food and Drug Administration Amendments Act of 2007
(FDAAA) to help patients find trials for which they might be eligible,
enhance the design of clinical trials and prevent duplication of
unsuccessful or unsafe trials, improve the evidence base that informs
clinical care, increase the efficiency of drug and device development
processes, improve clinical research practice, and build public trust
in clinical research. The requirements apply to the responsible party
(meaning the sponsor or designated principal investigator) for certain
clinical trials of drug products (including biological products) and
device products that are regulated by the Food and Drug Administration
(FDA) and for pediatric postmarket surveillances of a device product
that are ordered by FDA.
DATES: These regulations are effective on January 18, 2017. Additional
information on the effective date and the compliance date can be found
in Section IV.F.
FOR FURTHER INFORMATION CONTACT:
Regulatory Process: Jerry Moore, NIH Regulations Officer, Office of
Management Assessment, telephone (301-496-4607) (not a toll-free
number), Fax (301-402-0169), or by email at [email protected].
Technical Information: Kevin Fain, Senior Advisor for Policy and
Research, ClinicalTrials.gov, National Center for Biotechnology
Information, NLM, NIH, Department of Health and Human Services,
telephone (301-402-0650) (not a toll-free number), Fax 301-402-0118, or
by email at [email protected].
SUPPLEMENTARY INFORMATION:
Executive Summary
Purpose of This Regulatory Action
This final rule clarifies and expands requirements for the
submission of clinical trial registration and results information to
the ClinicalTrials.gov database, which is operated by the NLM. It
implements the provisions of section 402(j) of the Public Health
Service Act (PHS Act) (42 United States Code (U.S.C.) 282(j)) as
amended by Title VIII of FDAAA and including technical corrections made
to FDAAA under Public Law 110-316), which were intended to improve
public access to information about certain clinical trials of U.S. FDA-
regulated drugs, biological products, and devices (also referred to as
``FDA-regulated drugs, biological products, and devices'' in this
preamble) and certain pediatric postmarket surveillances of a device.
Under section 402(j) of the PHS Act, those responsible for specified
clinical trials of these FDA-regulated products have been required to
submit registration information to ClinicalTrials.gov since December
26, 2007, summary results information for clinical trials of approved
products as of September 27, 2008, and certain adverse events
information since September 27, 2009. Section 402(j) of the PHS Act
requires the Secretary of Health and Human Services to use rulemaking
to expand the requirements for submission of summary results
information, and authorizes the Secretary to use rulemaking to make
other changes that enhance, but do not decrease, the available
information about the specified trials.
This final rule does not impose requirements on the design or
conduct of clinical trials or on the data that must be collected during
clinical trials. Instead it specifies how data that were collected and
analyzed in accordance with a clinical trial's protocol are submitted
to ClinicalTrials.gov. No patient-specific data are required to be
submitted by this rule or by the law this rule is intended to
implement.
The major provisions of this rule are summarized below. More
detailed discussions of these provisions are in Sections III and IV of
this preamble.
Summary of the Major Provisions of the Regulatory Action
Applicable Clinical Trial
This final rule clarifies which clinical trials of FDA-regulated
drug products (including biological products) and device products and
which pediatric postmarket surveillances of a device product, are
applicable clinical trials for which information must be submitted to
ClinicalTrials.gov. The final rule considers all interventional
clinical trials with one or more arms and with one or more pre-
specified outcome measures to be controlled clinical trials. The final
rule does not consider any expanded access use (e.g., access under
treatment INDs or treatment protocols, which provide widespread access,
access for intermediate-sized patient populations, or access for
individual patients) to be an applicable clinical trial. The final rule
also describes an approach for evaluating, prior to registration,
whether a particular clinical trial or study is an applicable clinical
trial (see Section IV.A.5 and Section IV.B.2).
Responsible Party
This final rule specifies that there must be one (and only one)
responsible party for purposes of submitting information about an
applicable clinical trial. The sponsor of an applicable clinical trial
will be considered the responsible party, unless and until the sponsor
designates a qualified principal investigator as the responsible party.
This final rule specifies the approach for determining who will be
considered the sponsor of an applicable clinical trial under various
conditions, what qualifies a principal investigator to be designated a
responsible party by a sponsor, and how responsibility reverts to the
sponsor if a designated principal investigator is unable to fulfill the
requirements for submitting information to ClinicalTrials.gov unless
and until the sponsor designates another principal investigator as the
responsible party (see Section IV.A.2).
Registration
This final rule specifies requirements for registering applicable
clinical trials at ClinicalTrials.gov. It requires that the responsible
party register an applicable clinical trial not later than 21 calendar
days after enrolling the first human subject (also referred to as
participant or subject), and it specifies the data elements of clinical
trial information that must be submitted at the time of registration.
These data elements include the descriptive information, recruitment
information, location and contact information, and administrative data
elements listed in section 402(j) of the PHS Act, as well as additional
required data elements under the Secretary's authority to modify the
registration information requirements by
[[Page 64983]]
rulemaking as long as such modifications improve, and do not reduce,
the clinical trial information available to the public in
ClinicalTrials.gov. We consider these additional required registration
data elements necessary to enable the NIH to implement other statutory
provisions, indicate the status of human subjects protection review of
the trial, facilitate the public's ability to search and retrieve
information from ClinicalTrials.gov, and help ensure that entries are
meaningful and unambiguous. We note that some of these additional data
elements required under this rule were included in ClinicalTrials.gov
before FDAAA was enacted or have been implemented since 2007 as
optional data elements (see Section IV.B).
Although section 402(j) of the PHS Act includes a provision
delaying public posting of registration information for applicable
clinical trials of unapproved or uncleared device products until the
device product is approved or cleared, the final rule includes a
provision under which the responsible party for an applicable device
clinical trial can indicate to the Agency that it is authorizing the
public posting of clinical trial registration information that would
otherwise fall under the delayed posting provision prior to approval or
clearance of the product (see Section IV.B.5).
Expanded Access Information
Section 402(j) of the PHS Act requires the submission of
information regarding whether, for an applicable drug clinical trial of
an unapproved drug product (including an unlicensed biological
product), expanded access to the investigational product being studied
in the applicable clinical trial is available under section 561 of the
Federal Food, Drug, and Cosmetic Act (FD&C Act). If the responsible
party for an applicable clinical trial of an unapproved drug product
(including an unlicensed biological product) is both the sponsor of the
applicable clinical trial being registered and the manufacturer of the
unapproved product, this rule requires the submission of a separate
expanded access record containing details about how to obtain access to
the investigational product. Once an expanded access record has been
created for a particular investigational product and a National
Clinical Trial (NCT) number has been assigned to it, the responsible
party must update the applicable clinical trial(s) with that NCT number
and provide that NCT number when submitting clinical trial registration
information for any future applicable clinical trial(s) studying the
same investigational product. The NCT number for the expanded access
record allows ClinicalTrials.gov to link the existing expanded access
record to the study record for the clinical trial (see Section IV.B.5
and Section IV.D.3).
Results Information Submission
This final rule addresses the statutory requirement for the
submission of summary results information for applicable clinical
trials of drug products (including biological products) and device
products that are approved, licensed, or cleared by FDA. It also
extends the requirement for results information submission to
applicable clinical trials of drug products (including biological
products) and device products that are not approved, licensed, or
cleared by FDA. The rule requires the submission of data in a tabular
format summarizing participant flow; demographic and baseline
characteristics; primary and secondary outcomes, as well as results of
any scientifically appropriate statistical tests; and adverse event
information. In addition, the rule requires the submission of the full
protocol and statistical analysis plan (if a separate document) (see
Section III.D).
In general, this rule requires the submission of results
information not later than 1 year after the completion date (referred
to as the ``primary completion date'') of the clinical trial, which is
defined as the date of final data collection for the primary outcome
measure. Results information submission could be delayed for up to 2
additional years from the date of submission of a certification that
either an unapproved, unlicensed, or uncleared product studied in the
trial is still under development by the manufacturer or that approval
will be sought within 1 year after the primary completion date of the
trial for a new use of an approved, licensed, or cleared product that
is being studied in the trial. This rule also permits responsible
parties to request extensions to the results information submission
deadlines for ``good cause'' as well as a permanent waiver of results
information submission requirements for extraordinary circumstances
(see Section IV.C.3 and Section IV.C.6).
Adverse Events Information
This final rule requires the responsible party to submit
information summarizing the number and frequency of adverse events
experienced by participants enrolled in a clinical trial, by arm or
comparison group, as well as a brief description of each arm or group
as a component of clinical trial results information. It also requires
submission of three tables of adverse event information: One
summarizing all serious adverse events; another one summarizing other
adverse events that occurred with a frequency of 5 percent or more in
any arm of the clinical trial; and finally, one summarizing all-cause
mortality data by arm or group. This final rule clarifies that these
adverse event tables must include information about events that
occurred, regardless of whether or not they were anticipated or
unanticipated. In addition, this rule requires responsible parties to
provide the time frame for adverse event data collection and specify
whether the collection approach for adverse events was systematic or
non-systematic. The final rule does not require a responsible party to
collect adverse event information that is not specified in the protocol
(see Section IV.C.4).
Updates and Other Required Information
This final rule requires that all submitted information be updated
at least annually if there are changes to report. More rapid updating
is required for several data elements to help ensure that users of
ClinicalTrials.gov have access to accurate, up-to-date information
about important aspects of an applicable clinical trial or other
clinical trial. The final rule also requires timely corrections to any
errors discovered by the responsible party or the Agency during quality
control review of submissions or after the information has been posted.
The rule clarifies that the responsible party's obligation to submit
updates and correction of errors ends on the date on which the required
data elements for clinical trial results information have been
submitted for all primary and secondary outcomes and all adverse events
that were collected in accordance with the protocol, and the quality
control review process has concluded (see Section IV.D.3).
Effective Date and Compliance Date
This final rule will be effective January 18, 2017. As of that
date, the ClinicalTrials.gov system will allow responsible parties to
comply with the rule. Responsible parties will have 90 calendar days
after the effective date to come into compliance with the requirements
of this rule (see Section IV.F).
Legal Consequences of Non-Compliance
This final rule outlines the potential civil or criminal actions,
civil monetary penalty actions, and grant funding
[[Page 64984]]
actions that may be taken if responsible parties fail to comply with
the rule's requirements. It does not outline all potential legal
consequences, e.g., laws governing the veracity of information
submitted to the federal government, however, and should not be
understood as describing the exclusive means of enforcement that the
government might undertake with respect to compliance with the
provisions of section 402(j) of the PHS Act, including these
regulations (see Section IV. E).
Costs and Benefits
Based on our cost estimates, this regulatory action is expected to
result in $59.6 million in annual costs, and it is not expected to have
a significant impact on the economy. The costs consist primarily of the
time needed to organize, format, and submit to ClinicalTrials.gov
information that was prepared for or collected during the clinical
trial (e.g., summary of key protocol details and clinical trial results
information). The potential benefits include greater public access to
information about ongoing and completed applicable clinical trials.
Such information may help potential clinical trial participants to
better understand their options for participating in new trials; to
better enable funders and clinical researchers to determine the need
for new trials; to provide more complete information for those who use
evidence from clinical trials to inform medical and other decisions;
and to better enable the scientific community to examine the overall
state of clinical research as a basis for engaging in quality
improvement (e.g., with regard to research methods). The rule is also
expected to provide greater clarity about what is required for those
who are subject to the legal mandate to submit information to
ClinicalTrials.gov (see Section V).
Commonly Used Abbreviations
ANDA Abbreviated New Drug Application
API Application Program Interface
BLA Biologics License Application
CBER Center for Biologics Evaluation and Research, FDA
CDER Center for Drug Evaluation and Research, FDA
CDISC Clinical Data Interchange Standards Consortium
CDRH Center for Devices and Radiological Health, FDA
CFR Code of Federal Regulations
CONSORT Consolidated Standards of Reporting Trials
CSR Clinical Study Report
CTRP Clinical Trial Reporting Program, NCI
EMA European Medicines Agency
EU European Union
EudraCT European Clinical Trials Database
FDA Food and Drug Administration, HHS
FDAAA Food and Drug Administration Amendments Act of 2007
FDAMA Food and Drug Administration Modernization Act of 1997
FD&C Act Federal Food, Drug, and Cosmetic Act
FOIA Freedom of Information Act
FR Federal Register
HDE Humanitarian Device Exemption
HHS Department of Health and Human Services
ICH International Conference on Harmonization of Technical
Requirements of Pharmaceuticals for Human Use
ICMJE International Committee of Medical Journal Editors
IDE Investigational Device Exemption
IND Investigational New Drug Application
IOM Institute of Medicine (now the Health and Medicine Division of
the National Academies of Sciences, Engineering, and Medicine)
IPD Individual Participant Data
IRB Institutional Review Board
IVD In Vitro Diagnostic
LPLV Last Patient Last Visit
MedDRA Medical Dictionary for Regulatory Affairs
MeSH[supreg] Medical Subject Headings
NCI National Cancer Institute, NIH
NCT National Clinical Trial
NDA New Drug Application
NIH National Institutes of Health, HHS
NLM National Library of Medicine, NIH
NPRM Notice of Proposed Rulemaking
OHRP Office for Human Research Protections, HHS
PCORI Patient-Centered Outcomes Research Institute
PDF Portable Document Format
PHS Act Public Health Service Act
PMA Premarket Approval
PRS Protocol Registration and Results System, ClinicalTrials.gov
RFA Regulatory Flexibility Act
SAP Statistical Analysis Plan
SNOMED CT[supreg] Systematized Nomenclature of Medicine--Clinical
Terms[supreg]
UMLS Unified Medical Language System
U.S. United States
U.S.C. United States Code
U.S. TSA U.S. Trade Secrets Act
UTSA Uniform Trade Secrets Act, Uniform Law Commission
WHO World Health Organization
XML Extensible Markup Language
Table of Contents
I. Background
II. Overview of Statutory Provisions
III. Discussion of Public Comments on Selected Key Issues
A. Scope and Applicability
B. Submission of Results Information for Applicable Clinical
Trials of Unapproved, Unlicensed, or Uncleared Products for Any Use
C. Submission of Technical and Non-technical Summaries
D. Submission of Protocols and Statistical Analysis Plans
IV. Discussion of Public Comments Related to Specific Provisions of
the Regulations
A. Subpart A--General Provisions
1. What is the purpose of this part?--Sec. 11.2
2. To whom does this part apply?--Sec. 11.4
3. What are the requirements for the submission of truthful
information?--Sec. 11.6
4. In what format must clinical trial information be
submitted?--Sec. 11.8
5. What definitions apply to this part?--Sec. 11.10
B. Subpart B--Registration
1. Who must submit clinical trial registration information?--
Sec. 11.20
2. Which applicable clinical trials must be registered?--Sec.
11.22
3. When must clinical trial registration information be
submitted?--Sec. 11.24
4. What constitutes clinical trial registration information?--
Sec. 11.28
5. By when will the NIH Director post clinical trial
registration information submitted under Sec. 11.28?--Sec. 11.35
C. Subpart C--Results Information Submission
1. Who must submit clinical trial results information?--Sec.
11.40
2. For which applicable clinical trials must clinical trial
results information be submitted?--Sec. 11.42
3. When must clinical trial results information be submitted for
applicable clinical trials subject to Sec. 11.42?--Sec. 11.44
4. What constitutes clinical trial results information?--Sec.
11.48
5. By when will the NIH Director post clinical trial results
information submitted under Sec. 11.48?--Sec. 11.52
6. What are the procedures for requesting and obtaining a waiver
of the requirements clinical trial results information submission?--
Sec. 11.54
D. Subpart D--Additional Submissions of Clinical Trial
Information
1. What requirements apply to the voluntary submission of
clinical trial information for clinical trials of FDA-regulated drug
products (including biological products) and device products?--Sec.
11.60
2. What requirements apply to applicable clinical trials for
which submission of clinical trial information has been determined
by the NIH Director to be necessary to protect the public health?--
Sec. 11.62
3. When must clinical trial information submitted to
ClinicalTrials.gov be updated or corrected?--Sec. 11.64
E. Subpart E--Potential Legal Consequences of Non-compliance
1. What are potential legal consequences of not complying with
the requirements of this part?--Sec. 11.66
F. Effective Date, Compliance Date, and Applicability of
Requirements in This Part
V. Regulatory Impact Statement
A. Comments and Response
B. The Final Rule
C. Need for the Final Rule
D. Benefits of the Final Rule
E. Costs Associated With the Final Rule
1. Registration of Applicable Clinical Trials
2. Results Information Submission
3. Delayed Submission of Results Information via Certification
or Extension Request
[[Page 64985]]
4. Triggered Submission of Clinical Trial Information Following
a Voluntary Submission
5. Expanded Access Records
6. Institutional Compliance Costs
F. Alternatives to the Final Rule
G. Regulatory Flexibility Act
H. Unfunded Mandates Reform Act of 1995
I. Federalism
VI. Paperwork Reduction Act of 1995
VII. Legal Authority
VIII. References
Regulatory Text
I. Background
This final rule implements requirements for submitting registration
and summary results information for specified clinical trials of drug
products (including biological products) and device products to
ClinicalTrials.gov, the clinical trial registry and results data bank
operated by the NLM, NIH, since 2000. This final rule provides for the
expanded registry and results data bank specified in 402(j) of the PHS
Act (42 U.S.C. 282(j)), as amended by Title VIII of FDAAA and including
technical corrections made to FDAAA under Public Law 110-316. These
provisions are intended to enhance patient enrollment, provide a
mechanism to track subsequent progress of clinical trials, provide more
complete results information, and enhance patient access to and
understanding of the results of clinical trials (see 42 U.S.C. 282(j),
section 402(j) of the PHS Act).
The requirements apply to the responsible party (the sponsor or
designated principal investigator) for certain clinical trials of drug
products (including biological products) and device products regulated
by the FDA under designated sections of the FD&C Act.
The Notice of Proposed Rulemaking (NPRM) for Clinical Trials
Registration and Results Submission was published on November 21, 2014,
in the FR (79 FR 69566). We received nearly 900 comments during the 120
day public comment period, which closed on March 23, 2015. Of the total
comments received, about 60 percent were nearly identical in content,
expressing support for clinical trial transparency efforts and the
goals of the NPRM and provided specific perspectives on a number of the
proposals. Another large subset of comments also expressed support for
clinical trial transparency and the NPRM goals, but did not comment on
specific proposals. There were about 100 distinct comments that
addressed specific NPRM proposals. As reflected below, all of the
comments were reviewed and all points and perspectives were carefully
considered. Section III includes discussion of comments on several key
issues in the final rule, and Section IV includes discussion of
comments related to each specific provision in the final rule. For each
key issue and specific provision, we outline the statutory basis, the
NPRM proposal, the relevant public comments, our response to the
comments, and the approach taken in the final rule. The NPRM provided a
comprehensive review of the legislative background and history that led
to its development and, by extension, to this final rule. We review it
again here in brief.
NLM initially developed the database, known as ClinicalTrials.gov,
in response to the statutory mandate of section 113 of the Food and
Drug Administration Modernization Act of 1997 (FDAMA) to establish,
maintain, and operate a data bank of information on certain clinical
trials (these requirements currently are codified at 42 U.S.C. 282(i),
PHS Act 402(i)), and in support of NLM's statutory mission to improve
access to information to facilitate biomedical research and the public
health (see 42 U.S.C. 286(a)). The registry became publicly available
in February 2000. Since the establishment of ClinicalTrials.gov, the
scientific community, general public, and others have called for many
new measures to improve access to and transparency of information about
clinical trials. In addition, various parties have developed and
implemented trial registration policies including, for example, journal
editors (through the International Committee of Medical Journal Editors
(ICMJE)) [Ref. 1, 2] and industry (through the International Federation
of Pharmaceutical Manufacturers and Associations) [Ref. 3].
ClinicalTrials.gov accepts information on trials other than those
legally required to be registered in support of the mission of the NLM
and other policies such as those from the ICMJE [Ref. 1, 2]. With the
enactment of Title VIII of FDAAA, the legal mandate for
ClinicalTrials.gov reporting was expanded to include more registration
information for a broader set of clinical trials, as well as results
information.
As discussed in the proposed rule, there are significant public
health benefits to requiring the disclosure of the information required
under this rule. Enhancements to the scope of ClinicalTrials.gov
improve its utility in assisting individuals in finding trials for
which they may be eligible to enroll, and then ensuring that their
participation is honored and trust is enhanced by creating a public
record of the trial and its results. In addition, access to more
complete information about clinical trials has both scientific and
other public health benefits. The scientific benefits relate to the
prevention of incomplete and biased reporting of individual trials, and
the provision of information about a more complete and unbiased set of
trials; the resulting set of data about clinical trials can form a more
robust basis for current medical decision making and future research
planning. In addition, ClinicalTrials.gov provides an overview of the
clinical trials enterprise, facilitating quality improvement in study
focus, design, and reporting. The rule should also provide greater
clarity about what is required for those who are subject to the legal
mandate to submit information to ClinicalTrials.gov.
For many years, members of the scientific community, general
public, industry, and others have been in active discussions about the
need for increased access to information about clinical trials [Ref.
4]. Communities have expressed concern about the lack of publications
from clinical trials [Ref. 5] (regardless of outcomes) and bias in the
literature, [Ref. 6, 7] which may be due to selective reporting by
trial sponsors or by journals in response to manuscripts that they deem
less interesting. Interested parties have highlighted the importance of
filling this gap because of missed opportunities to share knowledge
that could have had implications for research participants who took
part in these trials, future research participants who may benefit from
this missing knowledge in the design of studies in which they will
participate, and patients who may have benefited from the missing
information in terms of a more robust understanding of their diseases,
conditions, and potential treatments.
Even before this rulemaking, extensive research had been conducted
using the clinical trial information that is publicly available on
ClinicalTrials.gov. The published literature relying on
ClinicalTrials.gov data includes:
Studies characterizing the clinical research for specific
conditions, such as acute kidney injury and the assessment of endpoints
and sample size in prevention trials [Ref. 8];
studies identifying research gaps in a domain, such as for
pediatric studies [Ref. 9];
studies assessing data mining methods, such as the
systematic identification of pharmacogenomics information from clinical
trials [Ref. 10];
studies characterizing the overall clinical research
landscape, such as the characteristics of clinical trials registered in
ClinicalTrials.gov [Ref. 11];
[[Page 64986]]
studies evaluating publication bias or selective
reporting, such as the lack of publication for trials registered on
ClinicalTrials.gov [Ref. 12];
studies of research reporting, for example, by examining
discrepancies between the ClinicalTrials.gov results database and peer-
reviewed publications [Ref. 13]; and
studies assessing specific research-related methods and
issues, such as the reporting of non-inferiority trials in
ClinicalTrials.gov [Ref. 14] and the use of ClinicalTrials.gov to
estimate condition-specific nocebo effects and other factors affecting
outcomes of analgesic trials [Ref. 15].
Many commenters identified the issues noted above, and supported
the need for greater access to information about clinical trials. A
large majority of comments in response to the NPRM expressed support
for the rule, with many noting the value of transparency of clinical
trials, in general. Commenters highlighted that accessible information
about trials is critical for the public, including patients, and will
contribute to better science in various ways. For example, one
commented that the proposed rule promotes transparency, benefitting
patients in the long run. Another asserted that doctors work with
uncertainty and that access to all results information, regardless of
statistical significance, can be important. Others argued that
requiring more trials to be registered and reported will allow science
to progress more quickly because scientists will be able to learn from
trials that they otherwise would not have had access to, helping them
to avoid ``reinventing the wheel.''
On the other hand, we recognize that the posting of results
information from applicable clinical trials of unapproved, unlicensed,
and uncleared products, as well as unapproved, unlicensed, or uncleared
uses of approved/licensed/cleared medical products, presents special
challenges. Despite the concerns raised by opponents to the rule (such
as concerns from device manufacturers and the pharmaceutical industry
about disclosure of what they view to be proprietary, confidential
information and its impact on innovation and investment incentives, and
concerns that the delay for submission of results information is
insufficient given the length and cost of drug development), it is
important that results information for each such clinical trial of an
unapproved, unlicensed, and uncleared product be presented in an
unbiased manner, but with the understanding that the evaluation of the
overall benefit and risk profile of each such product, or each use of
an already approved product, be determined by an assessment of the full
evidence base for that product (i.e., not from the results of any one
trial in isolation). Under the FD&C Act, the PHS Act, and their
implementing regulations, firms that market medical products are
generally required to submit an application to FDA for premarket
review, and provide robust scientific evidence that demonstrates that
the product is safe and effective for each of its intended uses, before
the firm distributes the product for each such use. During FDA
premarket review of medical products, FDA also generally reviews
proposed labeling for the intended use(s) of the product to ensure that
the labeling provides adequate information for the safe and effective
use of the product. Real harms have been associated with use of medical
products for unapproved uses--harms to health as well as the diversion
of resources to ineffective treatments [Ref. 16, 17].
A. Review of Scientific Benefits Related to Specific Provisions of the
Rule
Registration Information
A public registry of trials enables interested parties, including
patients, to find trials in which they might want to participate and
facilitates the discovery of trials for academic research centers with
experts studying particular diseases or conditions [Ref. 18]. The
highly structured data, along with the search engine, enable members of
the public to search for trials that might meet their needs by using a
variety of technical and non-technical terms [Ref. 19]. This is of
particular importance for trials that involve unapproved, uncleared, or
unlicensed medical products that might not have a generic name [Ref.
20]. These trials tend to use company-specific code names that
ClinicalTrials.gov links to their eventual generic name (if one is
assigned). As a result, a user of the system can find all trials
associated with a given product, even if they use different names (or
codes) at different stages of the product development cycle. Without
such a registry, there would be no single, centralized way to identify
trials studying any intervention for any disease regardless of sponsor
or funding for which an individual may be eligible (e.g., previous
Federal trial registries established under the Health Omnibus Extension
of 1988 for trials for human immunodeficiency virus infection and
acquired immune deficiency syndrome, commonly referred to as HIV/AIDS,
and FDAMA 113 for effectiveness studies for serious or life-threatening
diseases or conditions conducted under investigational new drug
applications (INDs) were limited to certain conditions and one
intervention type, i.e., drugs).
The public record also ensures that each individual's participation
in a trial is appropriately respected by preventing the conduct of
``secret'' trials, for which their existence is not publicly known
(and/or their results are never publicly reported after completion or
misreported--i.e., reporting bias) [Ref. 21, 22]. The unique identifier
assigned to each record (NCT number) also permits, for the first time,
a way to identify each clinical trial unambiguously [Ref. 23] and link
information about a single clinical trial from different resources/
databases [Ref. 24].
The searchable, structured listing of trials also enables
Institutional Review Boards (IRBs) [Ref. 25], researchers, funding
agencies, systematic reviewers [Ref. 26, 27], and other groups,
including the Presidential Commission for the Study of Bioethics Issues
[Ref. 28], and the National Academies of Science workshops [Ref. 29],
to see the landscape of trials on a given topic, by a particular
funder, by geography [Ref. 30], by population [Ref. 9], or other
relevant criteria. Providing these users with such a capability informs
their judgments about the potential value of new trials, scientific and
financial accountability of sponsors, as well as helping to ensure that
assessments of the risks and benefits of a potential intervention for a
particular use account for the totality of evidence from all prior
trials. Such analyses of the clinical research also provide feedback
and insights for the clinical research community itself, by informing
the design and analysis of future trials [Ref. 11, 31, 32].
The information that describes the clinical trial in the registry
records also facilitates assessments of the quality and appropriateness
of trial reporting by enabling journal editors, researchers, and other
readers of the medical literature to assess the degree to which the
disclosed results (e.g., journal articles, scientific conferences)
accurately reflect the prespecified protocol and have accounted for all
prespecified outcome measures. This helps to (1) prevent the type of
incomplete results reporting that has been documented in conference and
journal abstracts, as well as in full journal articles [Ref. 33] and
(2) allow the members of the public to assess fidelity to the protocol,
which is essential to understanding the validity of disclosed results
[Ref. 34].
[[Page 64987]]
The freely downloadable registry data enable third parties to use
the information that describes the clinical trial to meet other
specific needs [Ref. 35], such as reformatting the data for
constituents of various patient advocacy groups (e.g., patients with
breast cancer) [Ref. 36], data mining for associations among
interventions and diseases studied worldwide, and for use in semi-
automated data collection for conducting critical appraisals and
systematic reviews to support evidence-based medicine. For example,
while ClinicalTrials.gov does not itself match potential participants
with relevant trials, the rule ensures the timely posting of
registration information about trials currently enrolling participants.
This information is used by third parties to provide matching services
that help patients find trials that might be appropriate for them.
Summary Results Information
The public availability of results information helps investigators
design trials and IRBs review proposed trials, by allowing them to
weigh the proposed study's risks and benefits against a more complete
evidence base than is currently available through the scientific
literature [Ref. 37]. The rule facilitates better science through
aiding in the identification of knowledge gaps for trials of all types
of products, whether unapproved or approved and marketed. Mandatory
submission and posting of results information will also help
investigators avoid repeating trials on drug and device products
(including biological products) that have been found to be unsafe or
unsuccessful while also providing access to information that may help
verify findings.
While the registry information at ClinicalTrials.gov can be used to
determine where information might be missing from the literature (e.g.,
missing trials, missing outcome measures) [Ref. 13, 38, 39], the
results database fills many gaps in the medical evidence base by
providing tabular objective data that summarize findings from trials.
These data can be used by systematic reviewers and others who analyze
the literature to develop evidence-based treatment and policy
recommendations [Ref. 26].
FDAAA has led to the development of a minimum reporting set that
provides key facts about the aggregate analyses for each trial without
the accompanying narrative interpretations found in journal
articles[Ref. 40]. In this way, results are made available in a timely
manner for all prespecified primary and secondary outcome measures, and
all serious and frequent adverse events, and complement the published
literature [Ref. 41].
The submission and posting of results information on
ClinicalTrials.gov may occur before, simultaneously with, or after
journal publication, but is independent of journal submission and
publication. The legal requirements help to fill substantial gaps in
the database left by the non-publication (or very delayed publication)
of a substantial portion of clinical trials in the medical literature
[Ref. 42, 43]. In addition, the complete set of results information for
all primary and secondary outcome measures that were specified in a
study protocol supplements the more limited set of results data found
in the published literature [Ref. 44]. The availability of results
information from applicable clinical trials will help to prevent
skewing of the evidence base that is the foundation of systematic
reviews and clinical practice guidelines. In addition, if information
were to be presented publicly about the safety profile of an approved
drug product, the availability of clinical trial results information
through ClinicalTrials.gov could help inform the public record about
the drug product's safety [Ref. 45].
Review of Public Health Benefits Related to Specific Provisions of the
Rule
Results information for trials of unapproved products may inform
the assessment of risks and benefits that potential participants might
face in subsequent studies of those same or similar products; they may
also contribute to the overall assessments that are made of similar
marketed products [Ref. 46]. Trials of products that are unapproved,
unlicensed, and uncleared are unlikely to be published if the results
of these trials are insufficient to support applications for product
approvals (e.g., because the study resulted in negative findings or was
inadequately designed or executed). This rule's requirements that
responsible parties submit results information from clinical trials of
unapproved, uncleared, or unlicensed products regardless of whether
approval, clearance, or licensure is sought, as well as the public
posting of this information, are expected to alleviate the concerns
regarding bias in the literature and selective publication. Frequently
cited economic benefits of sharing clinical trial data generally
include avoiding a suboptimal return on the financial resources
invested by study funders and sponsors [Ref. 47], while the submission
and posting of results information from trials of unapproved,
uncleared, or unlicensed products in particular is expected to reduce
costs by minimizing the number of redundant trials. Overall, the rule's
requirement ensures the public availability and accessibility of
information that likely would not otherwise have been in the public
domain.
The reporting of an unambiguous accounting for all deaths, as
required by the final rule, within each trial enables researchers and
others to understand the most basic elements of the study in a way that
was not previously possible in many cases [Ref. 48].
Mandatory submission and posting of the protocol and statistical
analysis plan (SAP) for each reported trial provides a resource for
researchers and others interested in understanding the detailed methods
used to conduct a particular trial and analyze the collected data [Ref.
49, 50, 51]. Our reasoning behind their inclusion is more fully
explained in Section III.D on Submission of Protocols and Statistical
Analysis Plans, but we wish to emphasize that availability of the
protocol and SAP is expected to provide users of ClinicalTrials.gov
with a fuller picture of the trial. One of the aims of the statute and
of the rule is to ``provide more complete results information''
(section 402(j)(3)(D)(i) of the PHS Act), which we believe complements
the goals of increased transparency and accountability. As such, the
addition of the protocol as clinical trial results information to be
submitted and posted on ClinicalTrials.gov furthers this statutory
purpose and significantly enhances the understanding of the trial and
the context of the data fields and results information provided. It
also enables readers to conduct a more complete evaluation of results
[Ref. 47, 52, 53]. Although protocols are sometimes provided along with
published articles, they are currently distributed among different
journal Web sites and cannot be reliably found for most trials.
Protocols also help to provide a more nuanced understanding of key
trial methods, including, for example, the detailed eligibility
criteria; how information was collected for key outcome measures and
adverse events; and how data were handled, including detailed methods
of statistical analyses. Such details of trial methods can affect the
interpretation of a study's findings [Ref. 52, 53, 54, 55]. SAPs
describe the analyses to be conducted and the statistical methods to be
used, including ``plans for analysis of baseline descriptive data and
adherence to the intervention, prespecified primary and
[[Page 64988]]
secondary outcomes, definitions of adverse and serious adverse events,
and comparison of these outcomes across interventions for prespecified
subgroups. The full SAP describes how each data element was analyzed,
what specific statistical method was used for each analysis, and how
adjustments were made for testing multiple variables. If some analysis
methods require critical assumptions, data users will need to
understand how those assumptions were verified.'' [Ref. 47].
Limiting ClinicalTrials.gov to Objective Data
As described in greater detail in Section III.C on Submission of
Technical and Non-technical Summaries, the final rule does not require
the submission of technical or non-technical narrative summaries of
study results due to a lack of evidence that such summaries would
always meet the statutory standard of not being misleading or
promotional (section 402(j)(3)(D)(iii)(I) and section
402(j)(3)(D)(iii)(II) of the PHS Act). In fact, experts suggest that
such summaries can lead to biased reporting, whether because of
omission or commission [Ref. 56]. Presenting results information in a
tabular format leads to a more objective database. We believe that
actively avoiding the introduction of bias serves an important public
health interest--one that Congress foresaw--and prevents
ClinicalTrials.gov from being a platform in which data are conflated
with opinions or interpretation.
In this regard, it should be noted that nothing in this rule
authorizes a firm to use information posted in, or links to, other Web
sites available on ClinicalTrials.gov to promote unapproved,
unlicensed, or uncleared medical products or unapproved, unlicensed, or
uncleared uses of approved or cleared medical products, or supersedes
or alters other statutory and regulatory provisions related to such
communications. For example, under the FD&C Act, the PHS Act, and their
implementing regulations, firms that market medical products are
generally required to submit an application to FDA for premarket
review, and provide robust scientific evidence that demonstrates that
the product is safe and effective for each of its intended uses, before
the firm distributes the product for each such use. To the extent firms
make a product available for one use (whether as a medical product or
not), but make express or implied claims regarding the safety or
efficacy of that product for another medical product use, for which it
lacks the applicable approval, licensure or clearance, they are
effectively evading the premarket review requirements of the applicable
law and undermining the public health interests advanced by these
requirements.
In addition, where emerging and developing scientific data are not
yet sufficiently complete or robust to demonstrate safety and efficacy
of the product for an initial or additional intended use,
representations of safety and effectiveness can be misleading,
particularly if addressed to health care providers and/or patients
[Ref. 57, 58]. Marketing activities and communications can also be
designed to persuade, promote, and influence prescribing and use in
ways that are not based on valid scientific evidence, to the extent
such evidence exists [Ref. 59, 60].
It is important to note that even though we are limiting the
submissions to objective data elements, the government does not
independently verify the scientific validity or relevance of the
information submitted to ClinicalTrials.gov beyond the limited quality
control review by NIH, which is focused on the clarity and completeness
of the information submitted, not the quality, validity, meaning or
relevance of the trial itself. Accordingly, the inclusion of data and
information in the ClinicalTrials.gov platform, the links to other
studies and Web sites, and the conduct of the limited quality control
review by NIH, do not constitute a government affirmation or
verification that the information within or referenced in the database,
or communications that rely on that information, are truthful and non-
misleading.
Other Benefits
Other benefits relate to the role in assisting individuals in
finding trials in which to enroll, and then ensuring that their
participation is honored and trust is enhanced by creating a public
record of the trial and its results. It also fulfills an obligation to
trial participants that is established between them and the research
team. Individuals participate in clinical trials with the understanding
that the research will contribute to the expansion of knowledge
pertaining to human health. When trial information is withheld from
public scrutiny and evaluation, the interpretation of the data and the
public's trust in the research may be compromised. The rule helps to
further the goal of ensuring that participation in research leads to
accountability via the public reporting of information. Much has been
written about the importance of trust in clinical research, and
although many factors promote the development of trust, ensuring a
public record of the trials in which people participate contributes
significantly to this goal [Ref. 47, 61].
Finally, the availability of results information is expected to
assist people in making more informed decisions about participating in
a clinical trial by providing them and their care providers with access
to information about the results of a broader set of clinical trials of
various interventions that have been studied for a disease or condition
of interest.
B. Anticipated Long-Term Benefits of ClinicalTrials.gov Beyond the
Final Rule
ClinicalTrials.gov provides the scaffolding on which individual
participant data (IPD (the next frontier in transparency) and other
trial ``meta-data'' can be organized in the future. This is
particularly important to catalyze the enormous potential value of data
sharing. Such IPD (and, for example, associated biospecimens) are most
valuable if their availability is identified in a searchable system and
associated with key trial meta-data so that they can be used in a
scientifically appropriate manner. ClinicalTrials.gov provides
mechanisms for linking the trial records with sources of IPD and meta-
data about each trial as recommended by the Institute of Medicine
(IOM)in a 2015 report entitled Sharing Clinical Trial Data: Maximizing
Benefits, Minimizing Risks and ICMJE [Ref. 47, 62]; the search
interface allows for the easy identification of such data so that
researchers can identify data for their secondary use.
II. Overview of Statutory Provisions
The final rule clarifies and establishes additional procedures and
requirements for registering and submitting results information,
including adverse event information, for certain clinical trials of
drug products (including biological products) and device products, as
well as for pediatric postmarket surveillances of a device product that
are required by FDA under section 522 of the FD&C Act; the final rule
requirements implement section 402(j) of the PHS Act.
Title VIII of FDAAA, enacted on September 27, 2007, section 801(a),
amended the PHS Act by directing the Secretary of the Department of
Health and Human Services (HHS), acting through the Director of the NIH
(or the Agency) to expand the existing clinical trial registry data
bank known as ClinicalTrials.gov and to ensure that the data bank is
publicly available through the Internet. Among other duties, NIH is
[[Page 64989]]
directed to expand the data bank to include registration information
for a broader set of clinical trials than were required to register
under FDAMA. Section 402(j) of the PHS Act specifies that identified
entities or individuals, called responsible parties, are to submit
registration information for certain applicable clinical trials of
drugs (defined by section 402(j)(1)(A)(vii) of the PHS Act to include
biological products) and devices, including any pediatric postmarket
surveillance of a device required by FDA under section 522 of the FD&C
Act (21 U.S.C. 360l). Section 402(j)(2)(A)(iii) of the PHS Act
authorizes the Secretary of HHS to modify by regulation the data
elements required for registration, provided that the Secretary
provides a rationale for why such modification ``improves and does not
reduce'' the information included in the data bank. The statute
specifies certain deadlines by which registration information is to be
submitted to the data bank.
Section 402(j)(3) of the PHS Act further directs the Agency to
augment the registry data bank to include summary results information
through a multistep process, as follows:
First, for those clinical trials that form the primary basis of an
efficacy claim or are conducted after a product is approved, licensed,
or cleared, the registry data bank is to be linked to selected existing
results information available from the NIH and FDA (section
402(j)(3)(A) of the PHS Act). Such information includes citations to
published journal articles focused on the results of applicable
clinical trials, posted FDA summaries of FDA advisory committee
meetings at which applicable clinical trials were considered, and
posted FDA assessments of the results of any applicable drug clinical
trials that were conducted under section 505A or 505B of the FD&C Act
(21 U.S.C. 355a, 21 U.S.C. 355c).
Second, for each applicable clinical trial subject to section
402(j) of the PHS Act, the responsible party must submit to the data
bank results information required under section 402(j)(3)(C) of the PHS
Act. Such information is to include tables of demographic and baseline
characteristics of the ``patients who participated in the clinical
trial'' (section 402(j)(3)(C)(i) of the PHS Act), i.e., the enrolled
human subjects, and the primary and secondary outcome measures for each
arm of the clinical trial, as well as a point of contact for scientific
information about the clinical trial results and information on whether
certain agreements exist between the sponsor and the principal
investigator that limit the ability of the principal investigator to
discuss or publish the results of an applicable clinical trial after it
is completed. The ClinicalTrials.gov basic results component was
launched on September 27, 2008.
In addition, section 402(j)(3)(I)(i) of the PHS Act directs the
Secretary to issue regulations to ``determine the best method for
including in the registry and results data bank appropriate results
information on serious adverse and frequent adverse events for
applicable clinical trials (required to submit results information
under section 402(j)(3)(C) of the PHS Act) in a manner and form that is
useful and not misleading to patients, physicians, and scientists.'' If
regulations are not issued by September 27, 2009, then section
402(j)(3)(I)(ii) of the PHS Act specifies that the statutorily mandated
adverse event reporting provisions specified in section
402(j)(3)(I)(iii) of the PHS Act shall take effect, requiring the
submission of certain information summarizing serious and frequent
adverse events observed during an applicable clinical trial.
Regulations were not issued by the deadline, so the statutorily
mandated adverse event reporting provisions required by sections
402(j)(3)(I)(ii) and (iii) of the PHS Act took effect on September 27,
2009, at which time the ClinicalTrials.gov basic results database was
updated accordingly. Section 402(j)(3)(I)(v) of the PHS Act indicates
that adverse event information is ``deemed to be'' clinical trial
information that is included in the data bank pursuant to the
requirements for results information submission under section
402(j)(3)(C) of the PHS Act.
Third, section 402(j)(3)(D) of the PHS Act requires the Secretary
to further expand the data bank by regulation ``to provide more
complete results information and to enhance patient access to and
understanding of the results of clinical trials.'' It requires
consideration of specific issues in developing the regulations, in
particular:
(1) Whether to require submission of results information for
applicable clinical trials of products that are not approved, licensed,
or cleared (whether approval, licensure, or clearance was sought) (see
section 402(j)(3)(D)(ii)(II) of the PHS Act.); and if submission of
clinical trial results information is required for such applicable
clinical trials, the date by which that information is required to be
submitted. (See section 402(j)(3)(D)(iv)(III) of the PHS Act.);
(2) Whether non-technical written summaries of the clinical trial
and its results can be included in the data bank without being
misleading or promotional. (See section 402(j)(3)(D)(iii)(I) of the PHS
Act.);
(3) Whether technical written summaries of the clinical trial and
its results can be included in the data bank without being misleading
or promotional. (See section 402(j)(3)(D)(iii)(II) of the PHS Act.);
(4) Whether to require submission of the full clinical trial
protocol or only such information on the protocol as may be necessary
to help evaluate the results of the trial. (See section
402(j)(3)(D)(iii)(III) of the PHS Act.);
(5) Whether the 1 year period for submission of results information
should be increased to a period not to exceed 18 months. (See section
402(j)(3)(D)(iv)(I) of the PHS Act.); and
(6) Whether requirements for results information submission as set
forth in the regulations should apply to applicable clinical trials for
which results information required under section 402(j)(3)(C) of the
PHS Act is submitted before the effective date of such regulations.
(See section 402(j)(3)(D)(iv)(II) of the PHS Act.).
Section 402(j)(3)(D)(v) of the PHS Act further requires that the
regulations shall establish:
(1) A standard format for the submission of clinical trial
information. (See section 402(j)(3)(D)(v)(I) of the PHS Act.);
(2) Additional information on clinical trials and results written
in nontechnical, understandable language for patients. (See section
402(j)(3)(D)(v)(II) of the PHS Act.);
(3) Procedures for quality control, with respect to completeness
and content of clinical trial information, to help ensure that data
elements are not false or misleading and are non-promotional. (See
section 402(j)(3)(D)(v)(III) of the PHS Act.);
(4) Appropriate timing and requirements for updates of clinical
trial information and whether and how such updates should be tracked.
(See section 402(j)(3)(D)(v)(IV) of the PHS Act.);
(5) A statement to accompany the entry for an applicable clinical
trial when primary and secondary outcome measures for such applicable
clinical trial are submitted as a voluntary submissions after the date
specified in section 402(j)(2)(C) of the PHS Act. (See section
402(j)(3)(D)(v)(V) of the PHS Act.); and
(6) Additions or modifications to the manner of reporting the data
elements established under the results information submission
provisions of section 402(j)(3)(C) of the PHS Act. (See section
402(j)(3)(D)(v)(VI) of the PHS Act.).
[[Page 64990]]
Section 402(j)(3)(D)(vii) of the PHS Act requires the Secretary to
convene a public meeting to solicit input from interested parties on
those issues. The public meeting was convened on April 20, 2009, on the
NIH campus. The public meeting attracted more than 200 registered
participants and 60 written comments. All of the comments received
prior to, during, and after the public meeting are available in the
Clinical Trials Public Meeting Docket, ID: NIH-2009-0002, at the
www.regulations.gov Web site [Ref. 63]. We carefully reviewed the
comments received in developing the proposed provisions to address the
considerations enumerated in section 402(j)(3)(D) of the PHS Act. Many
of the comments helped inform development of the proposed rule, which
was issued on November 21, 2014, for public comment. For purposes of
this rulemaking, we prepared a memorandum summarizing these comments
from the public meeting and the issues commented upon [Ref. 64].
Furthermore, section 402(j)(4)(A) of the PHS Act directs that the
data bank accept ``voluntary submissions'' of complete registration or
complete results information for certain clinical trials for which such
information would not otherwise be required to be submitted, provided
that the responsible party complies with requirements that could
involve submission of information on additional clinical trials.
Section 402(j)(5) of the PHS Act specifies certain procedures and
penalties related to non-compliance. Among other things, it directs NIH
to publicly post notices of noncompliance in the data bank; requires
report forms under certain HHS grants to include a certification that
required registration and results information submission under section
402(j) of the PHS Act are complete; requires federal agencies to verify
compliance before future funding or continuation of funding under
section 402(j) of the PHS Act; and grants FDA the authority to sanction
responsible parties who fail to comply with section 402(j) of the PHS
Act.
Section 801(b) of FDAAA includes certain conforming amendments to
the FD&C Act, which make failure to comply with specified requirements
of section 402(j) of the PHS Act, and the submission of false or
misleading clinical trial information under section 402(j) of the PHS
Act, prohibited acts under the FD&C Act (see 21 U.S.C. 331(jj)(1)-(3)).
Committing any such prohibited act could subject the violator to
criminal and/or civil penalties, including civil money penalties.
Section 801(c) of FDAAA requires the Secretary to issue guidance on
how the requirements of section 402(j) of the PHS Act apply to a
pediatric postmarket surveillance of a device, where that pediatric
postmarket surveillance is not a clinical trial. The preamble of this
final rule addresses this topic and is intended to serve as the
required guidance.
Section 801(d) of FDAAA includes a preemption provision, which
states that ``[u]pon the expansion of the registry and results data
bank under section 402(j)(3)(D) of the PHS Act, as added by this
section, no State or political subdivision of a State may establish or
continue in effect any requirement for the registration of clinical
trials or for the inclusion of information relating to the results of
clinical trials in a database.''
III. Discussion of Public Comments on Selected Key Issues
A. Scope and Applicability
The final rule covers requirements for the submission of clinical
trial registration and results information to the ClinicalTrials.gov
database. It includes expanded requirements for the submission of
clinical trial registration and results information, as authorized by
section 402(j) of the PHS Act, to improve public access to information
about certain clinical trials of FDA-regulated drug products (including
biological products) and device products. However, the rule does not
impose requirements on the design or conduct of clinical trials or on
the data that must be collected during clinical trials. Instead it
specifies how data that were collected and analyzed in accordance with
a clinical trial's protocol are to be submitted to ClinicalTrials.gov.
Following the public comment period, we received comments on a
variety of the NPRM's sections and key issues, which are discussed in
detail in the other subsections of Section III and in Section IV of
this preamble. We also received comments from approximately 115
commenters on topics that, while important, are outside of the scope of
the NPRM and the rule. Although we are not responding to these
comments, the types of topics raised by these comments are described
below.
We received comments suggesting that the rule should establish
requirements for the conduct of clinical trials and that compliance
with the rule should affect whether future clinical trials may proceed.
For example, it was suggested that the rule should not permit trials
with placebo groups to be conducted where there is no benefit to the
participant and the condition studied is life-threatening. It was also
suggested that studies should not be allowed to proceed to the next
phase until all information submission requirements of the rule are
met. We emphasize neither section 402(j) of the PHS Act nor this rule
establishes requirements for clinical trial design or progress.
Commenters also provided input on the role of human subjects review
boards, suggesting that the rule should require all proposed studies to
be subject to their review, and that the rule should clarify HHS'
position on human subjects protection. The role of human subjects
review boards in the course of research is outside of the scope of this
rule, but Human Subjects Protection Review Board Status is a required
registration data element (see Sec. Sec. 11.10(b)(35) and
11.28(a)(2)(iv)(D)).
Commenters also provided input on how they see the role of the rule
with respect to FDA action. For example, it was suggested that the rule
should prohibit the approval of a product application submitted to FDA
unless results information submission requirements have been met. While
the rule's results information submission requirements are connected to
FDA approval, licensure, or clearance in terms of triggers for results
information submission in certain cases, the rule does not affect,
direct, or prohibit FDA from acting on a particular application or
submission. Although FDA's actions with respect to approval, licensure,
or clearance are outside the scope of this rule, FDA enforces FDAAA's
registration and results information submission requirements and the
requirement that a responsible party not submit false and/or misleading
information. As described in more detail in Section IV.E, if FDA
identifies a violation, the Agency may notify the responsible party
and, as appropriate, initiate administrative proceedings for civil
monetary penalties or the process for civil or criminal judicial
actions.
We received comments about enforcement of the rule, suggesting that
NIH and FDA should be enforcing the current requirements (i.e., before
the rule's effective date) as well as the additional results
information reporting requirements in the final rule. We have addressed
the applicability of the requirements of section 402(j) of the PHS Act
and final rule throughout this preamble, including in the Effective
Date, Compliance Date, and Applicability of Requirements in this Part
discussion in Section IV.F. A few commenters suggested that FDA should
enforce results information reporting requirements and that it should
cancel
[[Page 64991]]
marketing approvals ``in cases of egregious misrepresentations.''
Commenters also proposed specific penalty structures, such as only
penalizing the responsible party and not the institution and making all
intentional violations criminal with mandatory prison sentences. They
also proposed incentives, such as providing easier submission
mechanisms and citable credit for shared data sets. The specifics of
how and under what circumstances FDA will seek to enforce section
402(j) of the PHS Act are beyond the scope of the rule, as are issues
relating to the marketing of FDA-regulated products. FDA may issue
guidance regarding enforcement in the future. FDA enforces FDAAA's
registration and results information submission requirements and the
requirement that a responsible party not submit false and/or misleading
information. As described in more detail in Section IV.E, if FDA
identifies a violation, the Agency may may notify the responsible party
and, as appropriate, initiate administrative proceedings for civil
monetary penalties or the process for civil or criminal actions.
Although we did include in the preamble to the proposed rule a
general discussion of the statutory procedures and penalties related to
non-compliance (79 FR 69570), we did not otherwise discuss in detail
the legal ramifications of failure to comply with the requirements of
section 402(j) of the PHS Act, including these regulations. Other than
the requirement that a responsible party not submit false or misleading
information and the associated notice of potential liabilities for
doing so (see Sec. 11.6), the proposed codified text did not describe
the potential legal consequences of failing to comply with the
requirements of the rule. However, as discussed in Section IV. E below,
we are adding a new Sec. 11.66 that describes potential legal
consequences provided for in the FDAAA enforcement provisions for
failure to comply with the requirements in these regulations.
Some commenters suggested that the rule should require registered
trials to make IPD datasets available to qualified researchers and some
suggested that the rule should require the submission and disclosure of
de-identified IPD datasets to ClinicalTrials.gov. The sharing or
submission of de-identified IPD is not required or authorized in
section 402(j) of the PHS Act, and is, thus, not included in this rule.
In addition, ClinicalTrials.gov does not currently have a mechanism to
directly collect datasets containing de-identified IPD. As discussed in
Section I, however, ClinicalTrials.gov provides optional registration
data elements that allow responsible parties to specify whether there
is a plan to share the IPD or associated documents from the trial.
Providing such meta-data about IPD in a searchable system facilitates
identification of such data for use in a scientifically appropriate
manner. In this way, we anticipate that ClinicalTrials.gov can be used
in the future to catalyze IPD sharing.
Some commenters expressed concern about whether posting results
information might be considered ``prior publication'' by journal
editors thereby precluding subsequent publication of a journal article,
while others suggested that posting of results information could be
delayed an additional 12 months while papers undergo peer review. The
rule implements the directives of section 402(j) of the PHS Act and is
independent of the ICMJE clinical trial registration policy [Ref. 1,
2]. However, we note that the ICMJE has stated that submission of
summary results to ClinicalTrials.gov will not be considered prior
publication and will, thus, not interfere with journal publication
[Ref. 2]. Interested parties are encouraged to explore the policies of
the ICMJE and of the journals to which they seek to submit papers.
Some commenters also requested that NIH publish guidance clarifying
the rule's requirements and provide training to clinical investigators
about them. The Agency intends to continue making guidance documents
and other materials available, including examples, case studies, and,
as discussed below, a publicly-accessible checklist-based tool
available at https://prsinfo.clinicaltrials.gov (or successor site)
consisting of the relevant data elements and detailed explanation of
each criterion. One commenter also suggested that one of the reasons
for poor compliance with current law is the difficulty in
interpretation and complexities around results reporting. We expect
that the clarifications in this rule will help to address this concern.
Commenters provided suggestions regarding the usability of
ClinicalTrials.gov. Comments regarding technical changes to the Web
site are discussed in Section IV.A.4 (``In what format must clinical
trial information be submitted?--Sec. 11.8''). While the details of
the usability of ClinicalTrials.gov were not outlined in the NPRM or
codified in this rule, we do wish to address these comments. Some
commenters were dissatisfied with the process for entering data into
the Protocol Registration and Results System (PRS), noting it is
difficult to navigate, cumbersome, and complex. The PRS is the
electronic system maintained by ClinicalTrials.gov that responsible
parties use to register and submit results information for their
studies, described at https://prsinfo.clinicaltrials.gov. They pointed
to limitations of the PRS in sorting, filtering, and building queries,
and some had specific suggestions on elements by which the site should
be able to search, filter, and sort. We note that the PRS user
interface has been updated incrementally over time with significant
changes being made between 2014 and 2016, including the implementation
of features to help streamline the results data entry process. In
addition, based on usability study findings and expert evaluation, we
further streamlined the data submission process for registration and
results information, improved the reporting and portfolio management
functions (with this series of enhancements, including one made in
March 2016, addressing many of the concerns expressed by commenters),
and provided enhanced resource materials for data submitters. We have
also been providing 1-on-1 assistance to investigators submitting
results in the PRS. While we continue our efforts to enhance the
usability of the PRS and train personnel at academic institutions to
provide centralized support to their investigators, the 1-on-1
assistance initiative has proven to be effective for providing
customized support to investigators in fulfilling their requirements--
especially for the many investigators who are using the PRS to submit
results information for the first time. We will also expand the options
in the PRS to accommodate the requirements of the final rule.
Commenters wanted the site to be user-friendly and allow for
feedback, suggesting the NIH consult with experts to develop tools and
with members of the public to ensure a user-friendly interface. We have
conducted usability studies with a wide user audience and continue to
obtain valuable feedback from a survey implemented on the public site.
An example of a change that was made using this feedback was adding an
option to search for trials based on the specific age of the potential
participant (previously only age groups were easily searchable). We
note that users may continue to provide feedback by using the ``Contact
NLM Help Desk'' link on the bottom of every page on the
ClinicalTrials.gov public Web site and by responding to the survey,
when prompted. We intend to further consider this valuable input and
collect
[[Page 64992]]
additional input as we continue to refine the site and optimize it to
support provider and patient needs and to improve its scientific
utility. Our goal is for clinical researchers, data scientists, health
care providers, patients, and the public users of the site to have a
more positive experience and for the site to be functional for these
diverse audiences.
Other commenters wanted to be sure the Agency has sufficient
resources to carry out NLM's mission. Commenters also requested better
communication between the ClinicalTrials.gov staff that operate the PRS
and responsible parties, particularly via email, and suggested that the
NIH reinstate in-person training sessions. Over the last year, we have
expanded both the customer service and reviewer staff and provided
comprehensive training to help ensure communications with responsible
parties are as prompt, clear, and helpful as possible. We will continue
to ensure staff are well-trained and monitor the satisfaction of
responsible parties with the communications they receive. We will
continue to offer PRS training to responsible parties. In addition, we
will be launching a series of activities, such as webinars and
presentations at selected conferences, to educate the biomedical
research community about their obligations and to ensure that patients
and care providers are aware of the information available at
ClinicalTrials.gov. All such information will be available from https://prsinfo.clinicaltrials.gov. Overall, we are taking steps to improve
the usability of the resource for all users of ClinicalTrials.gov, data
submitters and data users alike.
Finally, a few commenters suggested that the law and the final rule
should apply to all researchers conducting clinical trials with NIH
funds. A number of commenters also took note of the proposed NIH Policy
on Dissemination of NIH-Funded Clinical Trial Information, which was
issued by NIH on November 19, 2014, in tandem with the publication of
the NPRM [Ref. 65]. The policy proposed that all NIH-funded awardees
and investigators conducting clinical trials should be expected to
register their clinical trials and submit results information to
ClinicalTrials.gov. NIH proposed that the policy would apply to
awardees and investigators conducting clinical trials, funded in whole
or in part by NIH, whether or not they are subject to section 402(j) of
the PHS Act. The policy would, thereby, also apply to NIH-funded phase
1 clinical trials of FDA regulated drugs, small feasibility studies of
devices, and trials of interventions not regulated by FDA, including
surgical and behavioral interventions.
The draft policy proposed that the same registration and results
information submission elements and reporting timeframes that would be
required under the final rule would also apply to those clinical trials
subject to the NIH policy, through the terms and conditions of the NIH
funding awards. Most of the NPRM commenters who also commented on the
draft NIH policy were supportive of it and of its application to a
wider range of clinical trials [Ref. 66]. NIH considered those comments
and comments received on the policy itself in developing the final
policy. The final policy is substantively the same as the proposed
draft policy in terms of scope, applicability, and the content and
timing of registration and results information submission. It requires
NIH-funded applicants and offerors to submit a plan for the
dissemination of NIH-funded clinical trial information that will
address how the policy's expectations for registration and results
information submission will be met. NIH-funded awardees and
investigators conducting clinical trials funded in whole or in part by
NIH will be required to comply with all terms and conditions of award,
including following their plan for the dissemination of NIH-funded
clinical trial information. The final NIH policy, NIH Policy on
Dissemination of NIH-Funded Clinical Trial Information, appears
elsewhere in this FR [FR OFFICE, PLEASE CROSS-REFERENCE NIH POLICY] and
includes a preamble discussing the public comments on the draft policy.
B. Submission of Results Information for Applicable Clinical Trials of
Unapproved, Unlicensed, or Uncleared Products for Any Use
Overview of Proposal
Section 402(j) of the PHS Act requires the submission and posting
of registration information and results information for applicable
clinical trials of approved, licensed, or cleared products, as well as
submission of registration information and posting requirements for
applicable clinical trials of unapproved, unlicensed, or uncleared
products. The statute provides the Secretary with the discretion
through rulemaking to require the submission of results information
from applicable clinical trials of products that are unapproved,
unlicensed, or uncleared, whether or not approval, licensure, or
clearance was sought. In particular, section 402(j)(3)(D)(ii)(II) of
the PHS Act specifies that the Secretary, through regulation, shall
establish whether results information should be required for ``(aa) an
applicable drug clinical trial for a drug that is not approved under
section [505 of the FD&C Act] and not licensed under section [351 of
the PHS Act] (whether approval or licensure was sought or not); and
(bb) an applicable device clinical trial for a device that is not
cleared under [section 510(k) of the FD&C Act] and not approved under
section [515 or section 520(m) of the FD&C Act] (whether clearance or
approval was sought or not).'' Given this authority and various factors
discussed in the NPRM (79 FR 69633), we proposed to require submission
of results information from applicable clinical trials of FDA-regulated
drugs (including biological products) and devices that are unapproved,
unlicensed, or uncleared for any use as of the completion date, whether
or not approval, licensure, or clearance was sought.
Regarding the scope of trials for which submission of results
information in accordance with subpart C of the proposed rule is
required, Sec. 11.42(a) proposed to require submission of results
information for all applicable clinical trials (i.e., regardless of
whether the product being studied was approved, licensed, or cleared)
for which submission of registration information was required under
proposed Sec. 11.22 and for which the completion date was on or after
the effective date of the rule. Section 11.42(b) proposed to require
submission of results information for those applicable clinical trials
for which submission of registration information was required under
proposed Sec. 11.22 and for which the completion date was before the
effective date of the rule, but for which the relevant results
information submission deadline in proposed Sec. 11.44 was on or after
the effective date of the rule and results information was submitted on
or after the effective date, consistent with the applicable deadline
established by proposed Sec. 11.44.
With respect to the proposed results information submission
deadlines for applicable clinical trials of drugs and devices that are
not approved, licensed, or cleared by FDA for any use as of the
completion date of the trial (where the completion date occurs prior to
the effective date of the final rule), but are subsequently approved on
or after the effective date, proposed Sec. 11.44(a)(2) would require
results information to be submitted by the earlier of (i) 1 year after
the primary completion date or (ii) 30 calendar days after FDA
approval,
[[Page 64993]]
licensure, or clearance, except as otherwise provided under Sec.
11.44(c), (d), or (e). Under proposed Sec. 11.44(c), results
information submission for applicable clinical trials studying FDA-
regulated drugs (including biological products) or devices that were
not approved, licensed, or cleared by the FDA for any use before the
completion date of the trial may be delayed for up to 2 additional
years (i.e., up to 3 years after the primary completion date) if the
responsible party certifies before the results information submission
deadline that initial approval, licensure, or clearance of the studied
product is being sought or may be sought by the sponsor at a future
date. If the responsible party so certifies, all required clinical
trial results information must be submitted by the earlier of (1) 30
calendar days after FDA approves, licenses, or clears the drug or
device for any indication studied in the applicable clinical trial, (2)
30 calendar days after a marketing application or premarket
notification is withdrawn and not resubmitted within 210 calendar days,
or (3) 2 years from the date of certification (proposed Sec.
11.44(c)(2)). Proposed Sec. 11.44(d) addressed the submission
requirements in situations where clinical trial results information has
not been collected for a secondary outcome measure by the completion
date.
The NPRM also addressed the situation in which results information
for an applicable clinical trial of a device not previously approved or
cleared is required to be submitted. Proposed Sec. 11.35(b)(2)
implemented section 402(j)(2)(D)(ii)(I) of the PHS Act, which prohibits
the Director from posting submitted registration information prior to
the date on which FDA approves or clears the device studied in the
applicable clinical trial. Therefore, the timelines for submitting and
posting clinical trial results information for applicable device
clinical trials for unapproved or uncleared devices in proposed
Sec. Sec. 11.44 and 11.52, respectively, could result in the public
availability of clinical trial results information for such trials
before the information submitted during registration is posted in
accordance with proposed Sec. 11.35(b)(2) for these same trials, and
for devices that are never approved or cleared, without such
registration information ever being posted.
As we explained in the NPRM, posting clinical trial results
information without sufficient corresponding public availability of
certain descriptive information about the trial (that is similar to the
type of information included as part of registration) would fail to
provide the necessary context for understanding clinical trial results
information, thereby significantly limiting understanding of posted
results information (79 FR 69580). Section 402(j)(3)(D)(ii)(II) of the
PHS Act authorizes the Secretary to require, through rulemaking, the
submission of clinical trial results information for applicable
clinical trials of products that have not been approved, licensed or
cleared, whether or not approval, licensure or clearance had been
sought. Specifically, it authorizes the Secretary to require, for an
applicable device clinical trial of a device that has not been
previously approved or cleared, the submission of the results
information that is described in section 402(j)(3)(D)(iii) of the PHS
Act. Section 402(j)(3)(D)(iii) of the PHS Act states that the
regulations ``shall require, in addition to the elements described in
[section 402(j)(3)(C) of the PHS Act] . . . [s]uch other categories as
the Secretary determines appropriate.'' Thus, for applicable device
clinical trials of unapproved or uncleared devices, the Secretary can
require, through rulemaking, submission of ``such other categories'' of
results information as the Secretary determines appropriate in addition
to the information required under section 402(j)(3)(C) of the PHS Act.
As discussed in the NPRM, in order to ``enhance patient access to and
understanding of the results of clinical trials'' as required by
section 402(j)(3)(D)(i) of the PHS Act, we interpreted ``such other
categories'' of results information for applicable device clinical
trials of unapproved or uncleared devices subject to proposed Sec.
11.35(b)(2) and for which posting of registration information continues
to be delayed to include, among other things, certain descriptive
information that is similar to the type of information that is required
to be submitted under section 402(j)(2)(A)(ii) of the PHS Act (79 FR
69581). Accordingly, proposed Sec. 11.48(a)(6) required responsible
parties for applicable device clinical trials of unapproved or
uncleared devices, for which the device remained unapproved or
uncleared at the time of results information submission to submit this
descriptive information as part of clinical trial results information.
Comments and Response
A number of commenters addressed the topic of results information
submission for applicable clinical trials of unapproved, unlicensed, or
uncleared products. Commenters who supported the proposal stated that
public availability of results information from trials of unapproved,
unlicensed, and uncleared drugs (including biological products) and
devices is expected to have public health benefits, as it helps protect
the safety of participants who volunteer to be in clinical trials by
reducing the likelihood that people will unknowingly design, approve,
or participate in clinical trials that are duplicative and unnecessary
(e.g., because similar clinical trials have already been conducted but
not published), or that are potentially ineffective or harmful (e.g.,
because similar interventions have been shown to be harmful or
ineffective in previous, unpublished clinical trials). Commenters also
stated that results information from trials of unapproved, unlicensed,
or uncleared products will reduce costs by minimizing the number of
redundant trials.
Commenters expected that public availability of results information
will assist potential human subjects in making more informed decisions
about participating in a clinical trial by providing them and their
care providers with information about the results of a broader set of
clinical trials of various interventions that have been studied for a
disease or condition of interest. Investigators and human subjects
protection review boards that already have access to unpublished
information from the sponsor of a clinical trial or the manufacturer of
a drug or device will have access via ClinicalTrials.gov to information
about other clinical trials of similar unapproved, unlicensed, or
uncleared products that might help them in designing or considering the
potential risks and benefits of participation in a clinical trial.
Commenters highlighted that results should be put to the broadest
use because participants in research often put themselves at risk to
participate and they deserve to have their participation contribute to
the advancement of medical science, so that future patients may benefit
from the knowledge gained. Commenters also indicated that increased
transparency could help researchers learn from failed trials, verify
findings, advance research, and improve overall understanding of
disease. Commenters stated that trial results that are never published
distort the evidence base for systematic reviews conducted to support
development of clinical practice guidelines, which increases the time
and effort needed to develop such guidelines. One commenter suggested
that because it is common for products to be used outside of their
approved marketing authorization in medical practice, information on
trials of unapproved, unlicensed, or uncleared products
[[Page 64994]]
should comply with robust reporting requirements in order to minimize
potential risk to the public.
A couple of commenters mentioned that the requirement to submit
results information from trials of unapproved products is consistent
with the 2014 European Union (EU) clinical trial regulations. We agree
with this point and note the ongoing regulatory efforts by the European
Medicines Agency (EMA) to make results information from clinical trials
of drugs conducted within the EU available in a publicly accessible
data bank, regardless of the approval status of the drug [Ref. 67, 68,
69]. As discussed in the NPRM, all clinical trials of drugs performed
within the EU are registered in EMA's European Clinical Trials Database
(EudraCT) database, with information on phase 2, 3, and 4 clinical
trials and all pediatric clinical trials made public through the EU
Clinical Trials Register (79 FR 69578) [Ref. 70]. In October 2013, EMA
released a new version of the EudraCT database to support the
submission and public posting of summary clinical trial results on the
EU Clinical Trials Register (EU CTR). The specified summary results
information differs from the detailed information that would be
submitted to EMA as part of a Marketing Authorization Application. As
noted in the EMA's announcement, the EudraCT summary results data
requirements are ``substantially aligned'' with those of the
ClinicalTrials.gov results database [Ref. 71].
Commenters who were opposed to the proposal suggested that
submission (and public posting) of results information for trials of
products still under development may curtail incentives to invest in
innovative research. Regarding devices in particular, it was suggested
that requiring results information submission for trials of uncleared
devices will have a negative effect on the development of new and
innovative devices. Comments suggested that the risk of disclosing such
results information would outweigh the benefit to the public, who
cannot use a product that is not approved, licensed, or cleared. See
the discussion of Sec. 11.44 in Section IV.C.3 of this preamble for
comments and the Agency response regarding the timeline for submission
of results information for trials of unapproved, unlicensed, or
uncleared products.
Several commenters raised legal challenges, citing the FD&C Act,
the Freedom of Information Act (FOIA), and the U.S. Trade Secrets Act
(U.S. TSA). We disagree with these comments. As an initial matter, we
would like to clarify that FDA's disclosure laws and regulations do not
apply to information submitted to ClinicalTrials.gov. FDA's statutory
provisions apply to information obtained by the FDA pursuant to the
enumerated statutory provisions of the FD&C Act, (see sections 301(j)
and 520(c) of the FD&C Act) and FDA's general and product-specific
disclosure regulations for drug products (including biological
products) and device products apply to FDA records. (See 21 CFR part 20
and 21 CFR 312.120, 314.430, 807.95, 812.38, and 814.9). Information
submitted to ClinicalTrials.gov is submitted to NIH pursuant to section
402(j) of the PHS Act and the regulations promulgated under it.
Registration and results information submitted to ClinicalTrials.gov is
not obtained pursuant to the FD&C Act, nor is it maintained as an FDA
record.
With respect to the FOIA (5 U.S.C. 552), although the FOIA provides
a general right to obtain information in Federal Agency records, it
also establishes certain exemptions from disclosure; thus, while the
FOIA is, broadly speaking, a disclosure statute, it also states that
the disclosure requirements do not apply to information in Agency
records if that information falls within one of the enumerated
exemptions (see 5 U.S.C. 552(b)). In other words, an Agency is not
required to release information under FOIA if that information falls
within one of the enumerated exemptions. One of the categories of
information that is exempted from disclosure is ``trade secrets and
commercial or financial information obtained from a person [that is]
privileged and confidential.'' (5 U.S.C. 552(b)(4)). In contrast, the
U.S. TSA (18 U.S.C. 1905) explicitly prohibits the release of such
information by an Agency employee from Agency records. However, the
U.S. TSA prohibitions do not apply when the disclosure of information
is authorized by law. As established by the Supreme Court in Chrysler
Corp. v. Brown, 441 U.S. 281 (1979), a statute or validly promulgated
regulation requiring disclosure constitutes ``authorization by law''
for purposes of the U.S. TSA. Section 402(j) of the PHS Act requires
that the Agency post certain registration and results information from
applicable clinical trials, and further requires the Secretary to
determine via rulemaking whether to require the submission and posting
of results information from applicable clinical trials of unapproved,
unlicensed, or uncleared drugs and devices (see section 402(j)(3)(D)(i)
and (ii)(II) of the PHS Act), as well as to determine what results
information must be submitted (see section 402(j)(3)(D)(iii)(IV) of the
PHS Act). Accordingly, to the extent that clinical trial information,
including but not limited to results information from applicable
clinical trials of unapproved, unlicensed, or uncleared drugs and
devices, described in section 402(j) of the PHS Act and this final rule
may contain trade secret and/or confidential commercial information,
the requirement that such information be posted on ClinicalTrials.gov
is authorized by law for the purposes of the U.S. TSA.
It was also suggested that the provision in section
402(j)(2)(D)(ii)(I) of the PHS Act for delayed disclosure of
registration information prohibits the posting of results information
for applicable clinical trials of unapproved or uncleared devices. We
believe the authority to require submission of results information for
applicable clinical trials of unapproved and uncleared devices is clear
from the language in section 402(j)(3)(D)(ii)(II)(bb) of the PHS Act.
We have explained above the reasoning for requiring responsible parties
to submit certain descriptive information as part of clinical trial
results information for certain applicable device clinical trials of
unapproved or uncleared device products, which is maintained in the
final rule at Sec. 11.48(a)(7).
One commenter also suggested that disclosure would be a forced
release of trade secrets and confidential commercial information in
violation of common law applicable to trade secrets. Another commenter
raised a constitutional challenge, suggesting that the Agency would be
disclosing trade secrets through this requirement, which they argued
would constitute a regulatory taking of property without just
compensation, in violation of the Fifth Amendment of the U.S.
Constitution. We disagree.
The Supreme Court found in Ruckelshaus v. Monsanto (467 U.S. 986
(1984)) that trade secrets are property for purposes of the application
of the Takings Clause of the Fifth Amendment. Most states have adopted
the Uniform Trade Secrets Act (UTSA) and its definition of ``protected
trade secret interests'': ``[I]nformation, including a formula,
pattern, compilation, program, device, method, technique, or process
that: (i) Derives independent economic value, actual or potential, from
not being generally known to, and not being readily ascertainable by
proper means by, other persons who can obtain economic value from its
disclosure or
[[Page 64995]]
use, and (ii) is the subject of efforts that are reasonable under the
circumstances to maintain its secrecy.'' (See UTSA with 1985 Amendments
Sec. 1(4)).
However, even if there is a protected trade secret interest, the
question of whether the government's proposed regulation amounts to a
taking under the Fifth Amendment requires additional analysis. In Penn
Cent. Transp. Co. v. City of New York (438 U.S. 104 (1978)), the
Supreme Court set forth a three-factor analysis for determining whether
a regulatory taking had occurred. Specifically, the Court identified
(1) The extent to which an Agency's regulation interferes with distinct
investment-backed expectations, (2) The economic impact of the
regulation on the claimant, and (3) The character of the governmental
action.
As an initial matter, none of the commenters identified any
specific information that they assert constitutes trade secret
information for purposes of a takings analysis, and that would be taken
as a result of the statutory and regulatory requirements regarding
submission to and posting on ClinicalTrials.gov. With respect to the
factors outlined by the Supreme Court in Penn Central, we do not
believe that drug and medical device manufacturers have a reasonable
expectation at this time that the results information described in the
final rule will be kept confidential. This is because (1) the field of
drug and device development is highly regulated, (2) there has been
robust public debate over the need for greater transparency of clinical
trial results, and (3) it has been clear since the proposed rule was
issued in 2014 (and in our view since the enactment of FDAAA, with its
requirement that the rulemaking address the issue of results
information submission and posting for applicable clinical trials of
unapproved, unlicensed, and uncleared products), that such information
can and may be made available to the public. None of the commenters
have identified specific information required under the regulations
that they believe would be of value to competitors, or that would allow
competitors to benefit from innovators' scientific and technical
advancements. Nor, as stated above, have they identified specific
clinical trial results information that would be required to be
submitted and that would meet the definition of a protected trade
secret property interest for purposes of a takings analysis.
Regarding the final factor under Penn Central, we reiterate that,
as discussed at length in this preamble, as well as in the proposed
rule, there are significant public health benefits to requiring the
disclosure of the information posted on ClinicalTrials.gov, including
for applicable clinical trials of unapproved, unlicensed, and uncleared
products. For many years the scientific community, general public,
industry and others have engaged in high-profile public discussions
about the need for increased access to information about clinical
trials. Potential societal harms associated with having an incomplete
medical evidence base have been reviewed; for example, studies have
revealed that selective publication of clinical trial results could
give a misleading picture about serious adverse effects of widely
marketed drugs and about increased risks of such effects in certain
segments of the population [Ref. 45].
As noted previously, the requirements for submission to and posting
on ClinicalTrials.gov have the additional public health benefit of
supporting international standards and norms (e.g., Declaration of
Helsinki, World Health Organization (WHO) Statement on Public
Disclosure of Clinical Trials Results) and with industry, governmental,
and other policies. The requirements under section 402(j) of the PHS
Act, including those in this final rule, reflect our careful
consideration and balancing of the burdens and benefits of the
disclosure of this information for the drug and medical device industry
and the public. These requirements further the important public health
goals of enhancing patient enrollment in clinical trials, providing a
mechanism to track the progress of clinical trials, and enhancing
patient access to and understanding of the results of clinical trials.
The final rule maintains the proposal to require the submission of
results information for applicable clinical trials of unapproved,
unlicensed, or uncleared products, regardless of whether FDA approval,
licensure, or clearance is or will be sought or obtained. We conclude
that this requirement is in furtherance of the express statutory
purpose of section 402(j)(3)(D)(i) of the PHS Act, which states that
the Secretary shall expand the registry and results data bank ``[t]o
provide more complete results information and to enhance patient access
to and understanding of the results of clinical trials.'' We considered
a number of factors, notably the potential public health benefits of
timely disclosure of results information for applicable clinical trials
of unapproved, unlicensed, or uncleared products; the potential effects
of disclosure on the competitive advantage of drug and device
manufacturers, including incentives to invest in the development of new
products intended to improve public health; and other results
information submission requirements and policies (e.g., those of the
EMA). Other considerations include the relative burden on the
responsible party of submitting results information for an applicable
clinical trial of an unapproved, unlicensed, or uncleared product, the
date by which results information must be submitted and practical
issues of implementation and compliance.
As discussed in the NPRM (79 FR 69578), we recognize that the
posting of results information about applicable clinical trials of
unapproved, unlicensed, and uncleared products presents special
challenges. Such information would be accessible to care providers and
their patients but describe products that are not approved, licensed,
or cleared, and thus may not be available outside of clinical trials.
Further, even for approved, licensed, or cleared products, the posted
results information might contain information about unapproved,
unlicensed, or uncleared uses and further information may be helpful in
understanding potential risks and benefits. We believe that the results
information from any individual applicable clinical trial should be
considered in the context of the broader set of information available
about the product and alternative products. In keeping with current
practice, we intend to establish links from clinical trial records in
ClinicalTrials.gov to additional sources of information, including but
not limited to the FDA and NIH information specified in section
402(j)(3)(A)(ii) of the PHS Act (we intend to indicate that the links
were added by the Agency and not by the responsible party for the
applicable clinical trial). We intend to provide information to assist
users in better understanding and interpreting the information
available in ClinicalTrials.gov, including materials that describe the
general purpose and content of the data bank, a general description of
the limitations of the results information presented, and cautions that
the information should be used in conjunction with advice from
healthcare professionals.
In this regard, it bears repeating that nothing in this rule
authorizes a firm to use information posted in, or links to other Web
sites available on, ClinicalTrials.gov, to promote unapproved,
unlicensed, or uncleared medical products or unapproved, unlicensed, or
uncleared uses of approved, licensed, or cleared medical products, or
supersedes or alters other statutory and regulatory provisions
[[Page 64996]]
related to such communications. In addition, the government does not
independently verify the scientific validity or relevance of the
information submitted to ClinicalTrials.gov beyond the limited quality
control review by NIH. As discussed in Section III.C.12 of the NPRM,
since responsible parties have been submitting results, the NIH has
used a two-step process for quality control, starting with an automated
system-based check prior to submission followed by a detailed, manual
review after submission. This detailed review is based on quality
review criteria for identifying apparent errors, deficiencies, or
inconsistencies that are not detected by the automated checks. If any
such problems are identified in the detailed, manual review, the
proposed rule stated, the Director would send an electronic
notification to the responsible party, indicating that the submission
contains apparent errors, deficiencies, and/or inconsistencies listing
such issues and requesting that they be addressed. Accordingly, the
inclusion of data and information in the ClinicalTrials.gov platform,
the links to other studies and Web sites, and the conduct of the
limited quality control review by NIH, do not constitute a government
affirmation or verification that the information within or referenced
in the database, or communications that rely on that information, are
truthful and non-misleading, particularly where they are being pointed
to in the context of treatment decisions relating to the use of a
product for an unapproved use.
The final rule does make a modification to the NPRM regarding
applicable clinical trials that are completed before the effective date
of the final rule and that study a product that is not approved,
licensed, or cleared as of the effective date of the final rule.
Proposed Sec. 11.44(a)(2) would have required that for: (1) Applicable
clinical trials that reach their completion date prior to the rule's
effective date, (2) of products that are unapproved, unlicensed, or
uncleared as of the completion date, and (3) for which the studied
product is approved, licensed, or cleared by FDA on or after the
effective date, if not otherwise subject to other deadlines specified
in proposed Sec. 11.44, results information must be submitted by the
earlier of one year after the completion date or 30 calendar days after
FDA approval, licensure, or clearance. A commenter suggested this could
result in a situation in which a trial ends shortly before FDA approval
or clearance and is not given a full year to submit results information
after the trial's primary completion date. This provision has been
removed from the final rule. As discussed in more detail below, an
applicable clinical trial of an unapproved, unlicensed, or uncleared
product that reaches its primary completion date before the effective
date of the final rule is not subject either to the results information
submission requirements in the final rule or the results information
submission requirements specified in section 402(j)(3)(C) and section
402(j)(3)(I) of the PHS Act.
Commenters also suggested changes to the scope of the results
information submission requirement for applicable clinical trials of
unapproved, unlicensed, or uncleared products and addressed the
statutory charge to the Secretary to determine whether the rule should
require the submission of results information from applicable clinical
trials of unapproved, unlicensed, or uncleared products, whether or not
approval, licensure, or clearance will be sought (section
402(j)(3)(D)(ii)(II) of the PHS Act). Commenters suggested various
options on the subject of the abandonment of product development,
including that abandoned products should be identified, but submission
of results information from applicable clinical trials of such products
should not be required; commenters also suggested that the rule should
only apply to applicable clinical trials of unapproved, unlicensed, or
uncleared products that have been declared abandoned by the sponsor.
As explained in the proposed rule and above, while limiting results
submission to those applicable clinical trials of unapproved,
unlicensed, or uncleared products for which product development has
been abandoned by industry would mitigate industry concerns about
disclosing potentially valuable information to competitors, it would do
little to address concerns about bias in the disclosure of information
(79 FR 69577). Considerable information of potential scientific,
clinical, and public significance would still be hidden from public
view and would continue to be unavailable for consideration by human
subjects protection review boards in assessing proposed clinical
trials, by individuals considering participation in them, or by other
researchers who are planning similar clinical trials or clinical trials
of similar products. In addition, limiting results information
submission and posting to applicable clinical trials of products for
which product development has been abandoned would be difficult to
administer because only the sponsor and/or manufacturer are in a
position to determine that product development has been abandoned for
all potential uses. Moreover, product development is often suspended
for periods of time before being resumed when company priorities change
or an investigational product is transferred to another company.
Information about unapproved, unlicensed, or uncleared products for
which product development may have been suspended might therefore
remain undisclosed for long periods of time, depriving the public of
the benefits that could result from disclosure.
A few commenters suggested that if the proposal is adopted, only a
limited number of primary or key secondary outcomes prior to regulatory
approval should be required to be submitted, or the final rule should
allow the submission of redacted results information, especially when
the product has not been approved, licensed, or cleared by FDA. The
Agency disagrees; we believe that results information submission for
all pre-specified primary and secondary outcomes, as required in the
statute, is necessary to serve the public interest in having access to
full and complete information. Selective reporting of results
information would produce an incomplete and potentially skewed
submission that ultimately would not serve the interests of the public
and users of ClinicalTrials.gov.
Finally, it was suggested that device manufacturers be permitted to
withhold proprietary information from the public as long as doing so
does not pose a risk to patients. As discussed in Section IV.B. 5,
trials of unapproved or uncleared device products qualify for a delay
in the disclosure of registration information. However, based on the
evidence available in the published literature as described in Section
I of this preamble, we have concluded that selectively withholding of
clinical trial information, including results information, at the
discretion of the responsible party does not best serve the public
interest. In addition, section 402(j) of the PHS Act requires the trial
results in summary form (rather than individual participant-level
form), which we believe can be provided without disclosing trade secret
or confidential commercial information. Commenters did not indicate how
such results information is or could be considered proprietary (or how
it could contain proprietary information). Furthermore, even if the
summary results information required to be submitted and posted does
include such proprietary information, as discussed above, section
402(j) of the PHS Act and
[[Page 64997]]
this final rule constitute authorization by law to disclose this
information.
Final Rule
Based on the comments received and the statutory requirements, this
final rule maintains the requirement to submit results information from
applicable clinical trials of unapproved, unlicensed, and uncleared
products consistent with the timelines outlined in Sec. 11.44. The
timely disclosure of results information, along with options for
limited delays in results information submission deadlines with
certification when seeking initial approval, licensure, or clearance,
or approval, licensure, or clearance of a new use, takes into
consideration the various interests at stake, including the public
health benefits of disclosure and the commercial interests of sponsors.
Registration information must be submitted by the deadlines
outlined in Sec. 11.24, which do not distinguish between the
submission of information from applicable clinical trials of approved,
licensed, or cleared products and information from applicable clinical
trials of unapproved, unlicensed, or uncleared products. Section 11.35
specifies (see Section IV.B.5) the timelines for posting of
registration information for applicable drug clinical trials
(regardless of product approval status), applicable clinical trials of
device products that previously were approved or cleared, and
applicable clinical trials of device products that have not been
previously approved or cleared (which qualify for delayed posting in
Sec. 11.35(b)(2)(i)). Section IV.B.5 also describes new Sec.
11.35(b)(2)(ii) that provides a process for a responsible party to
indicate to the Director that it is authorizing the Director to
publicly post its clinical trial registration information at
ClinicalTrials.gov prior to the date of FDA approval or clearance of
its device product. If the responsible party submits the Post Prior to
U.S. FDA Approval or Clearance data element under Sec.
11.28(a)(2)(i)(Q), the Director will post publicly the registration
information that would otherwise be subject to delayed posting as
specified in Sec. 11.35(b)(2)(i), except for certain administrative
data, as soon as practicable.
Under Sec. 11.44, delayed submission of results information for
applicable clinical trials involving products that are unapproved,
unlicensed, or uncleared for any use is permitted only if the
responsible party certifies as set forth in Sec. 11.44 (c) (and prior
to the standard results information submission deadlines as specified
in Sec. 11.44(a)) that the sponsor or manufacturer intends to continue
with product development, meaning that it is either seeking, or may at
a future date seek, initial approval, licensure, or clearance of the
product under study in the applicable clinical trial. For the purposes
of this final rule only, we interpret ``use'' to include
``indication.'' For the purposes of this final rule, ``indication''
means ``the disease or condition the product is intended to diagnose,
treat, prevent, cure, or mitigate.''
Section 402(j)(3)(D)(iv)(III) of the PHS Act directs that, in
determining the timeline for submission of results information from
applicable clinical trials of unapproved, unlicensed, or uncleared
products, the Secretary take into account both the certification
process under section 402(j)(3)(E)(iii) of the PHS Act ``when approval,
licensure, or clearance is sought'' and ``whether there should be a
delay of submission when approval, licensure, or clearance will not be
sought.'' Specifically with regard to applicable clinical trials of
unapproved, unlicensed, or uncleared products for which approval,
licensure, or clearance will not be sought, we interpret the phrase
``will not be sought'' in section 402(j)(3)D)(iv)(III)(bb) of the PHS
Act to mean that the sponsor or manufacturer has no intention of
continuing with commercial development of the product. For these
trials, as with the disclosure of clinical trial results information
from applicable clinical trials of all unapproved, unlicensed, or
uncleared products, we believe that the public benefits of disclosure
of results information outweigh any private, commercial interests (see
discussion in Section II, Overview of Statutory Provisions). With
respect to products for which initial approval, licensure, or clearance
is, or may at a future date be sought, we recognize that, in many
cases, this is information that will be known only to the sponsor or
manufacturer of the drug product (including biological product) or
device product and may not even be known to them at the time a clinical
trial is completed, especially for an earlier stage trial, such as a
phase 2 applicable drug clinical trial. Instead, the sponsor or
manufacturer may know only that it intends to continue with product
development, such as through the conduct of a subsequent clinical
trial. Therefore, as a condition of delaying results information
submission for unapproved, unlicensed, or uncleared products for any
use, Sec. 11.44(c) requires the responsible party to certify that the
sponsor intends to continue with product development and either is
seeking, or may at a future date, seek approval, licensure, or
clearance. If the responsible party elects to submit a certification
for delayed submission, it is the responsible party's obligation to
verify that the particular applicable clinical trial meets the Sec.
11.44(c) criteria, as explained in this preamble.
If, after submission of a certification under Sec. 11.44(c), the
drug product (including biological product) or device product studied
in the applicable clinical trial becomes approved, licensed, or cleared
for the use studied in the applicable clinical trial, results
information will be due 30 calendar days after the date of product
approval, licensure, or clearance. If, after submission of such a
certification, initial approval is no longer being sought (e.g.,
product development is abandoned), any continued delay in results
information submission is not warranted, and the responsible party
should submit results information as soon as practicable, but not later
than 30 calendar days after the application or premarket notification
is withdrawn without resubmission for no less than 210 calendar days
(i.e., 240 calendar days after submission of the withdrawal request).
We limit the allowable delay period for results information submission
for applicable clinical trials of unapproved, unlicensed, or uncleared
products for any use to 2 years after the submission of a certification
(i.e., up to a total of 3 years after the primary completion date) for
delayed results information submission, which parallels the
statutorily-mandated 2 year limitation in Sec. 11.44(b). The
certification must be submitted prior to the date on which results
information would otherwise be due under the standard submission
deadline in Sec. 11.44(a) (i.e., 12 months after the primary
completion date), and we permit only one certification to be submitted
for each clinical trial.
In addition, the final rule maintains Sec. 11.48(a)(6) as proposed
in final Sec. 11.48(a)(7), which requires responsible parties to
submit additional descriptive results information for applicable device
clinical trials of unapproved or uncleared devices for which
registration information is not posted at the time of results
information submission. In such situations, posting clinical trial
results information with certain descriptive information that is
similar to the type of information that is included as part of
registration, provides the necessary context for understanding clinical
trial results information and improves the understanding of posted
results information. As explained in the proposed rule, facilitating
this
[[Page 64998]]
understanding is why journal articles and other reports of the results
of clinical trials routinely include information about the disease or
condition and interventions under study, the inclusion and exclusion
criteria for participants, the location(s) of the trial, etc. Without
such information, results data about patient demographics, outcomes,
and adverse events could be uninterpretable and inaccessible. For
example, patients and other users typically access clinical trial
results by searching for (and retrieving) clinical trials with specific
characteristics that involve a particular intervention or type of
intervention, study a particular disease or condition, recruit certain
types of subjects, take place during a particular time period, are
conducted in a specific location or particular facility, are sponsored
by a particular organization, or match a title or identification number
they have found in other public sources.
Similarly, consistent with section 402(j)(3)(D)(i) of the PHS Act,
providing information about the purpose of the study, its design, the
intervention(s) studied, the types of subjects eligible to participate,
the duration of the study, and the outcome measures will enhance the
understanding of clinical trial results by researchers, healthcare
providers, patients and other users of ClinicalTrials.gov. Users can
benefit from knowing whether the clinical trial is completed, if data
are still being collected for other outcome measures, or if the
clinical trial was prematurely terminated. They can benefit from
understanding whether information has been submitted for all
anticipated outcome measures and corresponds to the outcome measures
that the clinical trial was designed to achieve or whether the outcome
measures changed during the course of the study. They can also benefit
from information to assist in comparing results with the results of
other clinical trials and with other publicly available information
about a clinical trial of interest and other trials. Whether the
clinical trial was reviewed for human subjects protection and who had
authority over the conduct of the trial can also be useful. In
addition, users may benefit from knowing who submitted the information
and when it was last verified (i.e., to indicate whether it might be
out of date). Such information is not readily available from
information submitted under Sec. 11.48(a)(1)-(5), but is similar to
the descriptive information provided during registration (e.g., Primary
Purpose, Primary Outcome Measure(s), Overall Recruitment Status) (see
Sec. 11.28(a)).
In addition, requiring responsible parties for applicable device
clinical trials of unapproved, unlicensed, or uncleared device products
to resubmit information submitted previously to the data bank during
registration under Sec. 11.28(a), in order to comply with Sec.
11.48(a)(7), would be inefficient and impose an unnecessary burden on
responsible parties. It would also introduce the possibility that the
additional information provided at the time of results information
submission would be inconsistent with the registration information and
require the Agency to perform an additional quality review of the
registration information. To promote efficiency, responsible parties
must fulfill the requirement under Sec. 11.48(a)(7) by affirming in
the data bank when submitting clinical trial results information that
they are submitting information that is already contained in the data
bank and that such information has been updated as specified in Sec.
11.64(a)(iii) and that it will be included as clinical trial results
information. Once this affirmation is made, any information listed in
Sec. 11.48(a)(7) that was previously submitted to the data bank will
automatically populate the results information data fields and be
posted when results information is posted.
As discussed in Section IV.B.5 of this preamble, we also note that
under final Sec. 11.35(b)(2)(ii), a responsible party can indicate to
the Director that it is authorizing the Director to publicly post its
clinical trial registration information, that would otherwise be
subject to delayed posting, as specified in Sec. 11.35(b)(2)(i), prior
to the date of FDA approval or clearance. For an applicable device
clinical trial for which registration information described in Sec.
11.28 has been posted in accordance with Sec. 11.35(b)(2)(ii) before
the submission of results information described in Sec. 11.48, the
requirement of Sec. 11.48(a)(7) will not apply.
C. Submission of Technical and Non-technical Summaries
Overview of Proposal
Sections 402(j)(3)(D)(iii)(I) and (II) of the PHS Act specify that
the regulations shall require ``[a] summary of the clinical trial and
its results that is written in non-technical, understandable language
for patients'' and ``[a] summary . . . that is technical in nature,''
respectively, ``if the Secretary determines that such types of summary
[both non-technical and technical] can be included without being
misleading or promotional.'' We interpreted this statutory condition to
mean that such summaries should be required only if the summaries can
be consistently produced by responsible parties in a way that is not
misleading or promotional.
In the NPRM, we acknowledged that if non-technical and technical
summaries could be consistently produced without being misleading or
promotional, patients, members of the general public, clinicians, and
researchers might benefit from brief, well-written, accurate, and
objective summaries of the results of individual clinical trials (79 FR
69581). We discussed considerations related to the optimal format for
narrative non-technical summaries and the question of whether a single,
brief summary of an individual trial can provide sufficient background
and context to avoid being potentially misleading to a clinician or
patient interested in the clinical significance of the results. We
described the challenges of producing summaries of trials with many
outcome measures and adverse events without being selective. In
addition to reviewing the relevant literature on the matter, we
consulted with the FDA Risk Communication Advisory Committee [Ref. 72]
and considered prior public comments from a public meeting held in 2009
[Ref. 63]. We indicated that, until further research could be conducted
to assess the value of these summaries to the public and whether they
can consistently be provided in a manner that is objective and not
misleading, we would defer the decision about whether or not to require
the submission of narrative summaries. We indicated that we would
continue to provide links, where possible, from individual clinical
trials in ClinicalTrials.gov to related peer reviewed literature and
other information about the intervention, disease, or condition
studied. The NPRM invited public comment pertaining to whether the
inclusion of technical and non-technical summaries should be required
in clinical trial data submission on ClinicalTrials.gov and what
methodologies could be employed to ensure non-misleading, non-
promotional, accurate, and consistent summaries (79 FR 69582).
Comments and Response
Comments addressed the question of whether the submission of
technical and non-technical narrative results summaries should be
required. Commenters noted that preparing both technical and non-
technical summaries would be burdensome (e.g., a commenter estimated
that providing a non-technical summary would add 4 hours to the overall
time to complete the
[[Page 64999]]
submission of the results information for a clinical trial) and raised
concerns regarding the ability of trial sponsors to write accurate,
non-promotional, and non-misleading summaries. Commenters suggested
that if results summaries were to be required, the Secretary would need
to develop and issue guidelines or templates regarding their
appropriate authorship, content, evaluation, and format to ensure
consistency across summaries. No comments addressed the methods that
might be employed to help answer the questions about whether narrative
summaries could be consistently produced in a non-promotional and non-
misleading manner. However, several commenters suggested external
organizations with whom the Secretary might collaborate on narrative
summary issues, namely the ICMJE to ensure that narrative summaries
would not preclude future journal publications; the Multi-Regional
Clinical Trials Center of Brigham and Women's Hospital and Harvard to
investigate the format they are using for summaries; the FDA regarding
Drug Trials Snapshots; and the Patient-Centered Outcomes Research
Institute (PCORI) regarding peer review and public release of research
findings. One commenter suggested that the summaries could be subject
to a peer review process or prepared by independent medical writers.
For both technical and non-technical summary results submission, there
were commenters who supported deferral of a decision pending further
exploration and the development of guidelines for preparing such
documents.
With regard to technical summaries specifically, some commenters
suggested that such summaries would be redundant to the required trial
results information proposed in the NPRM. Other commenters expressed
concerns regarding disclosure of proprietary information, particularly
if such summaries were to be posted prior to FDA product approval. One
commenter supported requiring technical summaries of results because
they would suit the needs of professionals, manufacturers, and others
in the industry. Several commenters suggested that as an alternative to
technical summaries, ClinicalTrials.gov could systematically link to
published reviews and/or clinical study reports (CSRs) submitted to
FDA.
With regard to non-technical summaries specifically, commenters
pointed out that it may be difficult for members of the public to
understand study results provided in a technical summary and that the
provision of lay summaries would enhance public understanding of the
results. Others highlighted the difficulty inherent in writing a simple
summary that presents the nuances of complex research findings, noting
that systematic reviews, which synthesize all available evidence, are
better sources of information for the lay public than brief summaries
of a single trial. One commenter suggested that the informed consent
document could be required in lieu of a lay summary because it provides
important basic information in non-technical terms and has been
reviewed by an independent party, i.e., an IRB.
Taking the public comments into consideration, and given concerns
about the potential for harm to public health from the promotion of
medical products for unapproved uses, the Secretary is declining at
this time to require narrative results summaries until further research
is conducted to determine whether and, if so, how, summaries can be
reliably and consistently produced without being promotional or
misleading. Current approaches in the dissemination of trial summaries,
such as FDA's Drug Trials Snapshots, PCORI's summary reports, and
industry efforts to return summary results to participants, may be
informative and will be reviewed and considered as part of any further
research.
To provide additional information to the general public about a
registered clinical trial, we will accept optional submission of the
final version of the informed consent document to be posted on the
associated record. Although the informed consent document does not
provide information on interpreting the results of the trial, the
document is written in lay language and its description of the trial's
purpose, procedures, risks and potential benefits may help put the
trial results into clearer context.
Final Rule
The final rule does not require the submission of technical or non-
technical summaries of results to ClinicalTrials.gov because we have
not identified evidence on the basis of which to conclude that there is
a feasible way to ensure that the information contained in such
summaries will be consistently produced without being misleading or
promotional. We will continue to explore automated ways to consistently
produce result summaries in a non-promotional, non-misleading way as
well as mechanisms for linking results to information that might assist
users in interpreting the results of clinical trials, such as
systematic reviews and summary outcome information that sponsors and
investigators provide to participants following the trial's completion.
Should we determine in the future that narrative summaries can be
consistently produced in a non-promotional, non-misleading way, a
separate rulemaking process with notice and public comment will be
undertaken.
D. Submission of Protocols and Statistical Analysis Plans
Overview of Proposal
Section 402(j)(3)(D)(iii)(III) of the PHS Act stipulates that
regulations for an expanded registry and results data bank shall
require at the time of results information submission, in addition to
basic results information, the submission of ``[t]he full protocol or
such information on the protocol for the trial as may be necessary to
help to evaluate the results of the trial'' (emphasis added).
The NPRM noted that this statutory requirement could be satisfied
in several ways, such as ``(1) [r]equiring submission of additional
structured data elements derived from, or describing, the protocol; (2)
requiring submission of portions of the final protocol or other
narrative information about the conduct of the study that is associated
with the protocol (e.g., a SAP, if not part of the protocol); or (3)
requiring submission of the full protocol at the time of results
submission, meaning the final version of the protocol, including all
protocol amendments, in a format such as Portable Document Format
(PDF)'' (79 FR 69582). As we explained in the NPRM, given the proposals
for submission of additional registration and results information, we
did not propose to require submission of the protocol or other
``information on the protocol.'' We did, however, solicit public
comment on whether the registration and results information proposed
for submission was sufficient to meet the statutory requirement. We
asked for perspectives on the relative benefits and burdens of
preparing and submitting any additional information and how such
information would help evaluate the results of the clinical trial.
Comments and Response
Commenters supportive of a requirement for protocol submission
maintained that it improves transparency and quality of reporting by
providing information to the public about inclusion and exclusion
criteria, the interventions studied, and trial outcomes. They suggested
that the availability of the protocol allows users to compare reported
outcomes and
[[Page 65000]]
analyses against those pre-specified in the protocol. Some commenters
asserted that a full understanding of the trial results is not possible
without having access to the protocol and the trial's procedural
details, details they stated permit the study to be replicated or built
upon and that are pivotal to improving the design of future trials.
Some commenters pointed to an IOM recommendation that called for
sharing of the protocol and SAP not only to help other investigators
understand the original analysis, replicate or reproduce the study, and
carry out additional analyses, but also because it complements trial
registration in identifying trials that were initiated, allows future
auditing of data sharing, facilitates meta-analyses and systematic
reviews, promotes greater standardization of protocol elements (e.g.,
interventions, outcomes), and may help reduce unnecessary duplication
of studies [Ref. 47].
Another commenter maintained that an added benefit of making
protocols available through ClinicalTrials.gov was that it would help
journal editors, reviewers, and readers verify the a priori or post hoc
nature of trial outcomes. They noted that journal editors encounter
situations where outcomes reported in manuscripts do not match those
listed on ClinicalTrials.gov and that posting of study protocols would
be an important additional safeguard against reporting bias. Another
commenter pointed out that a central archive for protocols would
alleviate the burden on clinical trial investigators in addressing
multiple requests for a copy of their protocols.
Commenters in support of a requirement for protocol submission also
noted that, unless a standardized protocol format were required, the
burden would be minimal because the document already exists. One
commenter suggested that because the requirement is virtually burden-
free and the benefits are so great, the requirement should be
retroactive as far back as possible.
Commenters opposed to requiring protocol submission offered a
number of reasons for this position. They suggested that the proposed
registration and results elements provide sufficient information to
understand the results of a clinical trial. Some thought the protocols
should not be required because they will be confusing to the public and
detrimental to recruitment, noting that they are technical, not
standardized, and may have multiple amendments. Some asserted that
protocols contain personally identifiable information, proprietary
information, or other information that, if publicly disclosed, could be
damaging to business interests. They suggested that a submission
requirement would conflict with protections under the FD&C Act, FDA
regulations, and FOIA. Commenters in support of protocol submission
suggested redaction of such information was an appropriate remedy that
should be allowed before submission. Finally, other commenters opposed
redaction of information based on concerns it would be too burdensome
and time consuming, with one commenter suggesting that allowing
responsible parties to redact proprietary information might result in
the exclusion of essential details needed for others to understand the
results of the trial. No specific burden estimates associated with
protocol redaction and submission were provided.
We appreciate that the data elements proposed in the NPRM are
helpful to those reviewing and analyzing entries in ClinicalTrials.gov,
and it was due to these additional elements that we did not propose the
submission of the protocol in the NPRM. However, we found compelling
and persuasive the arguments that protocols provide information in a
context that is not captured by these elements alone and that the
protocol will improve transparency and the quality of reporting by
providing a more complete picture of the trial. We understand that
although the registration data elements include descriptors of key
features of the protocol, there are times when this additional detail
may be helpful to researchers and others with an interest in the
clinical trial's results and the ability to assess those results. For
example, the protocol provides more detail than the registry and
results data elements about methods of participant selection,
randomization, masking, and assignment to arms; methods of collecting
clinical trial data; specific information about clinical trial
interventions (e.g., other elements of care that were provided in
addition to the specified interventions); and assessment of adverse
events. The protocol may also contain information on the statistical
techniques used to analyze collected results information, which helps
others in interpreting the submitted results of a clinical trial. The
protocol's description of the approach and circumstances that led to
data collection may be helpful in contextualizing the submitted results
information. We agree that this picture will help users of
ClinicalTrials.gov to interpret the data elements that are required by
this rule and that the protocol will be an important part of results
information reporting for those wishing to fully understand the trial
and its reported outcome measures.
We were also persuaded by the rationale for protocol submission
discussed in the 2015 IOM report on sharing clinical trial data [Ref.
47], which described the value it would have for journal editors,
reviewers, and readers in helping to verify trial outcomes and
safeguard against reporting bias, and that it would help investigators
in addressing multiple individual requests for a copy of their
protocols. Further, it would allow for access to this information long
after any prevailing document retention requirements have lapsed.
We did not find the argument that some might not understand the
protocol to be a sufficient reason to not require its submission.
Rather, although we acknowledge that there may be some individuals who
may not understand the protocol, we believe that in general it will
enhance understanding through its detail, content, and context.
Regarding the suggestion that its posting could be detrimental to
recruitment, we require the protocol at the time of results information
submission, thereby eliminating the concern that posting the protocol
will affect a trial's recruitment.
With regard to the argument that the protocol contains proprietary
information, section 402(j)(3)(D)(iii)(III) of the PHS Act specifically
requires the Agency to determine via this rulemaking whether to require
the submission of the protocol. As discussed above in Section III.B, a
statute or validly promulgated regulation requiring disclosure
constitutes authorization by law to disclose information that might
otherwise be considered to be trade secret and/or confidential
commercial information as those terms are defined in the FOIA and the
TSA. However, notwithstanding this authorization, if there is a case in
which a responsible party believes that a protocol does contain trade
secret and/or confidential commercial information, the responsible
party may redact that information, so long as the redaction does not
include any specific information that is otherwise required to be
submitted under this rule. For example, the Intervention Name(s) for
each intervention studied must be submitted under Sec.
11.28(a)(2)(i)(J); therefore, this information may not be redacted from
the protocol for that trial.
The burden of redacting protocols prior to submission is on the
responsible party; the Agency does not intend to review protocols to
assess
[[Page 65001]]
whether they contain trade secret and/or confidential commercial
information. Regarding the concern that redaction might result in a
protocol lacking in essential details necessary to understand the
results, we emphasize that responsible parties must comply with all
other applicable results information submission requirements of this
rule. The Agency may contact a responsible party if it appears that the
responsible party has redacted information that is otherwise required
to be submitted under these regulations. More specific guidance
regarding redaction will be considered in the future.
In addition, we believe that concerns that might exist about a loss
of competitive advantage are mitigated because the submission of the
protocol is not required until after the trial is completed and
clinical trial results information is submitted in accordance with the
deadlines specified in Sec. 11.44. We also note that Sec. 11.44(c)
provides for delays in submitting clinical trial results information
for an applicable clinical trial that studies a product that is not yet
approved by the FDA, thereby allowing for additional time before the
protocol is required to be submitted.
Moreover, in our experience, protocols do not contain proprietary
information or manufacturer details. However, as noted above, should
there be a case in which a protocol does contain such information,
redaction of such information will be allowed as long as the redaction
does not encompass the information that is otherwise required to be
submitted under this rule.
While some commenters were concerned about posting of personal
information contained in protocols, in our experience, protocols
generally do not contain information about individual clinical trial
participants. However, if such information were to be included in a
protocol, it should be redacted. Again, the burden of doing so is on
the responsible party; the Agency does not intend to review protocols
to assess whether they include personal information about trial
participants. However, if it comes to the Agency's attention that
personal information about trial participants has been included in a
protocol, the Agency may contact the responsible party regarding the
matter.
Protocols can include information about principal investigators and
other individuals associated with conducting a clinical trial. In
response to the concerns expressed by the commenters, responsible
parties may redact personally identifying information about individuals
who are involved in conducting the clinical trial if that information
is not otherwise required to be submitted as part of clinical trial
information. The Agency anticipates that because information such as
work email addresses and contact information related to the clinical
trial is likely available through other public sources (e.g., a medical
center's Web site), in many cases this information will not need to be
redacted and, therefore, the burden associated with redaction will be
minimal.
Because the protocol document already exists, we do not foresee
this additional submission requirement to be burdensome. Rather,
submission of the protocol itself is expected to be a minimally
burdensome requirement that would involve an upload of an existing
electronic document. We also expect that it will be less burdensome for
a responsible party to submit the protocol than to extract and submit
specified portions or selected information from a protocol. Similarly,
as mentioned above, we do not expect redactions of any proprietary or
personal information to be burdensome. The submission of the protocol
at the time of the submission of clinical trial results information,
rather than at the time of clinical trial registration information,
also minimizes the burden on responsible parties in that any amendments
that occurred over the course of the trial would already be
incorporated into the document.
We also agree with the commenters who urged requiring submission of
the SAP if it is not included in the protocol document. Many of the
benefits of the protocol that were cited by commenters (summarized
above) derived from the statistical analysis section of the protocol.
If that section were written as a separate document (the SAP), then
that document would be necessary to derive those same benefits (e.g.,
better understanding of how data were collected and analyzed). As noted
by commenters, the IOM recommended that both the full protocol and the
SAP, including all versions and amendments, ``should be shared to help
other investigators understand the original analysis, replicate or
reproduce the study, and carry out additional analysis'' [Ref. 47].
SAPs describe the analyses to be conducted and the statistical methods
to be used, including ``plans for analysis of baseline descriptive data
and adherence to the intervention, prespecified primary and secondary
outcomes, definitions of adverse and serious adverse events, and
comparison of these outcomes across interventions for prespecified
subgroups. The full SAP describes how each data element was analyzed,
what specific statistical method was used for each analysis, and how
adjustments were made for testing multiple variables . . . if some
analysis methods require critical assumptions, data users will need to
understand how those assumptions were verified'' [Ref. 47]. Some
commenters objected to requiring the submission of both the protocol
and the SAP, for the reasons described above; other commenters raised
similar objections specifically with respect to the submission of SAPs.
We find these objections unpersuasive for the reasons described above
related to protocols. Therefore, we are requiring submission of the SAP
as part of clinical trial results information.
If the SAP is submitted as part of the protocol, it need not be
separately submitted. Some commenters objected to submission of SAPs
because the SAPs might contain proprietary information. Although we
think it unlikely that SAPs will contain proprietary information, we
will accept redacted SAPs under the same terms as redacted protocols.
We wish to emphasize that neither this requirement nor anything in this
rule sets standards or creates requirements for the substantive content
of protocols or SAPs.
Final Rule
The final rule requires submission of the full version of the
protocol and the SAP (if a separate document) as part of clinical trial
results information, as specified in Sec. 11.48(a)(5). Submission of
the protocol and SAP allows interested users of ClinicalTrials.gov to
contextualize the reported clinical trial results information. We
emphasize that this rule does not create requirements for the
substantive content of protocols or SAPs. However, to allow for
unambiguous identification of the submitted document(s), the protocol
and SAP (if submitted as separate document) must contain a cover page
that lists the Official Title (as defined in Sec. 11.10(b)(2)), NCT
number (as defined in Sec. 11.10(a), if available), and the date of
each document. We are requiring the inclusion of this additional
information pursuant to our authority in section 402(j)(3)(D)(iii)(IV)
of the PHS Act.
The requirements for submission of the protocol and the SAP are
detailed in Sec. 11.48(a)(5) of the final rule, which stipulates that
``[a] copy of the protocol and the statistical analysis plan (if not
included in the protocol), including all amendments approved by a human
subjects protection review board (if applicable), before the time of
submission under this subsection and that apply to all clinical trial
Facility
[[Page 65002]]
Locations'' must be submitted. It further indicates that ``[t]he
responsible party must include the Official Title (as defined in Sec.
11.10(b)(2)), NCT number (as defined in Sec. 11.10(a)) (if available),
and date of the protocol and the statistical analysis plan on the cover
page of each document.'' In addition, ``[t]he responsible party may
redact names, addresses, and other personally identifiable information,
as well as any trade secret and/or confidential commercial information
(as those terms are defined in the Freedom of Information Act (5 U.S.C.
552) and the Trade Secrets Act (18 U.S.C. 1905)) contained in the
protocol or statistical analysis plan prior to submission, unless such
information is otherwise required to be submitted under this part. The
protocol and statistical analysis plan must be submitted in a common
electronic document format specified at https://prsinfo.clinicaltrials.gov.''
The protocol and, if separate, the SAP, will be posted with other
clinical trial results information, in accordance with Sec. 11.52. If
amendments are made to the protocol between the initial submission of
partial clinical trial results information and later submission of
additional partial results information, the responsible party must
submit a copy of the revised protocol at the time of the later
submission of partial results information, in accordance with Sec.
11.44(d)(3)(i). However, the Protocol and Statistical Analysis Plan
results data element in Sec. 11.48(a)(5) are excluded from the
updating requirements in Sec. 11.64(a)(2)(i). Each submitted version
of the protocol and SAP will continue to be available through the
ClinicalTrials.gov archive site.
IV. Discussion of Public Comments Related to Specific Provisions of the
Regulations
A. Subpart A--General Provisions
1. 11.2--What is the purpose of this part?
Overview of Proposal
The NPRM described in Sec. 11.2 the overall purpose of the
regulations. Implementing section 402(j) of the PHS Act (42 U.S.C.
282(j)), the rule provides the requirements and procedures for the
submission of clinical trial information for certain applicable
clinical trials and other clinical trials to the Director of the NIH to
be made publicly available through ClinicalTrials.gov.
Comments and Response
As noted earlier, more than half of the submitted comments were
identical in content. These commenters addressed proposed Sec. 11.2 by
recommending that the final rule be expanded to require registration
and results information submission for all clinical trials. They
reasoned that it was important and in the public interest for data on
all clinical trials of drugs, biological products, and devices, and not
only ``certain applicable clinical trials,'' to be posted before the
trial moves from one phase to the next. These commenters also suggested
replacing the phrase ``certain applicable clinical trials'' in proposed
Sec. 11.2 with ``all clinical trials.''
The statute required the Agency to make a number of decisions
through rulemaking, including whether to expand the requirement to
report results information to applicable clinical trials of unapproved,
unlicensed, or uncleared products, but it did not call for
consideration of whether all clinical trials should be subject to
registration and reporting requirements. Since the statute limits the
applicability to applicable clinical trials as defined, these comments
are outside the scope of the current rulemaking. Comments on the scope
of the rule are further discussed in Section III.A of this preamble,
Scope and Applicability, and in Section IV.B.2 in the discussion of
Sec. 11.22.
Final Rule
No changes are made in Sec. 11.2 of the final rule.
2. 11.4--To whom does this part apply?
Overview of Proposal
Proposed Sec. 11.4(a) specified that the regulations would apply
to any person or entity that is considered to be the ``responsible
party,'' defined in section 402(j)(1)(A)(ix) of the PHS Act, for an
applicable clinical trial that is required to be registered under Sec.
11.22 or a clinical trial for which clinical trial information is
submitted voluntarily under Sec. 11.60. Proposed Sec. 11.4(b), which
would implement section 402(j)(1)(B) of the PHS Act, required the
responsible party to communicate their identity and contact information
to the Director by submitting the Responsible Party Contact Information
data element during registration. Proposed Sec. 11.4(c) outlined
procedures for determining the responsible party for each applicable
clinical trial or other clinical trial subject to this part. In
particular, Sec. 11.4(c)(1) specified who would be considered the
sponsor and required that each applicable clinical trial or other
clinical trial must have one sponsor. Furthermore, Sec. 11.4(c)(2)
established the requirements and procedures for a sponsor to designate
a principal investigator to be the responsible party. If and when a
designated principal investigator becomes unable to meet all of the
requirements for being designated as a responsible party, proposed
Sec. 11.4(c)(3) outlined the mechanisms by which the sponsor would
become the responsible party.
Comments and Response
Commenters suggested replacing the phrase ``applicable clinical
trial'' in proposed Sec. 11.4 with ``all clinical trials.'' Commenters
also expressed their opinions regarding proposed Sec. 11.4 which
focused on the designation of a responsible party. While commenters
expressed support for assigning one responsible party per applicable
clinical trial, they sought clarification regarding procedures for when
a designated responsible party becomes unable to meet all of the
requirements under Sec. 11.4(c)(2)(i) (e.g., principal investigator
leaves the institution, principal investigator dies). Furthermore, a
commenter suggested that the responsible party remain responsible for
clinical trial information submission requirements even after leaving
his/her institution and another suggested that the responsible party be
able to change the sponsor, for example, when the principal
investigator changes institutions.
As explained in the response to comments for Sec. 11.2, section
402(j) of the PHS Act did not call for consideration of whether all
clinical trials should be subject to registration and results
information reporting requirements, and it limits the applicability to
applicable clinical trials as defined. The Agency outlines in Sec.
11.4(c)(2) and (3) of the final rule the procedures on the designation
of a responsible party. These procedures specify that in the event a
principal investigator who has been designated the responsible party no
longer meets or is no longer able to meet all the requirements of Sec.
11.4(c)(2)(i), the sponsor must withdraw the designation in the format
specified at https://prsinfo.clinicaltrials.gov (or successor site), at
which time the sponsor will be considered the responsible party unless
and until the sponsor makes a new designation. These procedures,
however, do not allow for a principal investigator who has been
designated as the responsible party to change the sponsor because Sec.
11.4(c) defines the sponsor as the default responsible party.
Consistent with the statute, the sponsor is permitted to designate a
principal
[[Page 65003]]
investigator as the responsible party. However, if the designated
principal investigator no longer meets or is no longer able to meet the
criteria for being designated a responsible party (e.g., due to
changing institutions), the role of responsible party reverts back to
the original sponsor.
Commenters also suggested that it would be more helpful if the
electronic ClinicalTrials.gov system, i.e., PRS, used by responsible
parties to register and submit results information for their trials
included a way for sponsors to designate a principal investigator as
the responsible party. Commenters also suggested that PRS
administrators should be allowed to control the settings in the
Responsible Party field so they can set the ``default'' according to
policies or preferences established by an institution.
Sponsors are not only responsible for assigning the role of
responsible party, but they must also ensure that a designated
principal investigator knows that he/she has been assigned the
responsibility and has accepted the role and designation. Given the
legal ramifications of the responsible party role, we do not believe it
is appropriate for the assignment to be set through a default mechanism
controlled through the PRS. We note that tools are available in the PRS
to help remind responsible parties, including principal investigators
designated as a responsible party, when a study record requires
attention (see https://prsinfo.clinicaltrials.gov or successor site).
We will continue to evaluate and develop tools in the PRS to help
ensure that responsible parties understand their reporting obligations.
Final Rule
Final Sec. 11.4 maintains the proposed approach of the NPRM, and
clarifies in Sec. 11.4(a) that the rule also applies to any
responsible party required by the Director to register under Sec.
11.62 to protect the public health (discussed in more detail in Section
IV.D.2). Thus, final Sec. 11.4(a) specifies that the rule applies to
the responsible party for an applicable clinical trial that is required
to be registered under Sec. 11.22, for which clinical trial
information is voluntarily submitted under Sec. 11.60 (discussed in
more detail in in Section IV.D.1), or for which the Director has
determined, consistent with Sec. 11.62, that clinical trial
information must be submitted in order to protect the public health.
The responsible party is either the sponsor of the clinical trial or a
principal investigator who meets the criteria specified in Sec.
11.4(c)(2) and has been so designated by the sponsor. In no case will
this rule apply to the sponsor or principal investigator or other
individual or entity associated with a clinical trial of drug or device
not subject to FDA jurisdiction. Although section 402(j)(4)(A) of the
PHS Act directs the Secretary to permit ``[v]oluntary submissions'' of
clinical trial information for ``a clinical trial that is not an
applicable clinical trial or that is an applicable clinical trial that
is not subject to'' the registration provisions of section 402(j)(2) of
the PHS Act, we interpret section 402(j) of the PHS Act and, thus, the
final rule as not applying to anyone who submits information to
ClinicalTrials.gov about trials of interventions that are not subject
to FDA jurisdiction under sections 505, 510(k), 515, 520(m), or 522 of
the FD&C Act, or section 351 of the PHS Act. Moreover, we interpret
section 402(j) of the PHS Act as not applying to anyone who submits
information to ClinicalTrials.gov for a study that is neither an
applicable clinical trial (including a pediatric postmarket
surveillance of a device product as defined in this part) nor a
clinical trial as defined in Sec. 11.10(a), even if it involves a drug
or device subject to sections 505, 510(k), 515, 520(m), or 522 of the
FD&C Act, or section 351 of the PHS Act. For example, section 402(j) of
the PHS Act would not apply to information submitted for a study using
a diagnostic tool that is a device product subject to section 510(k) of
the FD&C Act, such as a magnetic resonance imaging scanner, that is not
studying the device product and is not otherwise an applicable clinical
trial, clinical trial as defined in Sec. 11.10(a), or pediatric
postmarket surveillance of a device product as defined in this part.
(See the discussion of ``Studies a U.S. FDA-regulated Device Product''
in Section IV.B.4) Consistent with other statutory authorities of the
Agency and long-standing practice, however, ClinicalTrials.gov may, and
does, accept registration and results information on clinical studies,
as defined in Sec. 11.10(a), that are not subject to the requirements
of section 402(j) of the PHS Act (including under this rule).
Section 11.4(b) of the final rule implements section 402(j)(1)(B)
of the PHS Act, which provides that the Secretary ``shall develop a
mechanism by which the responsible party for each applicable clinical
trial shall submit the identity and contact information of such
responsible party to the Secretary at the time of submission of
clinical trial [registration] information.'' Section 11.4(b) provides
that the responsible party's identity and contact information must be
included as part of the clinical trial information that is submitted in
accordance with Sec. 11.28(a)(2)(iii)(B) and Sec. 11.28(a)(2)(iv)(F)
and updated in accordance with Sec. 11.64(a). Responsible party
contact information must be provided under the data element entitled
Responsible Party Contact Information (Sec. 11.28(a)(2)(iv)(F)) that,
as specified in Sec. 11.10(b)(37) includes the name, official title,
organizational affiliation, physical address (i.e., street address),
mailing address, phone number, and email address of the responsible
party or of a designated employee of the organization that is the
responsible party.
Section 11.4(c) outlines procedures for determining the responsible
party for each clinical trial subject to this part. The Agency believes
that there must be one (and only one) responsible party for each
clinical trial subject to this part for which clinical trial
information is submitted. Having only one responsible party for each
clinical trial facilitates procedural requirements during registration
and results information submission and prevents situations in which
both a sponsor and a principal investigator consider themselves the
responsible party and submit information for the same clinical trial.
Absent a responsible party, the objectives of registration and results
information submission cannot be met. The definition of responsible
party under section 402(j)(1)(A)(ix) of the PHS Act specifies, first,
that the sponsor will be the responsible party and, second, that the
principal investigator is the responsible party if delegated this role
through a designation ``by a sponsor, grantee, contractor, or
awardee.'' With regard to clinical trials, the Agency looks first to
determine who is the sponsor of the clinical trial, consistent with the
definition in this part, and assumes that such individual or entity is
the responsible party, unless the principal investigator has been
designated the responsible party in accordance with the procedure in
Sec. 11.4(c)(2). For a pediatric postmarket surveillance of a device
product that is not a clinical trial, the responsible party would be
considered the entity FDA, under section 522 of the FD&C Act, orders to
conduct the pediatric postmarket surveillance of a device product. In
the final rule, Sec. 11.4(c) clarifies that ``device'' means ``device
product.''
Section 11.4(c)(1) specifies who will be considered the sponsor.
The Agency believes that there must be a sponsor as that term is used
in section 402(j)(1)(A)(ix) of the PHS Act for each clinical trial and
that (as stated above)
[[Page 65004]]
there can be only one sponsor. Without a defined sponsor, there cannot
be a responsible party for a clinical trial because the responsible
party is defined as either the sponsor or the principal investigator
who has been so designated by the sponsor. The definition of sponsor in
Sec. 11.10(a) includes both a ``sponsor'' and a ``sponsor-
investigator'' as those terms are defined in 21 Code of Federal
Regulations (CFR) 50.3. or any successor regulation. Both definitions
in 21 CFR 50.3 refer to the sponsor as, in part, the person or entity
who ``initiates'' the clinical investigation. For purposes of this
rule, if a clinical trial is being conducted under an IND or
investigational device exemption (IDE), the IND/IDE holder is
considered to be the individual or entity who initiated the clinical
trial and, therefore, the sponsor, regardless of how the clinical trial
is being funded. For clinical trials not conducted under an IND or IDE,
the sponsor is considered to be the person or entity who initiated the
trial and would be identified as follows:
(1) Where the clinical trial is being conducted by an entity under
a research assistance funding agreement such as a grant or sponsored
research agreement, the funding recipient generally is considered to be
the initiator of the clinical trial, and therefore, the sponsor. This
is because, as a general rule, when a clinical trial is funded in this
manner, the funding recipient ``initiates'' the clinical trial process
by, for example, submitting a funding proposal and designing the
clinical trial.
(2) Where the clinical trial is being conducted by an entity under
a procurement funding agreement such as a contract, the party obtaining
the goods or services for its direct benefit or use (the funder)
generally is considered to be the initiator of the trial, and
therefore, the sponsor. This is because, as a general rule, when a
clinical trial is funded in this manner, it is the funder of the
clinical trial that initiates the clinical trial process by, for
example, contracting with another entity for that entity to conduct a
clinical trial meeting the specifications of the funder.
(3) Where there is no funding agreement supporting the clinical
trial, the person or entity who initiated the clinical trial by
preparing and/or planning the clinical trial, and who has appropriate
authority and control over the clinical trial to carry out the
responsibilities under section 402(j) of the PHS Act (including this
part) is the sponsor.
Furthermore, Sec. 11.4(c)(2) establishes the procedures for
designation of a principal investigator as the responsible party.
Section 402(j)(1)(A)(ix) of the PHS Act defines the responsible party,
as either ``the sponsor of the clinical trial'' (as defined in [21 CFR
50.3] (or any successor regulation)); or the principal investigator of
such clinical trial if so designated by a sponsor, grantee, contractor,
or awardee,'' so long as such person meets certain criteria. In order
to give practical effect to this provision, we conclude that, for any
given applicable clinical trial or other clinical trial subject to this
part, only one entity--the sponsor--can designate the principal
investigator as the responsible party. We believe this interpretation
is consistent with section 402(j) of the PHS Act because in many
situations the sponsor of the clinical trial will also be a grantee,
contractor, or awardee. In addition, interpreting this provision in a
different manner could result in situations in which both a sponsor
(e.g., an IND/IDE holder) and a principal investigator (designated by a
separate grantee, contractor, or awardee) consider themselves the
responsible party and submit information for the same clinical trial.
This would not only increase the overall burden associated with
registration, but more importantly would undermine the integrity of the
data bank and potentially cause confusion to users of the system.
Section 402(j)(1)(A)(ix) of the PHS Act permits a principal
investigator to serve as a responsible party only if he or she ``is
responsible for conducting the trial, has access to and control over
the data from the clinical trial, has the right to publish the results
of the trial, and has the ability to meet all of the requirements under
[section 402(j) of the PHS Act] for the submission of clinical trial
information.'' Accordingly, if the principal investigator does not meet
the specified conditions for serving as the responsible party, the
sponsor cannot designate the principal investigator as the responsible
party, and the sponsor must remain the responsible party. In Sec.
11.10(a) we define, for purposes of this part, the term principal
investigator to mean ``the individual who is responsible for the
overall scientific and technical direction of the study.'' We note that
under section 402(j)(1)(A)(ix) of the PHS Act, in order to be
designated the responsible party, the principal investigator must be
responsible for ``conducting the trial'' and must have ``access to and
control over the data from the clinical trial.'' We interpret ``the
trial'' to refer to the ``clinical investigation'' as defined in 21 CFR
312.3 and this part, and to mean ``the entire clinical investigation.''
Similarly, we interpret ``the data'' to mean ``all of the data,''
including data collected at all sites of a multi-site trial.
To clarify our understanding of section 402(j)(3)(C)(iv) of the PHS
Act as it relates to whether a principal investigator would be eligible
to serve as the responsible party, this section requires the
responsible party to indicate, as an element of clinical trial results
information, whether there exist ``certain agreements,'' which are
described, with certain exceptions, as ``an agreement . . . that
restricts in any manner the ability of the principal investigator,
after the completion date of the trial, to discuss the results of the
trial at a scientific meeting or any other public or private forum, or
to publish in a scientific or academic journal information concerning
the results of the trial.'' We do not view the presence of such an
agreement as necessarily disqualifying a principal investigator from
serving as the responsible party. Rather, we view only those agreements
that prevent the principal investigator from performing the functions
described in section 402(j)(1)(A)(ix)(II) of the PHS Act and Sec.
11.4(c)(2)(i) of this part or from submitting clinical trial
information or any updates to such information required by section
402(j) of the PHS Act and this part as preventing the principal
investigator from serving as the responsible party.
To provide for the orderly implementation of section
402(j)(1)(A)(ix)(II) of the PHS Act, pursuant to which the sponsor may
designate a principal investigator as the responsible party, and ensure
that the principal investigator has notice of the designation, we have
detailed the process in Sec. 11.4(c)(2)(ii) for designating a
principal investigator. It indicates that the sponsor shall provide
notice of the designation to the principal investigator and obtain
acknowledgement of the principal investigator's understanding of their
responsibilities under this part. We intend to continue to provide
mechanisms in the PRS for the sponsor and the principal investigator to
indicate the designation and the acknowledgement, respectively. The
designation by the sponsor is currently reflected in ClinicalTrials.gov
by having the principal investigator submit clinical trial information
via the sponsor's organizational account (the sponsor must provide an
account for the principal investigator within the sponsor's PRS
organizational account). The acknowledgement is reflected by having the
principal investigator list their name as the responsible party and
indicate that they were designated as the responsible party by the
sponsor.
[[Page 65005]]
This approach has been available in ClinicalTrials.gov since 2011.
If and when a designated principal investigator no longer meets or
is no longer able to meet all of the requirements of a responsible
party, Sec. 11.4(c)(3) outlines the mechanisms by which, if the
withdrawal of such designation occurs, the sponsor would become the
responsible party. This might occur if, for example, a principal
investigator dies, retires, changes jobs, or turns control of the
clinical trial data over to the sponsor. Final Sec. 11.4 modifies the
NPRM approach by clarifying in Sec. 11.4(c)(3) that the sponsor, and
not the clinical investigator, must withdraw the designation of a
principal investigator as the responsible party. Because of this
clarification, proposed Sec. 11.4(c)(3)(ii) is no longer necessary, so
Sec. 11.4(c)(3)(i) is designated as Sec. 11.4(c)(3).
We note that even if a sponsor designates a principal investigator
as the responsible party for an applicable clinical trial registered
under Sec. 11.22, there may be times when the sponsor would need to
provide the principal investigator with certain information in order
for the principal investigator to meet the obligations of the
responsible party. For example, in order for a principal investigator
who has been designated as the responsible party to satisfy the
conditions for submitting a certification for delayed submission of
results information under Sec. 11.44(b) or (c), the sponsor would
likely have to provide the investigator with information about the
conditions involving FDA action on a product application or submission,
such as approval, that would require the responsible party to submit
clinical trial results information as set forth in Sec. 11.44(b) or
(c).
Although we expect that a principal investigator who has been
designated as the responsible party to request such information from
the sponsor, we also expect a sponsor who has designated a principal
investigator as the responsible party to provide appropriate
information in a timely fashion. A principal investigator who is not
provided the information necessary to enable him or her to meet all of
the requirements for submitting and updating clinical trial information
does not meet the criteria set forth in Sec. 11.4(c)(2)(i) to serve as
the responsible party. If the sponsor does not provide the principal
investigator with the requisite information to meet the criteria under
Sec. 11.4(c)(2)(i), the principal investigator cannot be designated,
or continue to act, as a responsible party and the responsible party
would be, or would revert to, the sponsor.
3. 11.6--What are the requirements for the submission of truthful
information?
Overview of Proposal
Section 402(j)(5)(D) of the PHS Act specifies that ``clinical trial
information submitted by a responsible party under this subsection
shall not be false or misleading in any particular.'' In addition, the
NPRM described other federal laws that address the submission of false
or misleading information to the Federal Government (79 FR 69597).
Specifically, it is a prohibited act under section 301(jj)(3) of the
FD&C Act to submit clinical trial information under section 402(j) of
the PHS Act that is false or misleading in any particular. In addition,
other federal laws govern the veracity of information submitted to the
Federal Government, such as 18 U.S.C. 1001 (making it a crime to make
certain false statements to the executive, legislative, or judicial
branch of the U.S. Government).
Proposed Sec. 11.6 set out the requirements for the submission of
truthful information. Proposed Sec. 11.6(a) stated that submitted
clinical trial information must not be false or misleading and that
submission of such information may subject the responsible party to
civil or criminal liability. Proposed Sec. 11.6(b) required the
responsible party to certify that submitted information is truthful and
not misleading and that the responsible party is aware of the potential
consequences of submitting such information. The certification was
intended to ensure that responsible parties are aware of these
statutory requirements and to provide an opportunity for them to attest
to the veracity of the information at the time of submission.
Comments and Response
Commenters addressed proposed Sec. 11.6. While no commenters
disagreed with the proposal to include an explicit requirement that
submitted clinical trial information must not be false or misleading
and that a warning that submission of such information would subject
the responsible party to civil, criminal, and/or administrative
liability, commenters did address the proposal to require responsible
parties to certify that submitted information is truthful and not
misleading and that the responsible party is aware of the potential
consequences of submitting such information. Several commenters noted
that Title VIII of FDAAA did not stipulate that the Agency should
require such a certification in the context of submissions to
ClinicalTrials.gov. They also suggested that the requirement
effectively duplicated three other statutory requirements beginning
with two provisions in Title VIII of FDAAA that require the information
submitted to ClinicalTrials.gov to not be false or misleading (section
282(j)(5)(D) of the PHS Act), which is reflected in proposed Sec.
11.6(a) and the requirement that sponsors submit a certification to
accompany the product applications or submission to FDA stating that
the sponsor is in compliance with Title VIII of FDAAA (section
282(j)(5)(B) of the PHS Act), and reflected in the prohibited acts
provisions (21 U.S.C. 331(jj)(3). They also pointed to the statutory
prohibition on making false statements to the Federal Government at 18
U.S.C. 1001, which carries criminal penalties.
One commenter questioned the appropriateness of requiring
responsible parties to certify that information submitted is not
misleading due to a concern about how members of the public might react
to the information. The concern was related to the fact that the
structured nature of the database limited the responsible party's
ability to provide clarifying contextual information, which if allowed
to be provided, in the view of the commenter, would minimize the
possibility of misleading a reader about some aspect of the clinical
trial. The commenter also suggested that the proposed certification
requirement would require a responsible party to evaluate whether
providing the submitted information could ``mislead'' a member of the
public and that, if the responsible party concluded that such a result
were even remotely possible, they would be in an untenable position of
having to reconcile conflicting legal obligations (i.e., the
responsible party could not satisfy its legal obligation to submit the
clinical trial information under the PHS Act without certifying
otherwise).
Commenters suggested alternatives to the certification requirement.
One suggested that the requirement be reworked to focus on assuring
that the submitted information is ``truthful and complete'' rather than
the subjective ``not misleading.'' Another suggested that it would be
more appropriate to require the responsible party to certify that ``the
information contained in this submission is accurate to the best of the
sponsor's knowledge.'' Notwithstanding the general support expressed
for Sec. 11.6, and although we do not agree that providing structured
data entry in standard data formats could lead to misinterpretations of
the data, we
[[Page 65006]]
conclude that the commenters who addressed proposed Sec. 11.6(b)
specifically raised some valid concerns. The commenters suggested that
responsible parties are well aware that they are legally bound to
submit truthful information to the Federal Government and that a
specific attestation to the veracity of the information at the time of
information submission to ClinicalTrials.gov is unnecessary. As such,
and given the other provisions in section 402(j) of the PHS Act that
protect against the submission of false or misleading information, we
have decided to drop the requirement that the responsible party certify
that submitted information is truthful and not misleading and that the
responsible party is aware of the potential consequences of submitting
such information. With regard to the hypothetical concern that
providing structured data entry in standard data formats could lead to
misinterpretations of the data, it is important to note that we are not
aware that such misunderstandings have occurred nor did any comments
identify a specific example. Section 11.6(a) will be retained as a
stand-alone provision of the final rule.
Final Rule
The final rule eliminates proposed Sec. 11.6(b) and retains the
requirement that submitted clinical trial information must not be false
or misleading. The final rule also clarifies in Sec. 11.6 that a
responsible party who submits false and/or misleading information may
be subject to civil monetary penalties and/or to other civil or
criminal remedies available under U.S. law. Eliminating proposed Sec.
11.6(b) does not change the responsible party's obligation to be
truthful and not misleading in submissions to ClinicalTrials.gov.
4. 11.8--In what format must clinical trial information be submitted?
Overview of Proposal
Section 402(j)(3)(D)(v)(I) of the PHS Act requires the
establishment of a ``standard format'' for the submission of clinical
trial information. Section 402(j)(2)(B) of the PHS Act also requires
that clinical trial information be submitted in such a way that is
searchable by the public. Proposed Sec. 11.8 set forth the required
format for submitting clinical trial information to ClinicalTrials.gov.
The proposal specified that information must be submitted
electronically to ClinicalTrials.gov in the format specified at http://prsinfo.clinicaltrials.gov and explained that no other format would be
accepted. Although the proposal used the phrase ``form and manner''
instead of ``format,'' we are using ``format'' in the final rule to be
consistent with the language of the statute in section
402(j)(3)(D)(v)(I). As discussed in sections II.B and III.C.10 of the
NPRM, NLM is adopting a tabular, structured data entry system to
promote objective reporting, optimize data display, permit effective
searching of ClinicalTrials.gov, and facilitate cross-trial
comparisons.
Proposed Sec. Sec. 11.10, 11.28, and 11.48 specified the
individual data elements of clinical trial information that must be
submitted to ClinicalTrials.gov at the time of registration and results
information submission (and updated in accordance with proposed Sec.
11.64), including the subelements that are considered to be part of a
data element (e.g., proposed Sec. 11.10(b)(5) specifies that the Study
Design data element includes the subelements Interventional Study
Model, Number of Arms, Arm Information, Allocation, Masking, and Single
Arm Controlled).
In sections IV.B.4 and IV.C.4 of the NPRM, we described the
specific format in which data elements and subelements would be
required to be submitted to ClinicalTrials.gov. For some data elements
and subelements, responsible parties would be required to submit
information in free-text form. For other data elements and subelements,
responsible parties would be required to select the best response from
menus of options presented in ClinicalTrials.gov. The Agency also
developed a mechanism for uploading registration and results data in an
automated electronic fashion using eXtensible Markup Language (XML)
files.
We explained in the NPRM preamble that the Agency might make minor
changes from time to time to the specific format in which responsible
parties would be required to submit individual data elements and
subelements to ClinicalTrials.gov (79 FR 69598). We indicated that we
would provide prior notice and seek public comment on any proposed
changes to the format of submitting clinical trial information and that
any changes would ultimately be reflected in the PRS.
We invited comment on the specific format described in the proposed
rule for submitting data elements and subelements of proposed clinical
trial information, including comments on the benefits and burden
associated with providing proposed data elements and subelements,
whether proposed menu options are sufficient to accommodate the range
of potential entries (e.g., for different trial designs), and whether
an ``other'' option is needed in additional data elements (79 FR
69598). We also invited comment on the proposed approach described in
this section for modifying the format of submitting clinical trial
information over time.
Comments and Response
Commenters addressed the proposed format of submission. Some
comments explicitly supported the proposed rule requirements for
information to be submitted in a structured format. Other comments
addressed data formatting issues in the PRS. Some of these commenters
recommended that the PRS allow submissions in Microsoft Excel[supreg]
files, such as for adverse events, particularly because academic
medical centers are generally not familiar with XML. We note that the
PRS system has allowed for the submission of adverse event information
in spreadsheet format, including Excel, since 2013 and will continue to
allow this format.
Other commenters requested that the PRS accept submissions in the
same electronic formats as required by the Agency and other federal
funders for submissions to their own databases (e.g., Clinical Trial
Reporting Program (CTRP) for the National Cancer Institute (NCI)). This
approach of broadly accepting the same electronic format as other
systems is not feasible. Any single standard data format adopted by
ClinicalTrials.gov must provide sufficient generality and flexibility
to accommodate accurate reporting of the mandated clinical trial
information for a wide range of clinical trial designs, research areas/
domains, and funder/sponsor classes covered by the law. While the
Agency appreciates that accepting a variety of submission formats from
other federal databases may be less burdensome for responsible parties,
the PHS Act requires the final rule to establish a standard format for
the submission of clinical trial information. This standard format
will, in turn, facilitate search and comparison of entries in the
registry data bank, as is also required under the statute. Furthermore,
it is possible for other systems to map their content to the standard
data format at ClinicalTrials.gov. For example, because the data
elements used to describe a clinical trial in the NCI's CTRP are
designed to be compatible with the standard format required for
submitting clinical trial registration information to
ClinicalTrials.gov, responsible parties who have previously submitted
trial information to CTRP can submit that same information directly
into the PRS at ClinicalTrials.gov. NCI intends to continue to ensure
that the information
[[Page 65007]]
collected in CTRP is compatible with the requirements of the final
rule, while continuing to collect and maintain other information that
meets distinct CTRP purposes. NIH is also taking steps to bring more
standardization to the information obtained from clinical trial
applicants and awardees in order to enhance its stewardship of clinical
trials. These efforts will also take into consideration the data
elements in ClinicalTrials.gov.
ClinicalTrials.gov supports this information exchange by making
available to all organizations the specific data elements and their
definitions, an XML schema, an application program interface (API), and
information about validation messages. We, therefore, retain the PRS
submission format in the final rule in order to meet the requirements
of the law, but will continue to allow responsible parties who have
previously submitted clinical trial data elements to a number of other
databases that are compatible with the PRS standard format to transfer
clinical trial information automatically from those databases into
ClinicalTrials.gov.
Some commenters recommended the use of the Clinical Data
Interchange Standards Consortium (CDISC) data format to ensure
harmonization for registration and results information reporting. To
our knowledge, there is no existing standard data format that supports
the entirety of the requirements in the final rule. However, if such a
standard data format is developed and adopted by a significant number
of responsible parties, the Agency will work to provide appropriate
interfaces for providing information in that format. In general, the
PRS will accept XMLs that meet the requirements of the PRS and that
include information that satisfies the elements and subelements
required in this regulation.
A number of commenters also stressed the importance of
harmonization with international and other standard data formats for
uniformity in registration and results information submissions. Some
commenters requested that data formats be made consistent and be
harmonized with databases such as the EU EudraCT database administered
by the EMA [Ref. 70], or the WHO International Clinical Trial Registry
Platform Trial Registration Data Set (Version 1.2.1) [Ref. 73]. One
commenter requested specifically that any new data technologies and
database functionalities should be consistent with the EU and other
registration databases.
We note that the NPRM preamble identified data elements that are
consistent with the WHO Trial Registration Data Set (i.e., brief title,
official title, study design, primary disease or condition being
studied in the trial, focus of the study, intervention name, primary
and secondary outcome measures, eligibility criteria, overall
recruitment status, and secondary identifications (IDs)) (79 FR 69611
et al). These data elements are maintained in the final rule. In
addition, the Agency provided technical assistance to the EMA during
development of the EudraCT results database so that EudraCT's data
requirements are substantially aligned with the requirements for
ClinicalTrials.gov [Ref. 71]. Also, in April 2015, WHO issued a
Statement on Public Disclosure on Clinical Trial Results [Ref. 74].
Although section 402(j)(3)(D)(vi) of the PHS Act requires the Agency to
consider the status of consensus data elements set of the WHO for
reporting clinical trial results information, the WHO's April 2015
statement did not include any consensus data elements. The Agency notes
that opportunities to incorporate newer data formats in the future will
be available through the procedures described for format changes in the
section below.
One commenter requested that the Systematized Nomenclature of
Medicine--Clinical Terms (SNOMED CT[supreg]) be used for terminology,
or in the alternative ICD-10, to ensure the standard's ability to
``map'' to electronic health records. SNOMED CT[supreg] is a
comprehensive clinical terminology owned, maintained, and distributed
by the International Health Terminology Standards Development
Organization [Ref. 75], which includes NLM as the U.S. member. SNOMED
CT[supreg] is used in systems of the Federal Government for the
electronic exchange of clinical health information and is a required
standard data format in interoperability specifications of the U.S.
Healthcare Information Technology Standards Panel [Ref. 76]. Since
SNOMED CT[supreg] provides clinical terminology, it applies most
directly to the data element of ``primary disease or condition being
studied in the trial, or focus of the study'' (Sec. 11.10(b)(9)). We
note that the rule allows the use of SNOMED CT[supreg] for this data
element or any other vocabulary that has been mapped to Medical Subject
Headings (MeSH[supreg]) [Ref. 77] with the Unified Medical Language
System (UMLS) Metathesaurus. The use of ONC-certified or endorsed
terminologies is encouraged where possible, including, but not limited,
to SNOMED CT and Logical Observation Identifiers Names and Codes, known
by its acronym LOINC[supreg].
Finally, some comments requested that an ``Other'' category option
be provided for all data elements. We have instead included an
``Other'' category as menu options only for those data elements where
we believe it is necessary and appropriate. In some instances, such as
for Study Phase and Study Type, the menu list is comprehensive and no
``Other'' category is needed. An advantage of providing a comprehensive
list of substantive options, when possible, is to mitigate confusion
and potential errors during data entry. Another key advantage of using
only controlled terms as menu items is that it increases structure of
the database, thereby facilitating accurate search and complete
information retrieval. Allowing the selection of an ``Other'' option
with additional free-text elaboration can limit the specificity and
searchability of the database. Thus, we have limited the number of data
elements that provide an ``Other'' category as an option. As the nature
of clinical research methodologies and practices evolve and we gain
more experience with certain data elements, we anticipate that menu
options will likely change. As described in more detail in the final
rule discussion for Sec. 11.8, we will use a notice-and-comment
process before adding any new menu options for a data element.
Final Rule
The final rule maintains Sec. 11.8, with some modification for
further clarity, in requiring ``Information submitted under this part
must be submitted electronically to ClinicalTrials.gov, in the format
specified at https://prsinfo.clinicaltrials.gov.'' The final rule also
modifies in the section title the phrase ``form and manner'' to
``format'' to be consistent with the language used in section
402(j)(3)(D)(v)(I) of the PHS Act.
This final rule also specifies the data elements and subelements
defined in Sec. 11.10 and required by Sec. 11.28 and Sec. 11.48. In
addition, by describing the registration and results information to be
submitted to ClinicalTrials.gov, this final rule preamble specifies the
format in which information will be submitted (such as free text or
menu selections). The format specified in this final rule preamble will
be described at https://prsinfo.clinicaltrials.gov (or successor site).
The choice of providing menu options versus free-text fields and the
set of menu options offered for specific data elements and subelements
are
[[Page 65008]]
based on our experience in operating ClinicalTrials.gov and on comments
received from users of ClinicalTrials.gov, including those who
commented on the FDA draft and final guidance documents that were
issued in 2002 and 2004 [Ref. 78, 79] (79 FR 69570) and the preliminary
version of the results database and adverse event module that were
available for testing beginning in the spring of 2008 (73 FR 29525).
Some menus offer a fixed set of options without an ``Other'' option;
others offer a prespecified set of options plus an ``Other'' option. In
most cases, responsible parties selecting the ``Other'' option would be
required to provide a free-text response to elaborate on the ``Other''
selections. Some data elements without an ``Other'' option also include
an optional free-text field in which responsible parties could
voluntarily provide additional information about the option selected.
The use of menu options is intended to promote the entry of data in
a structured format that allows users to search ClinicalTrials.gov and
retrieve comparable information, consistent with the requirements of
sections 402(j)(2)(B) and (3)(D)(v)(I) of the PHS Act. Menu options
have been used in ClinicalTrials.gov since its launch and are routinely
used to improve the quality and to help ensure the completeness of data
submitted to information systems. Their use can reduce typographical
errors in data entry and minimize the data entry burden on responsible
parties by providing a set of predefined options for common entries. By
standardizing the set of available responses, they also promote the use
of consistent terminology across entries and can improve the ability of
users to search the data bank and compare entries easily across
clinical trials.
We further note that to reduce the burden on responsible parties
related to the submission of information to the data bank,
ClinicalTrials.gov accommodates both interactive, online entry of
information for a specific clinical trial and automated uploading of
information that is prepared in XML format. Responsible parties
submitting information on multiple clinical trials may upload
information that is prepared as a batch submission. ClinicalTrials.gov
also supports uploading of adverse event information using a
spreadsheet program, such as Microsoft Excel[supreg], so long as it
conforms to the specified data format of the PRS. Additional
information about submitting information to ClinicalTrials.gov is
available at https://prsinfo.clinicaltrials.gov.
As described in the NPRM, the Agency might periodically make minor
changes to the specific format in which responsible parties submit
individual data elements and subelements to ClinicalTrials.gov (79 FR
69598). Such changes would not require a responsible party to submit
different or more clinical trial information than is specified in the
final rule, but would alter the way in which the information is
entered, with the general aim of making sure the menu options contain
the most relevant, useful, and convenient options for responsible
parties and users of the system. For example, if the research community
develops a new type of clinical trial design, we might expand the list
of menu options under the Interventional Study Model subelement of the
Study Design data element to include it. If we find that many of the
free-text entries for the Why Study Stopped data element fall into a
small number of categories, we might offer them as menu options (in
addition to accepting free-text for ``Other'' reasons) to reduce the
burden of data entry and improve the consistency and comparability of
responses across registered clinical trials. We will provide prior
notice and seek public comment on any proposed changes of substantive
nature to the format of submitting clinical trial information. There
may be times when changes of a technical nature may be required (e.g.,
updates to the XML, redesign of the user interface, modifications to
PRS on-screen instructions), for which no public comments will be
sought.
5. 11.10--What definitions apply to this part?
Section 11.10 of the NPRM defined certain terms and data elements
used in the proposed part. The terms defined in proposed Sec. 11.10(a)
included terms explicitly defined in section 402(j) of the PHS Act
(e.g., ``applicable clinical trial,'' ``responsible party''); terms
used but not defined in section 402(j) of the PHS Act (e.g., ``clinical
trial''); and terms not specifically found in section 402(j) of the PHS
Act but which are important for implementing the statutory provisions.
With respect to terms not defined in the statute, we proposed
definitions to fit within the proposed framework for the expanded data
bank and for the purposes of satisfying the statutory goals, clarifying
the application and operation of this proposed rule, in particular as
related to information to be submitted to ClinicalTrials.gov, and/or
for convenience. We also referenced some terms defined under the PHS
Act and the FD&C Act and implementing regulations, as necessary.
For each term defined in proposed Sec. 11.10(a), we describe below
the proposed definition, any specific public comment(s) we received and
our response(s), and the term and definition that is adopted in Sec.
11.10(a) of the final rule. The list below is alphabetized according to
the name assigned to the term in the final rule. For example, the term
``FDA-regulated device'' proposed in the NPRM is ``U.S. FDA-regulated
device'' in the final rule, so it appears toward the end of the list.
Adverse Event
In the NPRM, we defined ``adverse event'' in Sec. 11.10(a) as
``any untoward or unfavorable medical occurrence in a human subject,
including any abnormal sign (for example, abnormal physical exam or
laboratory finding), symptom, or disease, temporally associated with
the subject's participation in the research, whether or not considered
related to subject's participation in the research.''
As we explained in the NPRM, ``adverse event'' is a term used but
not defined in section 402(j)(3)(I) of the PHS Act to describe a
certain category of clinical trial results information (79 FR 69598).
Section 402(j)(3)(I)(iii) of the PHS Act requires the reporting of both
anticipated and unanticipated adverse events. Current FDA regulations
define the term ``adverse event'' with respect to drugs, but not to
devices. (FDA regulations for devices include a different but related
term, ``suspected adverse device effect,'' that is discussed in the
definition of the term ``serious adverse event.'') FDA regulations for
IND safety reporting requirements that were issued on September 29,
2010 (75 FR 59935), and took effect on March 28, 2011 define an adverse
event as ``any untoward medical occurrence associated with the use of a
drug in humans, whether or not considered drug related'' (21 CFR
312.32(a)). In addition to defining the term ``adverse event,'' those
FDA regulations have the additional purpose of identifying
circumstances in which certain adverse events (such as those that are
serious and unexpected and that also meet the definition of a
``suspected adverse reaction,'' meaning that the adverse event must
have a reasonable possibility of being caused by the drug) must be
reported in an expedited fashion while the trial is ongoing.
The HHS Office for Human Research Protections (OHRP) has a
definition of adverse event that covers drug, device, and other
interventions and includes both anticipated and unanticipated
[[Page 65009]]
event(s) regardless of whether they are attributed to the
intervention(s) studied in the clinical trial. As discussed in OHRP's
``Guidance on Reviewing and Reporting Unanticipated Problems Involving
Risks to Subjects or Others and Adverse Events'' (January 2007), an
adverse event means ``[a]ny untoward or unfavorable medical occurrence
in a human subject, including any abnormal sign (for example, abnormal
physical exam or laboratory finding), symptom, or disease, temporally
associated with the subject's participation in the research, whether or
not considered related to the subject's participation in the research''
[Ref. 80]. The OHRP definition was adapted from the definition used by
the International Conference on Harmonization of Technical Requirements
of Pharmaceuticals for Human Use (ICH) Guideline E6, Good Clinical
Practice: Consolidated Guidance [Ref. 81] which was published by FDA as
a guidance document in the FR in 1997 (62 FR 25692). The definition,
therefore, is consistent with international norms. Although the ICH
Guidelines are intended to apply to pharmaceutical products, the OHRP
definition is intended to apply broadly to research in humans that
involves any type of intervention.
We received comments on the adverse event definition. The
commenters asserted that the definition was inconsistent with FDA's
adverse event definition. One commenter noted that the definition of
``adverse event'' was vague and requested that the rule define the term
to be consistent with IRB reporting requirements at continuing review.
We disagree. The IRB requirements cited by the commenter are described
in the OHRP guidance from which we derived the adverse event
definition; this helps ensure consistency in the submission of adverse
event information for applicable device clinical trials and applicable
drug clinical trials. As explained above, this definition is consistent
with, but not identical to, FDA's definition of ``adverse event'' for
IND safety reporting in 21 CFR 312.32(a). The definition in Sec.
11.10(a) includes not only those adverse events defined in 21 CFR
312.32 (which apply to clinical trials of drug products), but also
adverse events more broadly from research participation subject to this
part (i.e., including clinical trials of device products) and ensures
consistency with the international standard. For example, a ``suspected
adverse event,'' defined by FDA as a subcategory of ``adverse event''
that requires a reasonable possibility of being caused by the drug, is
also included under the definition of ``adverse event'' in Sec.
11.10(a).
After considering these comments, we maintain the definition of
``adverse event'' in Sec. 11.10(a) of the final rule to mean ``any
untoward or unfavorable medical occurrence in a human subject,
including any abnormal sign (for example, abnormal physical exam or
laboratory finding), symptom, or disease, temporally associated with
the subject's participation in the research, whether or not considered
related to subject's participation in the research.''
Additionally, this final rule includes a requirement to submit to
ClinicalTrials.gov summary information about anticipated and
unanticipated adverse events observed during a clinical trial (as well
as a requirement to submit information about serious adverse events),
regardless of attribution (i.e., whether or not the investigator
believes they are related to the intervention(s)). These requirements
are consistent with the definition of ``adverse event'' in the final
rule, which is not limited to adverse events that are anticipated, are
likely to have been caused by the drug product (including biological
product) or device product (or other type of intervention used in the
clinical trial), or have a reasonable possibility of being related to
the intervention under study. The definition of ``adverse event,''
which includes all adverse events regardless of possible attribution
and regardless of whether they were anticipated, advances the statutory
goal of providing more information that may be related to medical
products' potential risks.
Applicable Clinical Trial
In the NPRM, we defined ``applicable clinical trial'' in Sec.
11.10(a) to mean ``an applicable device clinical trial or an applicable
drug clinical trial.'' As we explained, this definition, which is
identical to the statutory definition in section 402(j)(1)(A)(i) of the
PHS Act, designates the scope of clinical trials that may be subject to
the requirements to submit clinical trial registration and results
information as specified in this part (79 FR 69599). However, not all
trials meeting the definition of an ``applicable clinical trial'' are
subject to the clinical trial registration and results information
submission requirements. For example, an applicable clinical trial that
reached its primary completion date on or before September 27, 2007
(i.e., the date of enactment of FDAAA) is not subject to section 402(j)
of the PHS Act, nor is an applicable clinical trial that was ongoing as
of September 27, 2007, and reached its primary completion date prior to
December 26, 2007. In addition, in proposed Sec. 11.22(b), we
described an approach for determining whether a clinical study or trial
meets the definition of an ``applicable clinical trial.''
We received comments on this definition. One commenter supported
the proposed definition. Other commenters requested that the definition
include all clinical trials, and one of these commenters further
requested that the definition be amended in the final rule to include
any human experiment introducing any form of a drug, device, biologic,
radiation, or any other form of treatment into the human body. The
definition of ``applicable clinical trial'' is set forth in section
402(j) of the PHS Act.
Based on further review and analysis, we have reconsidered whether
any expanded access use falls within the definition of ``applicable
clinical trial.'' For the following reasons, we have determined that no
expanded access use would be considered an ``applicable clinical
trial'' under section 402(j) of the PHS Act.
FDAMA (Pub. L. 105-115) contained two related provisions addressing
expanded access use. FDAMA added section 561 to the FD&C Act, which
specifically authorized the Secretary to permit investigational drugs
and investigational devices to be made available for the diagnosis,
monitoring, or treatment of serious or life-threatening diseases or
conditions under certain circumstances. These so-called ``expanded
access'' provisions were implemented by FDA through its IND and IDE
regulations (see 21 CFR 312.300-320 and 21 CFR 812.36).
FDAMA also amended section 402 of the PHS Act to require the
Secretary to establish a data bank of information on experimental drugs
for serious or life-threatening diseases and conditions. This FDAMA-
created data bank included two specified aspects: ``(A) A registry of
clinical trials (whether federally or privately funded) of experimental
treatments for serious or life-threatening diseases and conditions
under regulations promulgated pursuant to section 505(i) of the [FD&C
Act] . . .'' and ``(B) Information pertaining to experimental
treatments for serious or life-threatening diseases and conditions that
may be available--(i) under a treatment investigational new drug
application that has been submitted . . . under section 561(c) of the
[FD&C Act] . . .'' (currently section 402(i)(3) of the PHS Act). In
addition, the FDAMA data bank could include information on ``the
results of clinical trials . . . with the
[[Page 65010]]
consent of the sponsor . . .'' (currently section 402(i)(3) of the PHS
Act).
These FDAMA provisions were implemented by NIH through the creation
of ClinicalTrials.gov. The FDAMA provisions were subsequently amended
to require information on clinical trials to also include a description
of whether, and through what procedure, the manufacturer or sponsor
would make the drug available for expanded access use, particularly in
children (section 15(c)(2) of Public Law 107-109; 115 Stat. 1420
(2002)). Thus, there is a distinction reflected in section 402(i) of
the PHS Act between a clinical trial and expanded access use.
The FDAAA provision adding current section 402(j) of the PHS Act
was intended to expand the ClinicalTrials.gov data bank. The structure
and language of section 402(j) reflect congressional intent to maintain
in the data bank the same distinction between clinical trials and
expanded access use. This congressional intent is evident in section
402(j)(2)(A)(ii)(II)(gg) of the PHS Act, which states that ``in the
case of an applicable drug clinical trial, if the drug is not approved
. . . specify whether or not there is expanded access to the drug under
section 561 of the [FD&C Act] . . .'' This provision implies that
expanded access use would not itself be considered an ``applicable
clinical trial.''
For these reasons, we have concluded that expanded access use under
section 561 of the FD&C Act does not fall within the definition of
``applicable clinical trial'' under section 402(j) of the PHS Act.
However, information on the availability of investigational drug
products (including biological drug products) for expanded access will
continue to be required to be submitted to the ClinicalTrials.gov
database under authority of the section 402(j) registration
requirements.
In the final rule, the definition of ``applicable clinical trial''
in Sec. 11.10(a) is revised by the addition, at the end of the
definition, of the following statement: ``Expanded access use under
section 561 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C.
360bbb) is not an applicable clinical trial.'' Other than this change,
we maintain the proposed definition of ``applicable clinical trial'' as
the first sentence of the definition in the final rule: ``Applicable
clinical trial means an applicable device clinical trial or an
applicable drug clinical trial.'' This first sentence of the definition
is identical to the statutory definition.
We also received comments specifically on the ``applicable device
clinical trial'' or ``applicable drug clinical trial'' components of
the proposed applicable clinical trial definition. These are addressed
within the definition for each.
Applicable Device Clinical Trial
In the NPRM, we defined ``applicable device clinical trial'' in
Sec. 11.10(a) to mean (1) a prospective clinical study of health
outcomes comparing an intervention with a device subject to section
510(k), 515, or 520(m) of the FD&C Act against a control in human
subjects (other than a small clinical trial to determine the
feasibility of a device, or a clinical trial to test prototype devices
where the primary outcome measure relates to feasibility and not to
health outcomes); and (2) a pediatric postmarket surveillance as
required under section 522 of the FD&C Act.
As we explained in the NPRM, ``applicable device clinical trial''
is the term used in section 402(j)(1)(A) of the PHS Act to designate
the clinical trial of a device and FDA-ordered pediatric postmarket
surveillance of a device for which clinical trial information must be
submitted to ClinicalTrials.gov under section 402(j) of the PHS Act (79
FR 69599). The proposed rule adopted, in Sec. 11.10, the definition of
applicable device clinical trial, as provided in section
402(j)(1)(A)(ii) of the PHS Act: ``(I) a prospective clinical study of
health outcomes comparing an intervention with a device subject to
section 510(k), 515, or 520(m) of the [FD&C] Act against a control in
human subjects (other than a small clinical trial to determine the
feasibility of a device, or a clinical trial to test prototype devices
where the primary outcome measure relates to feasibility and not to
health outcomes); and (II) a pediatric postmarket surveillance as
required under section 522 of the [FD&C] Act.'' In addition, the
proposed rule in Sec. 11.10 adopted the definition of ``device'' in
section 402(j)(1)(A)(vi) of the PHS Act as ``a device as defined in
section 201(h) of the [FD&C] Act.'' We provided additional elaboration
of the interpretation of applicable device clinical trial in the NPRM.
We received several comments on this definition. One commenter
supported the proposed rule's applicable clinical trial definition with
respect to devices, particularly that only a ``prospective'' clinical
study should be considered an ``interventional study,'' and thus an
applicable clinical trial. Many commenters requested that the
applicable device clinical trial definition be expanded to include any
trials in which a device is introduced into the human body, but they
agreed that the definition should not include observational studies.
One commenter requested that the definition include small device
feasibility studies, which are explicitly excluded by the statutory
definition. Two other commenters requested that the definition include
all studies conducted under an IDE.
We have not modified the definition of ``applicable device clinical
trial'' in the final rule based on these comments. The statutory
definition explicitly states which trials fall within the definition of
an applicable clinical trial; it does not include all device clinical
trials. Section 402(j)(1)(A)(ii) of the PHS Act requires that the
device must be subject to section 510(k), 515, or 520(m) of the FD&C
Act. Section 402(j)(1)(A)(ii) of the PHS Act also explicitly excludes
certain device feasibility studies from the ``applicable device
clinical trial'' definition. A device is considered to be subject to
section 510(k), 515, or 520(m) of the FD&C Act if any of the following
is required before it may be legally marketed in the United States: (1)
A finding of substantial equivalence under section 510(k) of the FD&C
Act permitting the device to be marketed, (2) an order under section
515 of the FD&C Act approving a pre-market approval application for the
device, or (3) a humanitarian device exemption (HDE) under section
520(m) of the FD&C Act. Such devices that are considered to be subject
to section 510(k), 515, or 520(m) of the FD&C Act include significant
risk devices for which approval of IDE is required under section 520(g)
of the FD&C Act, non-significant risk devices that are considered to
have an approved IDE in accordance with 21 CFR 812.2(b), or devices
that are exempt from the submission requirements of 21 CFR 812 (79 FR
69600).
Some commenters also requested clarification of definitional
elements. One commenter requested that the rule clarify the term
``health-outcomes'' for making an applicable clinical trial
determination. We have not provided a definition of ``health outcomes''
in the final rule for the applicable device clinical trial definition.
However, in the NPRM, we explained that a ``prospective clinical study
of health outcomes'' is a clinical study in which the primary objective
is to evaluate a defined clinical outcome related to human health (79
FR 69599). For example, a clinical study of a diagnostic device (such
as an in vitro diagnostic (IVD)) in which the primary purpose is to
evaluate the ability of the device to make a diagnosis of a disease or
condition is related directly to human health and, therefore, would be
considered a clinical study ``of health outcomes'' for purposes of this
rule. We
[[Page 65011]]
will consider additional guidance on this term if our experience
reflects it is needed.
Another commenter suggested that the term ``feasibility,'' as used
in the parenthetical exclusion in the definition of ``applicable device
clinical trial,'' was described in the NPRM in a way that is more
limited than FDA guidance and requested clarification in the final
rule. The ``feasibility study'' exclusion in the definition directly
incorporates the language from section 402(j)(1)(A)(ii)(I) of the PHS
Act: ``a small clinical trial to determine the feasibility of a device,
or a clinical trial to test prototype devices where the primary outcome
measure relates to feasibility and not to health outcomes'' is not an
``applicable device clinical trial.'' We explained in the NPRM that
clinical studies designed primarily to determine the feasibility of a
device or to test a prototype device are considered by the Agency to be
clinical studies conducted to confirm the design and operating
specifications of a device before beginning a full clinical trial (79
FR 69601). Feasibility studies are sometimes referred to as phase 1
studies, pilot studies, prototype studies, or introductory trials
(although we note that the use of these terms does not necessarily mean
that the study is a feasibility study under the definition). Our
explanation of this exemption is consistent with FDA's regulation of
devices. FDA published the guidance Investigational Device Exemptions
(IDEs) for Early Feasibility Medical Device Clinical Studies, Including
Certain First in Human (FIH) Studies (October 2013) to address the
development and review of IDE applications for early feasibility
studies of significant risk devices [Ref. 82]. For the purposes of the
guidance, the guidance defines an ``early feasibility study'' as a
limited clinical investigation of a device early in development,
typically before the device design has been finalized, for a specific
indication. The guidance further defines a ``traditional feasibility
study'' as a clinical investigation that is commonly used to capture
preliminary safety and effectiveness information on a near-final or
final device design to adequately plan an appropriate pivotal study.
Section 402(j)(1)(A)(ii)(I) of the PHS Act excludes ``small clinical
trial[s] to determine the feasibility of a device, or a clinical trial
to test prototype devices where the primary outcome measure relates to
feasibility and not to health outcomes'' from the definition of
``applicable device clinical trial.'' The excluded clinical trials
described in this statutory definition appear to be consistent with the
early feasibility study definition in the guidance, but not with that
of the traditional feasibility study, which evaluates preliminary
safety and effectiveness information (i.e., for ``health outcomes'').
Therefore, it is likely that only early feasibility studies would fall
within this exclusion under the Sec. 11.10 definition of an
``applicable device clinical trial.''
Two commenters requested that the rule define ``small,'' which is
used in the definition's ``feasibility study'' exemption. One of the
commenters requested that the rule use a ``threshold'' number of
subjects indicated for the Enrollment data element based on an
empirical database review, such as not more than 20-30 subjects for a
study. The other commenter requested clarification of the term
``small'' and suggested that a device trial with at least 10 subjects
could not qualify as ``small'' for the ``feasibility study'' exemption.
We are not including a threshold number in the definition, because some
studies with an enrolled subject total exceeding a specified threshold
might be more appropriately considered a ``small feasibility study,''
while other studies with an enrolled subject total below the specified
threshold, depending on the prevalence of the disease or condition,
might not be considered ``small'' for the purposes of this exemption.
We note that a trial with at least 10 subjects would generally not be
considered ``small.''
To determine whether a device trial is an applicable device
clinical device, one comment requested clarification as to whether a
device that is solely packaged and/or labeled in the United States
would be considered ``manufactured in'' the United States. The
commenter opposed considering devices that are solely packaged and/or
labeled in the United States as ``manufacture[d] in the U.S.'' and
requested clarification in the final rule. Pursuant to section 510 of
the FD&C Act, FDA's jurisdiction extends to the ``manufacture,
preparation, propagation, compounding or processing'' of devices, which
term is defined to include ``repackaging or otherwise changing the
container, wrapper, or labeling or any . . . device package in
furtherance of the distribution of the . . . device from the original
place of manufacture to the person who makes final delivery or sale to
the ultimate consumer or user.'' The NPRM used the term ``manufacture''
as a short-hand for all device activities within FDA's jurisdiction.
Therefore, a device product that is packaged and/or labeled in the
United States would be considered ``manufactured'' in the United States
and subject to section 510(k), 515, or 520(m) of the FD&C Act.
After considering the comments, we maintain the definition of
``applicable device clinical trial'' in Sec. 11.10(a), except that we
have clarified the status of certain clinical trials of combination
products, made clear that the term ``device'' refers to a particular
manufacturer's device product, and included the applicable United
States Code (U.S.C.) statutory citations. In Sec. 11.10(a) of the
final rule, we define ``applicable device clinical trial'' to mean
``(1) [a] prospective clinical study of health outcomes comparing an
intervention with a device product subject to section 510(k), 515, or
520(m) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 360(k),
21 U.S.C. 360e, 21 U.S.C. 360j(m)) against a control in human subjects
(other than a small clinical trial to determine the feasibility of a
device product, or a clinical trial to test prototype device products
where the primary outcome measure relates to feasibility and not to
health outcomes); (2) [a] pediatric postmarket surveillance of a device
product as required under section 522 of the Federal Food, Drug, and
Cosmetic Act (21 U.S.C. 3601); or (3) [a] clinical trial of a
combination product with a device primary mode of action under 21 CFR
part 3, provided that it meets all other criteria of the definition
under this part.''
The first part of the definition in section 402(j)(1)(A)(ii)(I) of
the PHS Act defines a clinical study as an applicable device clinical
trial if it meets the following four criteria: (1) It is a prospective
clinical study of health outcomes; (2) it compares an intervention with
a device against a control in human subjects; (3) the studied device is
subject to section 510(k), 515, or 520(m) of the FD&C Act; and (4) it
is other than a small clinical trial to determine the feasibility of a
device or a clinical trial to test prototype devices where the primary
outcome measure relates to feasibility and not to health outcomes.
Except as described below with regard to pediatric postmarket
surveillances of a device product, if a clinical investigation fails to
meet one or more of these criteria, it would not be considered an
applicable device clinical trial. We have considered the meaning of
these criteria carefully and our interpretation follows.
(1) ``Prospective clinical study of health outcomes.'' First, we
interpret the term ``clinical study,'' with respect to a device
product. We interpret ``clinical study'' with respect to a device
product to mean an investigation in which a device product is used in
one or more human subjects. For the purposes of
[[Page 65012]]
interpreting the term ``clinical study,'' we consider the term ``human
subject'' to have the same meaning as the term ``subject,'' which is
defined in FDA regulations as a ``human who participates in an
investigation, either as an individual on whom or on whose specimen an
investigational device is used or as a control. A subject may be in
normal health or may have a medical condition or disease'' (see 21 CFR
812.3(p)). For the purposes of only the requirements under section
402(j) of the PHS Act and this rule, the term ``human subject'' does
not include de-identified human specimens [Ref. 83]. Note that we use
the term ``participant'' interchangeably with ``human subject'' in this
document.
The term ``study'' is often used interchangeably with the term
``investigation.'' As pertaining to device products, ``investigation''
is defined as ``a clinical investigation or research involving one or
more subjects to determine the safety or effectiveness of a device.''
(See 21 CFR 812.3(h).) Although FDA regulations pertaining to device
products do not specifically define the term ``clinical
investigation,'' that term is defined in FDA regulations pertaining to
clinical investigations of drug products (including biological
products) as ``any experiment in which a drug is administered or
dispensed to, or used involving, one or more human subjects,'' where
``experiment'' is defined as ``any use of a drug except for the use of
a marketed drug in the course of medical practice'' (see 21 CFR 312.3).
In our view, these definitions can be applied to trials of a device
product by defining a ``clinical study of a device product'' as ``any
experiment in which a device product is administered, dispensed to, or
used involving, one or more human subjects,'' defining an
``experiment'' as ``any use of a device product except for the use of a
marketed device product in the course of medical practice,'' and using
the definition of ``subject'' described above (from 21 CFR 812.3(p)).
This interpretation helps improve consistency between definitions of
the terms ``applicable device clinical trial'' and ``applicable drug
clinical trial.'' In addition, our proposed interpretation of a
``clinical study'' of a device product would include studies in which
subjects are assigned to specific interventions according to a study
protocol. Studies in which a device product is used on a patient as
part of routine medical care and not because of a study or protocol
would not be considered clinical studies for the purposes of this rule.
An example of studies that would not be considered clinical
investigations include situations in which, after a device product has
been administered to patients in the course of routine medical practice
by a healthcare provider, a researcher not associated with the
administration of the device product reviews the patients' records in
order to assess certain effects, interviews the patients to assess
certain impacts, or collects longitudinal data to assess health
outcomes.
Second, turning to our interpretation of the term ``prospective,''
we consider a prospective clinical study to be any study that is not
retrospective or, in other words, one in which subjects are followed
forward in time from a well-defined point (i.e., the baseline of the
study) or are assessed at the time the study intervention is provided.
A prospective clinical study may also have non-concurrent (e.g.,
historical) control groups. An example of a retrospective study, and
therefore not an applicable device clinical trial, is a study in which
subjects are selected based on the presence or absence of a particular
event or outcome of interest (e.g., from hospital records or other data
sources) and their past exposure to a device product is then studied.
Third, with respect to our interpretation of the phrase ``of health
outcomes,'' for the purposes of the definition of ``applicable device
clinical trial,'' we consider a ``prospective clinical study of health
outcomes'' to be a clinical study in which one or more of the primary
or secondary outcome measures are biomedical or health-related. For
example, a clinical study of a diagnostic device (such as an IVD) in
which the primary outcome measure is the number of subjects with the
correct diagnosis, would be considered a clinical study of health
outcomes for the purposes of this proposed rule.
(2) ``Comparing an intervention with a device against a control in
human subjects.'' We interpret the phrase an ``intervention with a
device'' to be an intervention in which a device product is used on a
human subject in the course of a study. As stated above, the meaning of
the term ``human subject'' is consistent with the definition of
``subject'' in 21 CFR 812.3(p), except that for the purposes of only
the requirements under this part, the term ``human subject'' does not
include de-identified human specimens. We interpret the term
``intervention'' broadly, to include various techniques for using the
device product such as, among others, device regimens and procedures
and the use of prophylactic, diagnostic, or therapeutic agents.
A clinical study is considered, or intended, to ``compare an
intervention with a device against a control in human subjects'' when
it compares differences in the biomedical or health-related outcomes
between human subjects who received an intervention that included a
device product and human subjects who received other interventions or
no intervention (e.g., comparison with another device product,
comparison with usual clinical care that did not involve a device
product). The intervention under study may be one with a device product
that has never been cleared or approved or one with a device product
that has been cleared or approved, regardless of whether the clearance
or approval is for the use being studied. Such controlled clinical
studies include not only concurrent control groups, but also non-
concurrent controls such as historical controls (e.g., literature,
patient records, human subjects as their own control) or outcomes using
objective performance criteria such as performance criteria based on
broad sets of data from historical databases (e.g., literature or
registries) that are generally recognized as acceptable values. As
discussed further in the definition of ``control or controlled,'' we
clarify for the purposes of this part that all interventional studies,
whether single or multi-arm, with a pre-specified outcome are
considered to be controlled (i.e., comparing an intervention against a
control).
As discussed above, expanded access protocols under section 561 of
the FD&C Act, under which investigational devices are made available
under certain circumstances, do not fall within the definition of
``applicable device clinical trial.''
(3) ``A device subject to section 510(k), 515, or 520(m)'' of the
FD&C Act. A device product is considered to be subject to section
510(k), 515, or 520(m) of the FD&C Act if any of the following is
required before it may be legally marketed in the United States: (1) A
finding of substantial equivalence under section 510(k) permitting the
device product to be marketed, (2) an order under section 515 of the
FD&C Act approving a pre-market approval application for the device
product, or (3) an HDE under section 520(m) of the FD&C Act. Device
products that are considered to be subject to section 510(k), 515, or
520(m) of the FD&C Act include significant risk devices for which
approval of an IDE is required under section 520(g) of the FD&C Act,
non-significant risk devices that are considered to have an approved
IDE in accordance with 21 CFR 812.2(b), or
[[Page 65013]]
device products that are exempt from the submission requirements of 21
CFR part 812.
If a clinical study of a device product includes sites both within
the United States (including any U.S. territory) and outside of the
United States, and if any of those sites is using (for the purposes of
the clinical study) a device product that is subject to section 510(k),
515, or 520(m) of the FD&C Act, we would consider the entire clinical
study to be an applicable device clinical trial, provided that it meets
all of the other criteria of the definition under this part. However, a
clinical study of a device product that is being conducted entirely
outside of the United States (i.e., does not have any sites in the
United States or in any U.S. territory) and is not conducted under an
IDE may not be a clinical study of a device product subject to section
510(k), 515, or 520(m) of the FD&C Act and, therefore, is not an
applicable device clinical trial, depending on where the device product
being used in the clinical study is manufactured. If the device product
is manufactured in the United States or any U.S. territory, and is
exported for study in another country (whether it is exported under
section 801(e) or section 802 of the FD&C Act), the device product is
considered to be subject to section 510(k), 515, or 520(m) of the FD&C
Act. If the device product is manufactured outside of the United States
or its territories, and the clinical study sites are all outside of the
United States and/or its territories, the device product would not be
considered to be subject to section 510(k), 515, or 520(m) of the FD&C
Act. A device product that is packaged and/or labeled in the United
States would be considered ``manufactured'' in the United States
subject to section 510(k), 515, or 520(m) of the FD&C Act.
(4) ``Other than a small clinical trial to determine the
feasibility of a device, or a clinical trial to test prototype devices
where the primary outcome measure relates to feasibility and not to
health outcomes.'' Clinical studies designed primarily to determine the
feasibility of a device product or to test a prototype device are
considered by the Agency to be clinical studies conducted to confirm
the design and operating specifications of a device product before
beginning a full clinical trial. Feasibility studies are not considered
applicable device clinical trials under this part.
The second part of the definition in section 402(j)(1)(A)(ii)(II)
of the PHS Act specifies that an applicable device clinical trial
includes ``pediatric postmarket surveillance as required under section
522 of the Federal Food, Drug, and Cosmetic Act.'' Postmarket
surveillances can take many forms, from literature reviews to
controlled clinical trials. Based on the statutory language, any
pediatric postmarket surveillance of a device product under section 522
of the FD&C Act, regardless of its design, is an applicable device
clinical trial.
In addition, a combination product may include a device subject to
section 510(k), 515, or 520(m) of the FD&C Act, as well as a drug
(including a biological product) subject to section 505 of the FD&C Act
or section 351 of the PHS Act (see 21 CFR 3.2(e)). Drugs (including
biological products) and devices do not lose their discrete regulatory
identities when they become constituent parts of a combination product.
In general, the regulatory requirements specific to each constituent
part of a combination product also apply to the combination product
itself. However, because some requirements of section 402(j) of the PHS
Act are different for applicable device clinical trials than for
applicable drug clinical trials, there is a need for clarity as to
which requirements apply to applicable clinical trials of combination
products that include device and drug constituent parts. In order to
provide this clarity, the final rule specifies that an applicable
clinical trial of a combination product with a device primary mode of
action under 21 CFR part 3 would be considered an applicable device
clinical trial, provided that it meets all other criteria of the
definition under Sec. 11.10(a), and likewise, a clinical trial of a
combination product with a drug primary mode of action under 21 CFR
part 3 would be considered an applicable drug clinical trial, provided
that it meets all other criteria of the definition under Sec.
11.10(a).
Applicable Drug Clinical Trial
In the NPRM, we defined ``applicable drug clinical trial'' in Sec.
11.10(a) to mean ``a controlled clinical investigation, other than a
phase 1 clinical investigation, of a drug subject to section 505 of the
Federal Food, Drug, and Cosmetic Act or to section 351 of the Public
Health Service Act, where `clinical investigation' has the meaning
given in 21 CFR 312.3 (or any successor regulation) and `phase 1' has
the meaning given in 21 CFR 312.21 (or any successor regulation).''
As we explained in the NPRM, ``applicable drug clinical trial'' is
the term used in section 402(j)(1)(A) of the PHS Act to designate a
clinical trial involving a drug (including a biological product) for
which clinical trial information must be submitted to
ClinicalTrials.gov under section 402(j) of the PHS Act (79 FR 69601).
The proposed rule in Sec. 11.10 adopted the definition of applicable
drug clinical trial in section 402(j)(1)(A)(iii)(I) of the PHS Act and
further clarified that, as specified in sections 402(j)(1)(A)(iii)(II)
and (III), the term ``clinical investigation'' has the meaning given in
21 CFR 312.3 (or any successor regulation) and ``phase I'' has the
meaning given in 21 CFR 312.21 (or any successor regulation). We did,
however, propose to replace ``phase I'' with ``phase 1,'' to be
consistent with the numbering scheme used in FDA regulations (21 CFR
312.21). We provided additional elaboration of the interpretation of
the term ``applicable drug clinical trial'' in the NPRM (79 FR 69601).
In addition, for the purposes of implementing the rule, we proposed
to treat certain clinical trials of combination products as applicable
drug clinical trials. Combination products are defined in 21 CFR
3.2(e). A combination product is comprised of a drug and a device; a
biological product and a device; a drug and a biological product; or a
drug, a biological product, and a device that, for example, are
physically, chemically, or otherwise combined or mixed and produced as
a single entity or are separate products packaged together in a single
package or as a unit (see 21 CFR 3.2(e)(1) and (2)). Because the
definition of a ``drug'' in proposed Sec. 11.10 included a biological
product, we stated in the proposed rule that a combination product
would always consist, in part, of a drug. Therefore, we proposed to
treat clinical trials of combination products that meet the definition
in 21 CFR 3.2(e) as applicable drug clinical trials, for the purposes
of the rule, as long as the clinical trial of the combination product
is a controlled clinical investigation, other than a phase 1 clinical
investigation, and the combination product is subject to sections 505
of the FD&C Act and/or section 351 of the PHS Act and/or section
510(k), 515, or 520(m) of the FD&C Act.
Several commenters addressed the proposed definition. Many
commenters requested that the definition of ``applicable drug clinical
trial'' include ``phase 0'' or phase 1 studies. One commenter requested
that the definition include all interventional drug clinical trials,
including phases 1-4, consistent with the EU Clinical Trial
Registration requirements. Several commenters requested that the
applicable drug clinical trial definition be expanded to include any
trials in which a drug is introduced into the human body, but they
agreed that the definition should
[[Page 65014]]
not include observational studies. One commenter, as noted in the
discussion of an applicable device clinical trial, opposed considering
packaging or labeling in the United States as ``manufacture[d] in the
U.S.'' and requested clarification in the final rule. Another commenter
requested that the rule clarify whether foreign trials not conducted
under an IND with a drug product not exported from the United States,
but which are subsequently included as a pivotal trial in a new drug
application (NDA) or biologics license application (BLA), should be
considered applicable clinical trials and therefore listed in Item 10
of Form FDA 3674.
Section 402(j)(1)(A)(iii)(I) of the PHS Act explicitly requires
that the drug must be subject to section 505 of the FD&C Act or section
351 of the PHS Act and explicitly exempts phase 1 studies from the
definition of ``applicable drug clinical trial'' and, therefore, from
the registration and results information submission requirements. With
respect to the comment regarding packaging or labeling, pursuant to
section 510 of the FD&C Act, FDA's jurisdiction extends to the
``manufacture, preparation, propagation, compounding or processing'' of
drugs, which term is defined to include ``repackaging or otherwise
changing the container, wrapper, or labeling or any drug package . . .
in furtherance of the distribution of the drug . . . from the original
place of manufacture to the person who makes final delivery or sale to
the ultimate consumer or user.'' The NPRM used the term ``manufacture''
as short-hand for all drug activities within FDA's jurisdiction.
Therefore, a drug product that is packaged and/or labeled in the United
States would be considered ``manufactured'' in the United States
subject to section 505 of the FD&C Act or section 351 of the PHS Act.
With respect to the question about a foreign trial, the issue of which
trials should be listed on Form FDA 3674 is outside the scope of this
rulemaking.
Commenters requested that we change the interpretation of the terms
``applicable drug clinical trial'' and ``applicable device clinical
trial'' for combination products. The commenters asked that we rely on
the ``primary mode of action'' (see 21 CFR 3.2(m)) to determine whether
a combination product is an applicable drug clinical trial or
applicable device clinical trial. We agree with these commenters and
have modified the regulations to incorporate this change. FDA
regulations in 21 CFR part 3 specify that the primary mode of action of
a combination product is the single mode of action that provides the
most important therapeutic action of the intended therapeutic effects
of the combination product. A combination product with a device primary
mode of action under 21 CFR part 3 would be considered an applicable
device clinical trial, provided that it meets all other criteria of the
definition under this part. A combination product with a drug primary
mode of action under 21 CFR part 3 would be considered an applicable
drug clinical trial, provided that it meets all other criteria of the
definition under this part.
In Sec. 11.10(a) of the final rule, we define ``applicable drug
clinical trial'' to mean a controlled clinical investigation, other
than a phase 1 clinical investigation, of a drug product subject to
section 505 of the FD&C Act (21 U.S.C. 355) or a biological product
subject to section 351 of the PHS Act (42 U.S.C. 262), where ``clinical
investigation'' has the meaning given in 21 CFR 312.3 and ``phase 1''
has the meaning given in 21 CFR 312.21. In addition, a clinical trial
of a combination product, where the combination product meets the
definition in 21 CFR 3.2(e) and has a drug primary mode of action under
21 CFR part 3 will be considered an applicable drug clinical trial, as
long as the clinical trial of the combination product is a controlled
clinical investigation, other than a phase 1 clinical investigation,
and the combination product is subject to section 505 of the FD&C Act
and/or section 351 of the PHS Act.
We interpret the definition of applicable drug clinical trial under
section 402(j)(1)(A)(iii) of the PHS Act as having four operative
elements: (1) ``Controlled''; (2) ``clinical investigation''; (3)
``other than a phase [1] clinical investigation''; and (4) ``drug
product subject to section 505 of the Federal Food, Drug, and Cosmetic
Act or section 351 of th[e] [Public Health Service] Act.'' A clinical
investigation that meets all four elements is considered an applicable
drug clinical trial. Conversely, a clinical investigation that does not
meet one or more of these criteria would not be considered an
applicable drug clinical trial. We have carefully considered these four
criteria, and our interpretation follows in an order that facilitates
the explanation.
(1) With regard to a ``drug product subject to section 505 of the
Federal Food, Drug, and Cosmetic Act or section 351 of th[e] [Public
Health Service] Act,'' Sec. 11.10(a) adopts the definition of the term
``drug'' in section 402(j)(1)(A)(vii) of the PHS Act as follows: ``a
drug as defined in section 201(g) of the [FD&C Act] or a biological
product as defined in section 351 of th[e] [PHS Act].'' Section
11.10(a) also clarifies in the definition of ``applicable drug clinical
trial'' that the term ``drug'' refers to a particular manufacturer's
drug product. In keeping with the requirements of the FD&C Act and
section 351 of the PHS Act, a drug product or a biological product is
considered to be ``subject to section 505 of the [FD&C Act] or section
351 of th[e] [PHS Act],'' as applicable, if it is the subject of an
approved NDA or licensed BLA or if an approved NDA or licensed BLA
would be required in order for that drug product or biological product
to be legally marketed. A non-prescription drug product that is or
could be marketed under an existing over-the-counter drug monograph
(see 21 CFR 330-358) is not considered ``subject to section 505 of the
[FD&C Act].''
As discussed above, a clinical trial of a combination product with
a drug primary mode of action under 21 CFR part 3 would be considered
an applicable drug clinical trial, provided that it meets all other
criteria of the definition under Sec. 11.10(a).
A drug product or a biological product that is subject to section
505 of the FD&C Act or section 351 of the PHS Act and, therefore, would
require an approved NDA or licensed BLA in order to be marketed legally
can be shipped for the purpose of conducting a clinical investigation
of that product if an IND is in effect. Drug products (including
biological products) that are being studied under an IND are considered
``subject to section 505 of the FD&C Act'' both because (in most
situations) the drug product being studied would need an approved NDA
or licensed BLA to be marketed legally, and because INDs are issued by
FDA pursuant to the authority in section 505(i) of the FD&C Act. We
note that a substance characterized by a responsible party as a dietary
supplement could be considered a ``drug'' subject to section 505 of the
FD&C Act under the applicable drug clinical trial definition if the
trial is studying a use that meets the drug definition under the FD&C
Act. Furthermore, whether a drug product or biological product is
subject to section 505 of the FD&C Act or section 351 of the PHS Act is
a different question from whether a clinical investigator would need to
obtain an IND from FDA before beginning to enroll human subjects in a
clinical investigation. Therefore, a drug product or biological product
being studied in a clinical investigation can be subject to section 505
of the FD&C Act or section 351 of the PHS Act, even if a clinical
investigation of that drug product or biological product is ``IND
[[Page 65015]]
exempt'' (i.e., does not require an IND because that clinical
investigation falls within 21 CFR 312.2(b)). Therefore, provided it
meets all other criteria of the definition, a clinical investigation of
a drug product (including a biological product) can be an applicable
drug clinical trial under section 402(j) of the PHS Act and this part,
even if it does not require an IND. Furthermore, if a sponsor chooses
to obtain an IND (issued under section 505 of the FD&C Act) for a
clinical investigation of a drug product (including a biological
product) that is not otherwise subject to section 505 of the FD&C Act
or section 351 of the PHS Act, the sponsor, in so doing, agrees to
regulation under section 505 of the FD&C Act, and that clinical
investigation thus will be considered an applicable drug clinical
trial, provided that it meets all other criteria of the definition
under this part.
If a clinical investigation of a drug product (including a
biological product) includes sites both within the United States
(including any U.S. territory) and outside of the United States, and
any of those sites is using (for the purposes of the clinical
investigation) a drug product or biological product that is subject to
section 505 of the FD&C Act or section 351 of the PHS Act, we would
consider the entire clinical investigation to be an applicable drug
clinical trial, provided that it meets all other criteria of the
definition under this part. However, a clinical investigation of a drug
product (including a biological product) that is being conducted
entirely outside of the United States (i.e., does not have any sites in
the United States or in any U.S. territory) may not be a clinical
investigation of a drug product or biological product subject to
section 505 of the FD&C Act or section 351 of the PHS Act, and
therefore not an applicable drug clinical trial, depending on where the
drug product (including biological product) being used in the clinical
investigation is manufactured. If the drug product (including a
biological product) is manufactured in the United States or any U.S.
territory, and is exported for study in another country under an IND
(whether pursuant to 21 CFR 312.110 or section 802 of the FD&C Act),
the drug product or biological product is considered to be subject to
section 505 of the FD&C Act or section 351 of the PHS Act (as
applicable), and the clinical investigation may be an applicable drug
clinical trial, provided that it meets all other criteria of the
definition under this part. If the drug product (including a biological
product) is manufactured outside of the United States or its
territories, the clinical investigation sites are all outside of the
United States, and the clinical investigation is not being conducted
under an IND, the drug product or biological product would not be
considered to be subject to section 505 of the FD&C Act or section 351
of the PHS Act, and the clinical investigation would not be an
applicable drug clinical trial. A drug product that is packaged and/or
labeled in the United States would be considered ``manufactured'' in
the United States subject to section 505 of the FD&C Act or section 351
of the PHS Act.
(2) With regard to ``clinical investigation,'' section
402(j)(1)(A)(iii)(II) of the PHS Act provides that the term ``clinical
investigation'' has the meaning given to it in 21 CFR 312.3, which
defines a ``[c]linical investigation'' as ``any experiment in which a
drug is administered or dispensed to, or used involving, one or more
human subjects.'' The regulation further defines an ``experiment'' as
``any use of a drug except for the use of a marketed drug in the course
of medical practice.''
The FDA definition of a ``clinical investigation'' of a drug
includes studies in which human subjects are assigned to specific
interventions according to a research protocol. However, a situation in
which a drug product is administered or provided to a patient as part
of routine medical care and not under a study or research protocol is
not considered a clinical investigation for the purposes of this
rulemaking. A clinical investigation does not include situations in
which, after a drug product has been administered to patients in the
course of routine medical practice by a healthcare provider, a
researcher not associated with the administration of the drug product
reviews the patients' records to assess certain effects, interviews the
patients to assess certain impacts, or collects longitudinal data to
track health outcomes. Similarly, a situation in which a healthcare
provider only observes and records the effects of the use of a marketed
drug product in the course of his or her routine medical practice is
not considered a clinical investigation under this definition. Because
these activities are not considered clinical investigations under 21
CFR 312.3, they are not considered applicable drug clinical trials
under section 402(j) of the PHS Act and this part. Accordingly, in the
approach described in Sec. 11.22(b)(2), we consider an interventional
study (or investigation) of a drug product to be one of the criteria
for determining an applicable drug clinical trial.
(3) With regard to ``controlled,'' we consider a ``controlled
clinical investigation'' to be one that is designed to permit a
comparison of a test intervention with a control to provide a
quantitative assessment of the effect of the drug product. The purpose
of the control is to distinguish the effect of a drug product from
other influences, such as spontaneous change in the course of diseases,
the placebo effect, or biased observation. The control will provide
data on what happens to human subjects who have not received the test
intervention or who have received a different intervention. Generally,
the types of controls that are used in clinical investigations are as
follows: (1) Placebo concurrent control, (2) dose-comparison control,
(3) no intervention concurrent control, (4) active intervention
concurrent control, and (5) historical control (see 21 CFR 314.126(b)).
As discussed further in the definition of ``control or controlled,'' we
are clarifying for the purpose of this part that all interventional
studies, both single-armed and multi-armed, with a pre-specified
outcome measure are considered to be controlled (i.e., comparing an
intervention against a control).
In our view, a clinical investigation designed to demonstrate that
an investigational drug product is bioequivalent to a previously
approved drug product, or to demonstrate comparative bioavailability of
two products (such as for the purposes of submitting an abbreviated new
drug application (ANDA) under 21 U.S.C. 355(j) or an NDA as described
in 21 U.S.C. 355(b)(2)), is considered to be a controlled clinical
investigation. In this case, the control generally is the previously
approved drug product. However, as discussed below, a bioequivalence or
comparative bioavailability study that falls within the scope of 21 CFR
320.24(b)(1), (2), or (3) shares many of the characteristics of a phase
1 study and is considered to be a phase 1 trial (and, therefore, not an
applicable clinical trial) in this rule.
As discussed above, expanded access protocols under section 561 of
the FD&C Act do not fall within the definition of ``applicable drug
clinical trial.''
(4) With regard to the ``other than a phase [1] clinical
investigation'' element, an applicable drug clinical trial is defined
in section 402(j)(1)(A)(iii) of the PHS Act to exclude phase 1 clinical
investigations, consistent with 21 CFR 312.21. Under 21 CFR
312.21(a)(1), a phase 1 study ``includes the initial introduction of an
investigational new drug into humans. Phase 1 studies are typically
closely monitored and may be
[[Page 65016]]
conducted in patients or normal volunteer subjects. These studies are
designed to determine the metabolism and pharmacologic actions of the
drug in humans, the side effects associated with increasing doses, and,
if possible, to gain early evidence on effectiveness. During phase 1,
sufficient information about the drug's pharmacokinetics and
pharmacological effects should be obtained to permit the design of
well-controlled, scientifically valid, phase 2 studies. The total
number of subjects and patients included in phase 1 studies varies with
the drug, but is generally in the range of 20 to 80.'' Under 21 CFR
312.21(a)(2), ``[p]hase 1 studies also include studies of drug
metabolism, structure-activity relationships, and mechanism of action
in humans, as well as studies in which investigational drugs are used
as research tools to explore biological phenomena or disease
processes.'' Clinical trials that are phase 1 studies under 21 CFR
312.21 are not applicable drug clinical trials. Clinical trials that
are identified as phase 1/phase 2 trials (i.e., trials with
characteristics of both phase 1 and phase 2 studies) are not considered
phase 1 studies and may be applicable drug clinical trials if they meet
the other specified criteria.
Under certain circumstances, a clinical investigation designed to
demonstrate that an investigational drug product is bioequivalent to a
previously approved drug product, or to demonstrate comparative
bioavailability of two products (such as for the purposes of submitting
an ANDA under 21 U.S.C. 355(j) or an NDA as described in 21 U.S.C.
355(b)(2)) will be considered to be a phase 1 clinical investigation
under 21 CFR 312.21 for the purposes of determining whether a
particular clinical trial is an applicable drug clinical trial under
section 402(j)(1)(A)(iii) of the PHS Act. Although phase 1 clinical
investigations are generally designed to fit sequentially within the
development plan for a particular drug product, and to develop the data
that will support beginning phase 2 clinical investigations, 21 CFR
312.21(a) does not limit phase 1 clinical investigations to that
situation. A bioequivalence or comparative bioavailability study that
falls within the scope of 21 CFR 320.24(b)(1), (2), or (3) shares many
of the characteristics of a phase 1 clinical investigation as described
in 21 CFR 312.21(a), and, therefore, is considered to be a phase 1
clinical investigation for the purposes of section 402(j) of the PHS
Act (including in this rule). However, a bioequivalence or comparative
bioavailability clinical trial that falls within the scope of 21 CFR
320.24(b)(4) does not share the characteristics of a phase 1 clinical
trial as described in 21 CFR 312.21(a), and, therefore, is not
considered to be a phase 1 clinical trial for the purposes of section
402(j) of the PHS Act (including in this rule).
Approved Drug
In the NPRM, we defined ``approved drug'' in proposed Sec.
11.10(a) to mean ``a drug that is approved for any indication under
section 505 of the Federal Food, Drug, and Cosmetic Act or a biological
product licensed for any indication under section 351 of the Public
Health Service Act'' (see 79 FR 69603). We received several comments on
this proposed definition asserting that a clinical trial for a new use
of an approved drug product would subject the clinical trial to the
rule's requirements. We agree that clinical trials of new uses for an
approved drug product can be subject to the rule, if the clinical trial
also meets the definition of an ``applicable drug clinical trial'' and
meets the requirements of Sec. 11.22.
In the final rule, we maintain the definition except the final rule
definition uses the term ``use'' instead of ``indication'' for further
clarity. As explained elsewhere, for the purposes of this rule only, we
interpret ``use'' to include ``indication.'' We also clarified in the
final rule that ``drug'' refers to a particular manufacturer's drug
product. We also include the applicable U.S.C. statutory citations in
the definition. Based on our experience with ClinicalTrials.gov and
routine queries from users, we are also clarifying two issues here.
First, a drug product that is not approved for any use but is
``tentatively approved'' by FDA, as described in sections
505(j)(5)(B)(iv)(II)(dd)(AA) and (BB) of the FD&C Act, is not
considered to be an approved drug for the purposes of section 402(j) of
the PHS Act, and therefore is not included in the rule's definition of
``approved drug.'' Second, a drug product approved by FDA but for which
approval is later withdrawn under section 505(e) of the FD&C Act, and
that is no longer approved for any use, is not considered an approved
drug for purposes of this part.
Approved or Cleared Device
In the NPRM, we defined ``approved or cleared device'' in Sec.
11.10(a) to mean ``a device that is cleared for any indication under
section 510(k) of the Federal Food, Drug, and Cosmetic Act or approved
for any indication under sections 515 or 520(m) of that Act.'' As we
explained, section 402(j)(2)(D)(ii)(II) of the PHS Act uses the phrase
``a device that was previously cleared or approved'' to refer to a
subset of devices that, if studied in an applicable device clinical
trial, would trigger certain requirements under this proposed part with
respect to the public posting of clinical trial information (79 FR
69603). Accordingly, we proposed defining the term ``approved or
cleared device'' to refer to any device that has been approved or
cleared under the applicable section of the FD&C Act for any
indication, even if the applicable device clinical trial studies the
device for an unapproved or uncleared use. We received several comments
on this definition asserting that a clinical trial for a new use of an
approved or cleared device would subject the clinical trial to the
rule's requirements. We agree that clinical trials of new uses for an
approved or cleared device can be subject to the rule, if the clinical
trial also satisfies the ``applicable device clinical trial''
definition elements and other triggering requirements, such as Sec.
11.22 for registration.
The final rule maintains the definition, except that the final rule
definition uses the term ``use'' instead of ``indication'' for further
clarity. As explained elsewhere, for the purposes of this rule only, we
interpret ``use'' to include ``indication.'' We also clarified that the
term ``device'' refers to a particular manufacturer's device product
and include the applicable U.S.C. statutory citations in the
definition.
Arm
In the NPRM, we defined ``arm'' in Sec. 11.10(a) to mean ``a pre-
specified group or subgroup of human subjects in a clinical trial
assigned to receive specific intervention(s) (or no intervention)
according to a protocol.'' We received no comments on this definition,
and we maintain the definition in the final rule, except the final rule
definition modifies the phrase ``human subjects'' to ``human
subject(s)'' for further clarity.
Clinical Study
The NPRM did not propose a definition of ``clinical study'' in
Sec. 11.10(a) but we are including the term and data element in this
final rule. The term ``clinical study'' is used in the statutory
definition of ``applicable device clinical trial'' (see section
402((j)(1)(A)(ii)(I) of the PHS Act), and the NPRM discussed ``clinical
study'' in the context of this definition (79 FR 69599). ``Clinical
study'' is also used in the definition of ``clinical trial'' in Sec.
11.10(a) of this regulation. To provide
[[Page 65017]]
further clarity, we define the term ``clinical study'' in Sec.
11.10(a) to mean ``research according to a protocol involving one or
more human subjects to evaluate biomedical or health-related outcomes,
including interventional studies and observational studies.'' This
definition is consistent with our discussion of the term's meaning in
the NPRM (79 FR 69599).
Clinical Trial
In the NPRM, we defined ``clinical trial'' in Sec. 11.10(a) to
mean ``a clinical investigation or a clinical study in which human
subjects are prospectively assigned, according to a protocol, to one or
more interventions (or no intervention) to evaluate the effects of the
interventions on biomedical or health-related outcomes.'' As we
explained, the definition explicitly included biomedical in addition to
health-related outcomes because we have defined the term ``clinical
trial'' to include phase 1 studies, which may measure physiological
changes that are biomedical in nature but may not be related to health
effects (79 FR 69603). We defined the term ``clinical trial'' to
include phase 1 studies, in part, because phase 1 studies may be
voluntarily submitted under section 402(j)(4)(A) of the PHS Act. The
restriction of the scope of this definition to clinical investigations
or studies in which human subjects are prospectively assigned to
interventions was intended to distinguish clinical trials
(interventional studies) from observational studies, in which the
investigator does not assign human subjects to interventions, but, for
example, observes patients who have been given interventions in the
course of routine clinical care. Observational studies may also include
retrospective reviews of patient medical records or relevant
literature.
Several commenters addressed the proposed definition. Many
commenters requested that we define ``clinical trial'' to mean any
trial in which a drug, biologic, device, radioactive material, or any
other foreign body is introduced into the human body. We do not use
this alternative definition because it includes the use of drugs,
biologics, devices, or radioactive materials provided to a patient as
part of routine medical care, such as in observational studies. Other
commenters requested that we resolve any differences between the
proposed rule's definition and the definitions of ``clinical trial''
used by NIH and ICMJE, and the definition of ``qualified clinical
trial'' used by the Centers for Medicare & Medicaid Services. These
commenters expressed concern that any differences in definitions could
lead to inconsistencies in how responsible parties must register and
report results information across these contexts. We note that the
definition of ``clinical trial'' we proposed is consistent with the
NIH, ICMJE, and WHO definitions, although the scope of what needs to be
registered differs from other contexts because of the requirements of
section 402(j) of the PHS Act. We note that the ClinicalTrials.gov
system allows for the reporting of studies that are not subject to (or
are independent of) requirements under section 402(j) of the PHS Act,
including under different timelines and with additional information,
which means that reporting in these other contexts is not impeded.
Finally, the proposed definition of ``clinical trial'' did not
distinguish between approved, licensed, or cleared uses and unapproved,
unlicensed, or uncleared uses, and therefore human testing of an
approved drug or device for a new use can fall within the scope of a
clinical trial. These clinical trials, though, must meet the definition
of an ``applicable clinical trial'' and other conditions of the
regulation in order for registration and results information reporting
to be required under section 402(j) of the PHS Act.
In the final rule, we maintain the proposed definition for
``clinical trial,'' except the final rule definition modifies the
phrase ``human subjects'' to ``human subject(s)'' for further clarity.
In terms of defining the scope of a clinical trial, we recognize that
it may sometimes be difficult to determine whether two or more closely
related studies should be considered a single clinical trial for the
purposes of this part. In general, a clinical trial has a defined group
of human subjects who are assigned to interventions, and the collected
data are assessed and analyzed, based on a protocol. However, when two
different studies use the same protocol but involve different groups of
human subjects, and the plan is to analyze the data from the two
studies separately, the two studies should be considered separate
clinical trials. This is distinct from a situation in which multiple
sites of the same clinical trial follow the same protocol with
different groups of human subjects, but the intention is to analyze the
primary outcome measure(s) with pooled data from all the study sites.
Additionally, when some (or all) human subjects from a clinical trial
are offered the opportunity to participate in an additional clinical
trial that was not part of the original protocol (e.g., a follow-on
study), and participation requires a separate consent process, the
additional clinical trial would generally be considered a separate
clinical trial.
Clinical Trial Information
In the NPRM, we defined ``clinical trial information'' in Sec.
11.10(a) to mean ``the data elements, including clinical trial
registration information and clinical trial results information, the
responsible party is required to submit to ClinicalTrials.gov under
this part.'' As we explained, section 402(j)(1)(A)(iv) of the PHS Act
expressly provides that ``[c]linical trial information'' means ``those
data elements that the responsible party is required to submit under
paragraph (2) or under paragraph (3)'' of section 402(j) of the PHS Act
(79 FR 69603). Paragraph (2) refers to registration requirements,
including the registration information that is included in proposed
Sec. 11.28, and paragraph (3) refers to results information submission
requirements, including results information in proposed Sec. 11.48.
Section 402(j)(3)(I)(v) of the PHS Act also expressly provides that
adverse event information included in the data bank pursuant to
paragraph (3)(I) ``is deemed to be clinical trial information included
in such data bank pursuant to subparagraph (C).''
We received no comments on this definition. We are clarifying on
our own initiative that clinical trial information is submitted to
ClinicalTrials.gov as specified in section 402(j) of the PHS Act and as
specified in the final regulations; we also corrected a typographical
error. Therefore, for the purposes of the final rule, clinical trial
information means ``the data elements, including clinical trial
registration information and clinical trial results information, that
the responsible party is required to submit to ClinicalTrials.gov, as
specified in section 402(j) of the Public Health Service Act (42 U.S.C.
282(j)) and this part.''
Clinical Trial Registration Information
In the NPRM, we defined ``clinical trial registration information''
in Sec. 11.10(a) to mean ``the data elements that the responsible
party is required to submit to ClinicalTrials.gov, as listed under
Sec. 11.28.'' We received no comments on this definition. We clarify
that the full set of data elements specified in Sec. 11.28 must be
submitted in order to register an applicable clinical trial for
applicable clinical trials with an initiation date on or after the
effective date of the final rule, as discussed further in section IV.F.
Effective Date, Compliance Date, and Applicability of Requirements in
this part. For
[[Page 65018]]
applicable clinical trials with an initiation date before the effective
date of the final rule, clinical trial registration information must be
submitted as specified in section 402(j)(2)(A)(ii) of the PHS Act.
Therefore, for the purposes of the final rule, clinical trial
registration information means ``the data elements that the responsible
party is required to submit to ClinicalTrials.gov, as specified in
section 402(j)(2)(A)(ii) of the Public Health Service Act (42 U.S.C.
282(j)(2)(A)(ii)) or Sec. 11.28, as applicable.''
Clinical Trial Results Information
In the NPRM, we defined ``clinical trial results information'' in
Sec. 11.10(a) to mean ``the data elements that the responsible party
is required to submit to ClinicalTrials.gov under Sec. 11.48 or, if
applicable, Sec. 11.60(a)(2)(i)(B).'' We noted that clinical trial
results information includes the adverse event information set forth in
proposed Sec. 11.48(a)(4) pursuant to section 402(j)(3)(I)(v) of the
PHS Act, which indicates that the adverse event information included in
the registry and results data bank under section 402(j)(3)(I) of the
PHS Act ``is deemed to be clinical trial information included in [the]
data bank pursuant to [section 402(j)(3)(C) of the PHS Act]'' (79 FR
69603). We received no comments on this definition.
We clarify in the final rule that the full set of data elements
under Sec. 11.48 must be submitted when results information is
submitted for applicable clinical trials with a primary completion date
on or after the effective date of the final rule, as discussed further
in section IV.F. Effective Date, Compliance Date, and Applicability of
Requirements in this part. For applicable clinical trials with a
primary completion date before the effective date of the final rule,
results information must be submitted as specified in sections
402(j)(3)(C) and 402(j)(3)(I) of the PHS Act. We also note that, under
Sec. 11.60, if a responsible party seeks to submit clinical trial
results information voluntarily for an applicable clinical trial with a
primary completion date on or after the effective date and for which
clinical trial registration information is not submitted, clinical
trial results information is defined to include the data elements in
Sec. 11.48 and the data elements in Sec. 11.60(b)(2)(i)(B) or
(c)(2)(i)(B), as applicable. Therefore, for the purposes of the final
rule, ``clinical trial results information'' means ``the data elements
that the responsible party is required to submit to ClinicalTrials.gov,
as specified in sections 402(j)(3)(C) and 402(j)(3)(I) of the Public
Health Service Act (42 U.S.C. 282(j)(3)(C) and (I)) or Sec. 11.48, as
applicable. If a responsible party submits clinical trial results
information voluntarily for a clinical trial, clinical trial results
information also means Sec. 11.60(b)(2)(i)(B) or Sec.
11.60(c)(2)(i)(B), as applicable.''
Comparison Group
In the NPRM, we defined ``comparison group'' in proposed Sec.
11.10(a) to mean ``a grouping of human subjects in a clinical trial,
other than an arm, that is used in analyzing the results data collected
during the clinical trial'' (see 79 FR 69604). We received no comments
on this definition and maintain the definition in the final rule,
except the final rule definition clarifies that the grouping ``is or
may be'' used in analyzing the results data.
We clarify that, in some trials, results data are not analyzed
according to the arms to which human subjects were assigned; the data
may be combined into other groupings for analysis. For example, in a
cross-over study, human subjects in one arm of a trial may receive
intervention X for a period of time followed by intervention Y, while
human subjects in another arm of the trial may receive intervention Y
for a period of time followed by intervention X. In such studies,
outcome measures and adverse events are often analyzed and reported by
intervention (e.g., results for human subjects when receiving
intervention X versus results for human subjects when receiving
intervention Y), rather than by arm.[Ref. 84] When submitting results
information to ClinicalTrials.gov under Sec. 11.48, responsible
parties must submit data in the way in which they were analyzed,
whether by arm (as defined above) or by comparison group. We note that,
in general, the set of comparison groups for a particular trial should
account for all of the participants in the analysis.
Completion Date
In the NPRM, we defined ``completion date'' in Sec. 11.10(a) to
mean ``for a clinical trial, the date that the final subject was
examined or received an intervention for the purposes of final
collection of data for the primary outcome, whether the clinical trial
concluded according to the pre-specified protocol or was terminated. In
the case of clinical trials with more than one primary outcome measure
with different completion dates, this term refers to the date upon
which data collection is completed for all of the primary outcomes.''
As we explained in the NPRM, ``completion date'' is defined in
section 402(j)(1)(A)(v) of the PHS Act as ``the date that the final
subject was examined or received an intervention for the purposes of
final collection of data for the primary outcome, whether the clinical
trial concluded according to the pre-specified protocol or was
terminated'' (79 FR 69604). This term has particular significance
because the responsible party is required to submit ``the expected
completion date'' to ClinicalTrials.gov upon registration (see section
402(j)(2)(A)(ii)(I)(jj) of the PHS Act) and submit clinical trial
results information for certain applicable clinical trials not later
than 1 year after the earlier of the estimated or the actual completion
date (see sections 402(j)(3)(E)(i)(I) and (II) of the PHS Act), unless
the deadline is delayed or extended using one of the mechanisms
described in Sec. 11.44. For purposes of the proposed rule, we
interpreted ``expected completion date'' in section
402(j)(2)(A)(ii)(I)(jj) of the PHS Act to be synonymous with
``estimated completion date'' in section 402(j)(3)(E)(i)(I) of the PHS
Act.
The proposed rule adopted the statutory definition of ``completion
date'' with respect to applicable clinical trials but proposed one
modification. For a clinical trial that has multiple primary outcome
measures each with a different date on which the final human subject is
examined or receives an intervention for the purposes of final data
collection, we proposed that ``completion date'' would refer to the
date on which data collection is completed for all of the primary
outcomes. The proposed rule also defined ``completion date'' for a
pediatric postmarket surveillance of a device that is not a clinical
trial as ``the date on which the final report summarizing the results
of the pediatric postmarket surveillance is submitted to FDA.'' The
proposed rule also noted that the current implementation of
ClinicalTrials.gov uses the term ``primary completion date'' to refer
to ``completion date,'' as defined in section 402(j)(1)(A)(v) of the
PHS Act. This was done in the data bank to alert those submitting data
to ClinicalTrials.gov under section 402(j) of the PHS Act that the
definition of ``completion date'' differs from that of the term ``study
completion date,'' which refers to the date on which the last subject
makes the last visit as part of the clinical trial (commonly referred
to as Last Patient Last Visit (LPLV)) and is also collected by
ClinicalTrials.gov as an optional data element [Ref. 85]. We stated
that
[[Page 65019]]
ClinicalTrials.gov would begin to use the term ``completion date'' once
the final regulations take effect and that we would include a notice on
ClinicalTrials.gov to alert responsible parties to this change in data
element name.
We received comments on this definition. Commenters expressed
concern about confusion and possible misinterpretation among
responsible parties and the public about the definition. Many of these
commenters suggested replacing ``completion date'' with ``primary
completion date'' or ``primary outcome measure completion date,''
noting that ClinicalTrials.gov has used ``primary completion date''
since the enactment of FDAAA. Several other commenters requested that
``completion date'' be redefined to mean LPLV. In addition, several
commenters supported the NPRM position that when there are multiple
primary outcome measures, the completion date is interpreted as ``the
date upon which data collection is completed for all of the primary
outcomes.'' Two commenters also requested further clarification in the
definition about the term's application to trials that are terminated,
particularly when the decision to terminate occurs more than 1 year
after the last previously enrolled subject reached the data collection
point for a primary outcome measure, but before the enrollment goals
are reached. One commenter requested clarification regarding cases in
which sample analysis occurs after a patient's last visit. We did not
receive any comments on the definition of ``completion date'' for a
pediatric postmarket surveillance of a device that is not a clinical
trial.
We generally maintain the definition of ``completion date'' in
Sec. 11.10(a) in the final rule because the statute explicitly defines
the term in this way. We have made a minor modification, consistent
with the statutory definition, to clarify that the term ``clinical
trial'' includes an applicable clinical trial; we have also clarified
that ``device'' means ``device product.'' However, we agree with the
comments, so we are clarifying that ``completion date'' is synonymous
with ``primary completion date,'' to avoid confusion among researchers
and the public. We have revised the definition of ``completion date''
to state that for purposes of this part, the term ``completion date''
is referred to as ``primary completion date.'' We use the term
``primary completion date'' in this preamble and in the codified
provisions. We also add to final Sec. 11.10(a) the term ``primary
completion date,'' which is defined as and refers to the definition of
``completion date.'' In addition, ClinicalTrials.gov will continue to
use the term ``primary completion date'' and the related data element
to refer to ``completion date,'' as defined in Sec. 11.10(a) of the
final rule. We believe that this approach balances the need to
implement terms that are specifically defined by section 402(j) of the
PHS Act while being responsive to commenters' concerns that the
statutory definition of ``completion date'' differs from the way the
term is commonly used by the clinical research community. This change
will also help clarify the meaning of the statutory term for users.
Also, with regard to comments suggesting that ``completion date''
should mean LPLV, we note that adopting such an approach would be
inconsistent with the statutory definition. However, we do add the
Study Completion Date data element, which is currently an optional data
element in ClinicalTrials.gov, as a required component of clinical
trial registration information in the final rule, and we include a
definition of ``study completion date'' in Sec. 11.10(a). (See also
the discussion of ``study completion date'' later in this preamble.) As
supported by the commenters, we also maintain the definitional element
for multiple primary outcomes as proposed, i.e., that ``completion
date'' (and ``primary completion date'') means the date on which data
collection is completed for all of the primary outcomes. As explained
in the NPRM, while this approach may delay the submission and public
availability of clinical trial results information for the earliest
primary outcomes, we expect any such delays to be minimal (79 FR
69604). Most clinical trials registered on ClinicalTrials.gov to date
specify only a single primary outcome, and those with multiple primary
outcomes have measurement time frames that are relatively close in
time.
Moreover, this approach avoids cases in which the submission of
clinical trial results information would be required before data
collection has been completed for all of the primary outcomes in a
clinical trial and before all of the results data for the primary
outcomes have been ``unblinded,'' a situation that could threaten the
scientific integrity of the clinical trial. While a responsible party
could request a good-cause extension of the results information
submission deadline in such a situation under Sec. 11.44(e), the
definition in the final rule should reduce the number of good-cause
extension requests that responsible parties might be expected to file.
Submission of results information for all primary outcomes at the same
time will also aid in the interpretation of clinical trial results
information by providing users of ClinicalTrials.gov with a more
comprehensive set of results information from the clinical trial,
rather than results information for only some of the primary outcomes.
In response to the commenters seeking clarification about the
completion date for terminated clinical trials, we do not believe that
any changes to the definition are needed. Under the definition of
``completion date,'' the completion date of a terminated trial is the
date that the final subject was examined or received an intervention
for the purposes of final collection of data for the primary outcome,
which may be on or before the trial termination. By ``final subject,''
the definition means the last subject who was examined or received an
intervention before the trial was terminated. We do not interpret this
definition as meaning that all enrolled subjects must be examined or
receive an intervention before the clinical trial is terminated in
order for the trial to reach the completion date. As described in the
discussion of Sec. 11.48 in this preamble, the responsible party would
provide the clinical trial results information that had been collected
for those subjects who were examined or received the intervention up to
the point of termination. In response to one commenter, we clarify that
if an applicable clinical trial is terminated on a date that is after
the last subject was examined or received an intervention for a primary
outcome measure, the completion date would still be the date that the
final subject was examined or received an intervention for the primary
outcome before trial termination, regardless of when the decision to
terminate was made and whether the enrollment goals were reached. In
this scenario, it is possible that the decision to terminate the trial
could occur after the standard submission deadline for study results
information under Sec. 11.44(a) (i.e., 1 year after the primary
completion date) or may occur during a period that is much less than 1
year after the primary completion date. We clarify that upon trial
termination, a responsible party may submit a request demonstrating
good-cause for extending the results information submission deadline as
specified in Sec. 11.44(e). Finally, in response to another comment,
we do not agree that the date of sample analysis after a subject's last
examination or receipt of the intervention should qualify as the
``completion date'' under the definition. We view sample analysis as a
separate
[[Page 65020]]
step from data collection; moreover, including it in the definition of
``completion date'' would be inconsistent with the statutory
definition. We also note that an analysis could be conducted months or
even years after the last subject was examined or received an
intervention, which could significantly delay the reporting of results
information under Sec. 11.44. We clarify that if there are extenuating
circumstances that cause a delay in sample analysis that interferes
with meeting the results information submission deadline specified in
Sec. 11.44, the responsible party may submit a request for extending
the results information submission deadline as specified in Sec.
11.44(e).
In Sec. 11.10(a) of the final rule, we define ``completion date''
to mean ``for a clinical trial, including an applicable clinical trial,
the date that the final subject was examined or received an
intervention for the purposes of final collection of data for the
primary outcome, whether the clinical trial concluded according to the
pre-specified protocol or was terminated. In the case of clinical
trials with more than one primary outcome measure with different
completion dates, this term refers to the date on which data collection
is completed for all of the primary outcomes. For a pediatric
postmarket surveillance of a device product that is not a clinical
trial, completion date means the date on which the final report of the
pediatric postmarket surveillance of the device product is submitted to
FDA. For purposes of this part, completion date is referred to as
`primary completion date.'''
Control or Controlled
In the NPRM, we defined ``control or controlled'' in Sec. 11.10(a)
to mean ``with respect to a clinical trial, that data collected on
human subjects in the clinical trial will be compared to concurrently
collected data or to non-concurrently collected data (e.g., historical
controls, including a human subject's baseline data), as reflected in
the pre-specified primary or secondary outcome measures.'' ``Control''
and ``controlled'' are terms used in sections 402(j)(1)(A)(ii)(I) and
(iii)(I) of the PHS Act as part of the definitions of ``applicable
device clinical trial'' and ``applicable drug clinical trial,''
respectively. As we explained in the NPRM, the definition is consistent
with (but broader than) FDA regulations that define the related
concepts of ``adequate and well-controlled studies'' for drugs (21 CFR
314.126(b)(1) and (2)) and ``a well-controlled clinical investigation''
for devices (21 CFR 860.7(f)) (79 FR 69604). FDA has also adopted as
guidance the ICH E10: Choice of Control Group and Related Issues in
Clinical Trials, which describes considerations to be used in choosing
a control group [Ref. 86]. In FDA regulations, the critical attribute
of a well-controlled clinical trial, which is the intent of any
controlled trial, is ``a design that permits a valid comparison with a
control to provide a quantitative assessment'' of the effect of the
investigational intervention (see 21 CFR 314.126(b)(2)). The FDA
regulations recognize several types of concurrent controls (e.g.,
active control) and the non-concurrent, historical control. This can
refer to a control group for which data were collected at a different
time or place but can also refer to a clinical trial in which subjects
serve as their own controls (e.g., the clinical trial measures change
from baseline).
We explained in the NPRM that, for purposes of determining whether
it is an applicable clinical trial subject to this part, the proposed
definition of ``control or controlled'' would include any clinical
trial with multiple concurrent arms (79 FR 69574 and 69605). In
addition, we explained that some single-arm clinical trials would also
be included in the definition. Such trials would include single-arm
trials of FDA-regulated products that, as specified in their protocols,
intend to evaluate an effect by comparing measures taken after an
intervention to baseline measures taken from the participants prior to
the intervention. Many of these studies have explicitly defined
``change from baseline'' measures identified in their protocols, i.e.,
they are designed to compare a measure taken after an intervention to
the participant's state prior to the intervention. Other single-arm
trials that would be considered controlled include, for example,
studies with an identified measure of ``response rate'' or measures in
which the state prior to or without the intervention can be assumed
(e.g., studies in conditions that do not resolve over the time period
studied without the intervention, such as certain types of cancer).
We proposed in Sec. 11.10(b)(5) that the Study Design data element
include, for single-armed studies, whether or not the clinical trial is
controlled, as specified by the protocol or SAP. Accordingly, proposed
Sec. 11.28(a)(i)(v) would require that a responsible party that
registers a single-arm trial provide this information. We also proposed
in Sec. 11.22(b) that a trial or study that was described accurately
by the data elements listed in Sec. 11.22(b)(1) or (2) would be
considered to meet the definition of an applicable clinical trial. We
invited comments on the proposed approach for identifying single-arm
trials that would be considered controlled and on alternative ways to
identify such trials (79 FR 69574). In particular, we invited comments
on whether there are other specific, objective features of clinical
trials that could serve as the basis for differentiating between
single-arm studies that are and are not controlled. We also invited
comments on and information about the types of single-arm trials that
meet the other criteria for an applicable clinical trial and do or do
not meet our proposed definition of ``controlled.''
We received several comments on the definition. One commenter
supported the proposed definition, particularly including single-arm
studies. Several commenters sought clarifications of the definition.
Some commenters stated that all interventional studies in humans should
be considered controlled for the purposes of the NPRM, including
single-arm studies. Some commenters indicated that ambiguity around the
definition of controlled could result in responsible parties making
erroneous, subjective assessments and failing to register or submit
information for certain trials. One of these commenters suggested that
if the definition was not clarified to include all interventional
studies, the rule should require a responsible party registering a
single-arm study without a control to explain the trial's purpose,
ethical approval, justification for the lack of a control, and
knowledge to be obtained. Another commenter requested that the final
rule amend the definition of ``controlled'' to include single-arm
studies assessing changes from historical controls or baseline or,
alternatively, revise the definition to clarify that all single-arm
trials are considered controlled. Two commenters indicated that all
single-arm interventional studies should be considered controlled by
asserting that all such studies that otherwise meet the definitional
criteria specified in proposed Sec. 11.22(b) are considered to be
applicable clinical trials. One of these commenters emphasized that
single-arm studies should be considered controlled because they compare
collected data to other information (e.g., participant baseline data);
the other commenter objected that the NPRM's proposal to distinguish
controlled clinical trials from other trials is potentially confusing--
especially in light of FDA's regulatory definition of ``[adequate and]
well-controlled'' trials, and asserted that the ``controlled''
definition was
[[Page 65021]]
unnecessary for the applicable clinical trial determination. The
commenter also noted that removing the ``controlled'' criterion and
requiring results information reporting for all trials would better
align the rule to the EU Clinical Trials Regulation. Finally, several
commenters stated that no control groups should be allowed in clinical
trials involving life-threatening conditions.
Other commenters asserted that the current definition of ``control
or controlled'' is too broad. One stated that only multi-armed studies
are controlled and that the standard use of the term ``controlled'' in
the scientific community worldwide includes a comparison group. The
commenter requested that for any single arm studies to be defined as
controlled, a separate proposed rule with this approach should be
issued for comment. Two commenters also expressed concerns that the
meaning of ``controlled'' in the NPRM's definition differed from the
FDA's definition of ``adequate and well controlled,'' and one suggested
harmonizing the final rule with the EU Clinical Trials Regulation
requirements for results information reporting but limiting the scope
to ``adequate and well controlled'' studies under 21 CFR 314.126.
Another commenter suggested that the proposed definition may be too
broad and that it could conceivably encompass any interventional study
in which patient data are captured at baseline and post-intervention.
The commenter suggested that to be included in the definition, a
single-arm trial would need to be able to plausibly distinguish the
effect of an intervention from other causes and, furthermore, that the
definition could be revised to be limited to trials ``designed to
permit a comparison of a test intervention with a control to provide a
quantitative assessment of the effect of an intervention.'' The
commenter also requested that NIH provide additional guidance for
responsible parties on how to determine whether the study is
controlled. Another commenter stated that single-arm phase 2 studies
should be considered controlled only if they involve the comparison of
primary and secondary endpoints and adverse events with a specific
historical cohort. The commenter stated that a trial should not be
considered controlled simply by the use of a pre-specified benchmark
for the primary endpoint.
We have reconsidered our proposed approach based on the comments
and determined that all interventional studies with pre-specified
outcome measures should be considered controlled under the definition
in the final rule, whether the trial has a single group of human
subjects or involves two or more concurrent groups of human subjects.
We agree with those comments suggesting that any single-arm
interventional trial with pre-specified outcome measure(s) be
considered controlled since it implicitly or explicitly compares the
effect of the intervention to some other information (e.g., patient
baseline). Under our definition of ``interventional,'' the effect of
the intervention on biomedical or other health-related outcomes is
evaluated according to a research protocol. In order to assess the
effect of the experimental intervention, plans for single-arm trials
identify how the outcomes will be measured. Either explicitly or
implicitly, the measured outcomes are compared with either the patients
themselves prior to the intervention or historical data from other
patients (or subjects). Therefore, a single-arm interventional study
with pre-specified outcome measure(s) would always involve the use of
some type of control to evaluate the intervention's effect.
This revised approach simplifies the rule's application by making
it clearer, less subjective, and easier for responsible parties to
implement. For example, the revised approach eliminates the need for a
responsible party to rely on a subjective determination of
``controlled'' for single-group studies. In addition, the approach
minimizes the chances of an applicable clinical trial not being
registered (and subsequently not reporting results information). The
approach also harmonizes the definition of ``control or controlled''
for trials of drugs and device products. Importantly, we believe the
approach supports the purpose of the provisions of section 402(j) of
the PHS Act to make more information about clinical trials available to
the public. Accordingly, Sec. 11.10(a) of the final rule defines
``control or controlled'' to include not only concurrent control
groups, but also non-concurrent controls, which would include all
single-arm clinical trials with pre-specified outcome measures. In
addition, the following clarification is added to the end of the
definition: ``For purposes of this part, all clinical trials with one
or more arms and pre-specified outcome measure(s) are controlled.'' We
wish to note, however, that although in certain circumstances some
types of expanded access use under section 561 of the FD&C Act arguably
might fall within this definition, as discussed above, expanded access
use is not considered to fall within the definition of ``applicable
drug clinical trial.''
The definition of ``control or controlled'' in the final rule is
consistent with the types of controls recognized by FDA and the ICH E10
guidance (i.e., recognition of both concurrent and non-concurrent
controls) [Ref. 86]. The definition, however, is necessarily broader
than the definition of ``adequate and well-controlled'' used in FDA
regulations and the ICH E10 guidance because the purpose of this term,
as used in this rule, is different from the more limited circumstances
in which use of a non-concurrent control constitutes an ``adequate and
well-controlled'' clinical trial, i.e., one that might serve to support
marketing authorization. Our definition does not reflect a
consideration of the adequacy or appropriateness of the control or the
adequacy of the study design, e.g., whether adequate steps were taken
to minimize bias. Because the transparency goals underlying this final
rule also apply to clinical trials that may not be considered
``adequate and well-controlled'' under FDA regulations, we conclude
that responsible parties are required to register and submit results
information for such trials. Therefore, the definitions of ``applicable
device clinical trial'' and ``applicable drug clinical trial'' include
clinical trials with pre-specified outcome measures, whether using
concurrent or non-concurrent controls, regardless of whether they would
be considered ``adequate and well-controlled.''
Device
In the NPRM, we defined ``device'' in Sec. 11.10(a) to mean ``a
device as defined in section 201(h) of the Federal Food, Drug, and
Cosmetic Act (21 U.S.C. 321(h))'' as specified in section
402(j)(1)(A)(vi) of the PHS Act (see 79 FR 69668). We received no
comments on this definition, and we retain it without modification in
the final rule.
Director
In the NPRM, we defined ``Director'' in Sec. 11.10(a) to mean the
NIH Director or any official of the NIH to whom the NIH Director
delegates authorities granted in 42 U.S.C. 282(j) (see 79 FR 69668). We
received no comments on this definition, and we maintain it in the
final rule, except that we clarify the statutory reference as ``section
402(j) of the Public Health Service Act (42 U.S.C. 282(j)).''
Drug
In the NPRM, we defined ``drug'' in Sec. 11.10(a) to mean ``a drug
as defined in
[[Page 65022]]
section 201(g) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C.
321(g)) or a biological product as defined in section 351 of the Public
Health Service Act (42 U.S.C. 262),'' as specified in section
402(j)(1)(A)(vii) of the PHS Act (see 79 FR 69668). We received no
comments on this definition, and we retain it without modification in
the final rule.
Enroll or Enrolled
In the NPRM, we defined ``enroll or enrolled'' in Sec. 11.10(a) to
mean ``a human subject's agreement to participate in a clinical trial,
as indicated by the signing of the informed consent document(s).'' As
we explained, ``enroll or enrolled'' is a term used in section
402(j)(1)(A)(viii)(I) of the PHS Act as part of the definition of
``[o]ngoing'' and in 402(j)(2)(C)(ii) of the PHS Act as one of the
criteria used to establish the deadline by which a responsible party is
required to submit clinical trial registration information (79 FR
69605).
We received comments on this definition. Several commenters
asserted that the proposed definition of ``enrolled'' may be
inconsistent with the way the term is used for presenting information
about device studies in the Summary of Safety and Effectiveness or the
510(k) Summary, which are publicly available on FDA's Web site and to
which ClinicalTrials.gov is required to link. The commenters stated
that device trials can include subjects who, according to the trial
design, provide consent for screening but enroll only those subjects
who subsequently pass screening. The commenters asserted that the
definition of ``enrolled'' proposed in the NPRM would require the
inclusion of those subjects who provide consent for screening but do
not pass screening, thereby resulting in an inconsistency in enrollment
numbers reported on the ClinicalTrials.gov Web site and FDA's 510(k)
Summary or Summary of Safety and Effectiveness, which would lead to
confusion.
We acknowledge that there may be differences in the numbers of
participants who sign an informed consent, are screened for
participation, and are eligible to participate in the clinical trial.
Therefore, we clarify that the definition of ``enroll or enrolled''
does not include ``potential subjects who are screened for the purpose
of determining eligibility for the trial but do not participate in the
trial, unless otherwise specified by the protocol.''
We note that, in some cases, there may be a separate informed
consent document for trial screening and trial participation; the
signing of the latter aligns with the proposed definition. We clarify
that when there is only one informed consent for both trial screening
and trial participation, and it is signed prior to participant
screening, a participant is not considered enrolled until he or she has
met all the eligibility criteria assessed during screening, unless the
participant is considered enrolled specifically by the protocol. We
clarify that for the purposes of the registration submission
requirement in Sec. 11.24, clinical trial registration information is
required to be submitted no later than 21 calendar days after the first
subject signs the informed consent form for trial participation. When
there is only one informed consent for both trial screening and trial
participation, we clarify that clinical trial registration information
is required to be submitted pursuant to Sec. 11.24 no later than 21
calendar days after the first subject signs the informed consent form
and begins trial participation, in accordance with the protocol.
Commenters also stated that the definition of ``enroll or
enrolled'' should be expanded to include ``unless specifically defined
differently in the protocol.'' The commenters asserted that not all
studies consider the signing of informed consent to be the point of
enrollment, and that the signing of informed consent may not be
required. Moreover, based on these particular comments, we believe the
wording of the proposed definition may inadvertently suggest that a
written signature is the only acceptable confirmation of a subject's
consent to participate. We have modified the definition to account for
situations in which consent is provided by a subject's legally
authorized representative (e.g., a family member) because the subject
is not able to provide informed consent because of, for example, mental
incapacity. To address these and the previous comments, we are revising
the definition of ``enroll or enrolled'' to mean ``a human subject's,
or their legally authorized representative's, agreement to participate
in a clinical trial following completion of the informed consent
process as required in 21 CFR part 50 and/or 45 CFR part 46, as
applicable. For the purposes of this part, potential subjects who are
screened for the purpose of determining eligibility for the trial, but
do not participate in the trial, are not considered enrolled unless
otherwise specified by the protocol.''
Human Subjects Protection Review Board
In the NPRM, we defined ``human subjects protection review board''
in Sec. 11.10 to mean an ``institutional review board (IRB) as defined
in 21 CFR 50.3 and 45 CFR 46.102 (or any successor regulation), as
applicable, or equivalent independent ethics committee that is
responsible for ensuring the protection of the rights, safety, and
well-being of human subjects involved in a clinical investigation and
is adequately constituted to provide assurance of that protection.'' We
proposed to include this definition to clarify the scope of the review
boards for which Human Subjects Protection Review Board Status must be
submitted under Sec. 11.28 (79 FR 69605). We did not receive any
comments on this definition, but for further clarity we are modifying
the definition in the final rule to mean ``an institutional review
board (IRB) as defined in 21 CFR 50.3 or 45 CFR 46.102, as applicable,
that is responsible for assuring the protection of the rights, safety,
and well-being of human subjects involved in a clinical trial and is
adequately constituted to provide assurance of that protection. An IRB
may also be known as an `independent ethics committee.' '' For clinical
trials conducted in the United States or under an IND or IDE, the term
``human subjects protection review board'' means an IRB, as defined in
the cited regulations issued by FDA and HHS. For clinical trials
conducted outside the United States or which are otherwise not subject
to the FDA and/or HHS regulations for IRBs, the term refers to other
independent ethics committees that are responsible for ensuring the
protection of the rights, safety, and well-being of human subjects
involved in a clinical investigation and are adequately constituted to
provide assurance of that protection. This phrasing is consistent with,
but not identical to, the definition of the term ``independent ethics
committee'' in FDA regulations for INDs (see 21 CFR 312.3). It is also
consistent with longstanding use of the term ``human subjects
protection review board'' on ClinicalTrials.gov, which instructed
registrants to provide information about ``[a]ppropriate review
boards[, including] an Institutional Review Board, an ethics committee
or an equivalent group that is responsible for review and monitoring of
this protocol to protect the rights and welfare of human research
subjects'' [Ref. 85].
Interventional
In the NPRM, we defined ``interventional'' in Sec. 11.10 to mean
``with respect to a clinical study or a clinical investigation, that
participants are assigned prospectively to an intervention or
interventions according
[[Page 65023]]
to a protocol to evaluate the effect of the intervention(s) on
biomedical or other health related outcomes.'' The term
``interventional'' is used in Sec. 11.22 as one of the elements (i.e.,
interventional Study Type) used to determine whether a clinical study
or a clinical investigation is an applicable clinical trial that is
required to be registered. We proposed to define this term to
distinguish interventional studies from observational studies, as those
terms are used in the clinical research community (79 FR 69605).
Observational studies consist of medical research in which the
investigator does not assign human subjects to interventions.
Observational studies include prospective cohort studies in which
individuals received interventions as part of their medical care, after
which the investigator studies prespecified outcomes to examine the
impact of those interventions. Observational studies also include
retrospective reviews of patient medical records or relevant
literature. In contrast, in interventional studies, a researcher
assigns subjects to specific interventions (e.g., placebo, routine
medical care, or no intervention) according to a study protocol for the
purposes of the investigation. We explain in the preamble discussion
for the definition of ``protocol'' in Sec. 11.10(a) of the final rule
that a less formal research plan would also be considered a protocol
for the purposes of this part, including the definition of
``interventional.''
We received comments addressing the definition. Several commenters
requested that the definition of ``interventional'' include a study
(other than an observational study) of any approved or unapproved drug,
biologic, device, radionuclide, or any other substance that is
introduced into the human body during the study's experimental phase
(i.e., phase 0 through phase 4). As described in the preamble
discussion for the definition of ``applicable drug clinical trial,''
phase 0 and 1 studies are not included in the applicable clinical
trials that must be registered under Sec. 11.22, but such studies may
still meet the definition of ``interventional.'' The definition of
``interventional'' in the NPRM is generally consistent with what the
commenters recommended, except that we provided more detail to help
responsible parties apply the definition, including that interventional
studies are those that: (1) Prospectively assign participants to an
intervention, (2) do so according to a protocol, and (3) evaluate the
intervention's effect on biomedical or other health-related outcomes.
The commenters also described various types of observational studies
that they believed would be excluded from this definition, including
studies evaluating patients' responses independent of the actual
ongoing clinical trial or other activities that have no direct
interaction with the human body, but little detail was provided about
these examples. However, we note that certain studies described by
commenters did seem to fit the definition of ``observational'' (but not
``interventional'') because assignment to the intervention was based on
routine care instead of a protocol, such as a study of patients
receiving an intervention as part of routine medical care to assess any
correlation between certain biomarkers and the intervention's effect.
Similarly, a commenter requested that the final rule clarify
aspects of the ``prospectively assigned to the intervention per
protocol'' component of the definition. The commenter asked
specifically whether an intervention would be considered
``prospectively assigned'' if the administration of the test article
began before subjects participated in the study (i.e., the study
assessed the effect of a therapy that was ongoing at the time of
subject recruitment) and whether a drug provided as part of routine
medical care would meet the requirement of being ``prospectively
assigned'' if provision of the drug it occurred after subjects become
research participants. In general, the timing of the intervention's
administration in these cases would not be considered as relevant as
how decisions for the participant to receive the intervention were
made. If the decision for the participant to receive the intervention
was based on routine medical care and not on assignment according to a
protocol or research plan, the study would generally not be considered
interventional. We note that there may be other aspects of the study
design that were not described by the commenter that would otherwise
cause the study to meet the definition of ``interventional'' (e.g.,
other interventions are simultaneously being evaluated for their effect
on outcomes related to human health, such as an IVD test). We also
clarified in the NPRM that a study would meet the definition of
``interventional'' if assignment to the intervention is determined by
the researcher based on a formal protocol or research plan, even when
the medical products being studied are being used in a manner
considered to be the standard of care (79 FR 69605). We also note, as
discussed in Section V, that we will issue more guidance in the future
on examples of applicable clinical trials for the checklist described
in Sec. 11.22.
Another comment requested clarification of the meaning of
``biomedical or other health-related outcomes.'' We believe our
explanation of ``a prospective clinical study of health outcomes'' for
the definition of ``applicable device clinical trial'' is informative.
In the NPRM, we explained that a ``prospective clinical study of health
outcomes'' is a ``clinical study in which the primary objective is to
evaluate a defined clinical outcome related to human health'' (79 FR
69599). For example, a clinical study of a diagnostic device (such as
an IVD) in which the primary purpose is to evaluate the ability of the
device to make a diagnosis of a disease or condition is related
directly to human health and, therefore, would be considered a clinical
study of health outcomes for purposes of this rule.
After considering these comments, we maintain the definition of
``interventional'' in the final rule to mean ``with respect to a
clinical study or a clinical investigation, that participants are
assigned prospectively to an intervention or interventions according to
a protocol to evaluate the effect of the intervention(s) on biomedical
or other health-related outcomes.'' For the purposes of this part, we
use the term ``clinical trial'' to refer to interventional studies to
the exclusion of observational studies. (See the definition of
``clinical trial.'') The term ``interventional'' is one of the
responses that can be submitted as part of the Study Type data element
that is included as clinical trial registration information under Sec.
11.28 and defined in Sec. 11.10. Responsible parties must indicate
whether a study being registered is ``interventional'' or
``observational'' or is expanded access (see the discussion below). A
study that is designated as ``interventional'' can be an applicable
clinical trial if it meets the other criteria for an applicable
clinical trial that are specified in this part. (See the definitions of
``applicable device clinical trial'' and ``applicable drug clinical
trial.'') A study that is designated ``observational'' can be an
applicable clinical trial only if it is a pediatric postmarket
surveillance of a device product as defined in this part. (See the
definition of ``pediatric postmarket surveillance of a device
product.'')
Investigational Device Exemption (IDE)
In the NPRM, we defined ``Investigational Device Exemption (IDE)''
in Sec. 11.10(a) to have ``the meaning given in 21 CFR 812, or any
[[Page 65024]]
successor regulation'' (see 79 FR 69668). We did not receive any
comments on this definition, and we maintain it in the final rule.
Investigational New Drug Application (IND)
In the NPRM, we defined ``Investigational New Drug Application
(IND)'' in Sec. 11.10(a) to have ``the meaning given in 21 CFR 312.3,
or any successor regulation'' (see 79 FR 69668). We did not receive any
comments on this definition, and we maintain it in the final rule.
NCT Number
In the NPRM, we defined ``NCT number'' in Sec. 11.10(a) to mean
``the unique identification code assigned to each record in
ClinicalTrials.gov, including a record for an applicable clinical
trial, a clinical trial, or an expanded access program'' (79 FR 69606).
``NCT number'' refers to the term ``National Clinical Trial number''
used in section 402(j)(2)(B)(i)(VIII) of the PHS Act. We did not
receive any comments on this definition, and we maintain it in the
final rule.
Since its launch in 2000, ClinicalTrials.gov has assigned each
submitted clinical trial record a unique identifier once quality review
procedures have been completed for the submitted information. While the
identifier was originally called a ``National Clinical Trial number,''
that nomenclature was soon changed to ``NCT number'' in recognition of
the fact that ClinicalTrials.gov receives clinical trial information
about trials being conducted in countries other than the United States
and accommodates the registration of clinical studies other than
clinical trials (e.g., observational studies). NCT numbers are used in
many contexts to refer to clinical trial records or other types of
records (e.g., observational studies, expanded access programs) that
are accepted by ClinicalTrials.gov. Under the ICMJE registration
policy, for example, journals publishing original papers on the results
of clinical trials require the authors to include in their manuscripts
a unique identification number assigned by a recognized clinical trial
registry as evidence that the trial has been registered in compliance
with the ICMJE policy [Ref. 1, 2]. For trials registered on
ClinicalTrials.gov, this unique identifier is the NCT number. When
published in journal articles, NCT numbers are also included in the
Medical Literature Analysis and Retrieval System Online records and are
searchable through PubMed [Ref. 87]. Furthermore, section 402(j)(5)(B)
of the PHS Act specifies that ``such certification [to accompany drug,
biological product, and device applications or submissions to FDA]
shall include the appropriate National Clinical Trial control
numbers.''
Ongoing
In the NPRM, we defined ``ongoing'' in Sec. 11.10(a) to mean
``with respect to a clinical trial of a drug or a device and to a date,
that one or more human subjects is enrolled in the clinical trial, and
the date is before the completion date of the clinical trial.'' As we
explained in the NPRM, this proposed definition is the same as the
statutory definition, except the term ``human subjects'' has been
substituted for the term ``patients'' that is used in section
402(j)(1)(A)(viii) of the PHS Act (79 FR 69606). The reason for this
change is that clinical trials may include healthy volunteers as well
as human subjects who might be considered ``patients.'' With respect to
a pediatric postmarket surveillance of a device product, we defined the
term ``ongoing'' to mean ``a date between the date on which FDA
approves the plan for conducting the surveillance and the date on which
the final report is submitted to FDA.''
We received comments addressing this definition. Two commenters
asked that we clarify the definition and asserted that researchers
consider trials to be ongoing even after the statutorily defined
completion date. We note, though, that a trial cannot be considered
ongoing in accordance with the statutory definition if the date is on
or after the primary completion date (see the explanation above with
regard to use of the term ``primary completion date''). Therefore, on
or after the primary completion date, trials would not be considered
ongoing for the purposes of this part and the applicable requirements.
After considering these comments, we maintain the NPRM definition
of ``ongoing,'' except that (as discussed previously) we replace
``completion date'' with ``primary completion date,'' consistent with
the definition of ``completion date'' in this section, and we clarify
that ``drug'' means ``drug product'' and ``device'' means ``device
product.'' We define ``ongoing'' in the final rule to mean ``with
respect to a clinical trial of a drug product or a device product and
to a date, that one or more human subjects is enrolled in the clinical
trial, and the date is before the primary completion date of the
clinical trial. With respect to a pediatric postmarket surveillance of
a device product, ongoing means a date between the date on which FDA
approves the plan for conducting the surveillance and the date on which
the final report is submitted to FDA.''
Outcome Measure
In the NPRM, we defined ``outcome measure'' in Sec. 11.10(a) to
mean ``a pre-specified measurement that will be used to determine the
effect of experimental variables on the human subjects in a clinical
trial.'' As we explained in the NPRM, the experimental variables may be
the specific intervention(s) used in the clinical trial or other
elements of the clinical trial that vary between arms, e.g., diagnostic
or other procedures provided to participants in different arms (79 FR
69606). One commenter supported this definition.
We maintain the definition of ``outcome measure'' in the final rule
except we make conforming changes to two elements, i.e., we say ``an
experimental variable'' and ``on the human subject(s)'' to be
consistent with other definitions in the rule. In this part, ``outcome
measure'' refers to measurements observed or collected from those human
subjects who are enrolled in the clinical trial. Although it is not
uncommon to compare data derived from human subjects enrolled in a
clinical trial with data derived from other sources (e.g., literature,
other clinical trials), we believe that only measurements taken from
participants in the clinical trial of interest should be submitted as
results information to ClinicalTrials.gov. In our view, comparisons of
such data with results data derived from other sources are more
appropriately described in forums other than ClinicalTrials.gov (e.g.,
journal articles) where the other necessary information about the
comparator group can be provided. Clinical trial information submitted
to ClinicalTrials.gov would generally not include information or data
about the human subjects studied in another clinical trial (i.e., the
clinical trial record would not contain baseline and demographic
information about them, nor would it describe how they were allocated
to arms of the clinical trial to receive interventions). (See the
definitions of ``primary outcome measure'' and ``secondary outcome
measure.'')
Pediatric Postmarket Surveillance of a Device Product
Section 402(j)(1)(A)(ii)(II) of the PHS Act defines the term
``applicable device clinical trial'' to include ``a pediatric
postmarket surveillance as required under section 522 of the [FD&C]
Act.'' The term ``[a]pplicable device clinical trial'' includes ``a
pediatric postmarket surveillance as required under[section
[[Page 65025]]
522 of the FD&C Act].'' In the NPRM, we defined the term ``pediatric
postmarket surveillance of a device'' in Sec. 11.10(a) to mean ``the
active, systematic, scientifically valid collection, analysis, and
interpretation of data or other information conducted under section 522
of the [FD&C] Act about a marketed device that is expected to have
significant use in patients who are 21 years of age or younger at the
time of diagnosis or treatment (see 79 FR 69606). A pediatric
postmarket surveillance of a device may be, but is not always, a
clinical trial.'' Pursuant to section 522 of the FD&C Act, FDA defines
the term ``postmarket surveillance'' as ``the active, systematic,
scientifically valid collection, analysis, and interpretation of data
or other information about a marketed device'' (see 21 CFR 822.3(h)).
In Title III of FDAAA, Congress directed that the term ``pediatric,''
when used with respect to devices, refers to patients 21 and younger
(see Title III of FDAAA (``Pediatric Medical Device Safety and
Improvement Act of 2007''), amending section 520(m) of the FD&C Act).
FDA may order a pediatric postmarket surveillance of a device under
section 522 of the FD&C Act for any class II or class III device, as
defined by 21 U.S.C. 360c(a) and 21 CFR 860.3, meeting any of the
following criteria: (1) Its failure would be reasonably likely to have
serious adverse health consequences, (2) it is expected to have
significant use in pediatric populations, (3) it is intended to be
implanted in the body for more than 1 year, or (4) it is intended to be
a life-sustaining or life-supporting device outside a device user
facility (see 21 U.S.C. 360l(a)). Pediatric postmarket surveillances
under section 522 of the FD&C Act can take various forms, including a
detailed review of the complaint history and the scientific literature,
non-clinical testing, observational studies, and controlled clinical
trials.
Because section 402(j)(1)(A)(ii)(II) of the PHS Act defines the
term ``applicable device clinical trial'' to include pediatric
postmarket surveillances of a device, such surveillances must be
registered, and clinical trial results information must be submitted
for them. The final rule's approach for applying the registration
requirements to a pediatric postmarket surveillance of a device that is
not a clinical trial is described in Sec. 11.28(b), and the final
rule's approach for applying the results information submission
requirements to a pediatric postmarket surveillance of a device that is
not a clinical trial is described in Sec. 11.48(b). A pediatric
postmarket surveillance of a device that is a clinical trial is subject
to the general requirements of this final rule, including the clinical
trial registration and results information submission requirements in
Sec. Sec. 11.28(a) and 11.48(a), respectively.
We received no comments on this proposed definition, and we
maintain it in the final rule. However, for clarity and consistency,
``device'' is changed to ``device product.'' For completeness, we also
include the applicable U.S.C. statutory citation in the definition.
Primary Completion Date
As discussed above, based on comments we received, we have decided
to maintain the proposed rule's definition of ``completion date'' in
Sec. 11.10(a) of the final rule but, in order to prevent confusion
among researchers and the public, we use the term ``primary completion
date'' in this preamble and the codified provisions. Therefore, we add
the term ``primary completion date'' to Sec. 11.10(a), define it as
``completion date,'' and refer to the definition of that term.
Primary Outcome Measure(s)
In the NPRM, we defined ``primary outcome measure(s)'' in Sec.
11.10(a) to mean ``the outcome measure(s) of greatest importance
specified in the protocol, usually the one(s) used in the power
calculation. Most clinical trials have one primary outcome measure, but
a clinical trial may have more than one.'' The NPRM also noted that,
for the purpose of this part, ``primary outcome'' has the same meaning
as ``primary outcome measure'' (79 FR 69606). The term ``primary
outcome measure(s)'' is used, but not defined, in section 402(j) of the
PHS Act. Section 402(j)(2)(A)(ii)(I)(ll) of the PHS Act expressly
requires primary outcome measures to be submitted as a clinical trial
registration information data element. In addition, section
402(j)(1)(A)(v) of the PHS Act defines the completion date in relation
to the ``final collection of data for the primary outcome.'' Primary
outcome measure(s) is also expressly required as a clinical trial
results information data element by section 402(j)(3)(C)(ii) of the PHS
Act. As we explained in the NPRM, we believe this approach enables
users of ClinicalTrials.gov to identify the pre-specified primary
outcome measure(s) for the clinical trial submitted as part of the
clinical trial registration information and to examine the results data
collected for those outcome measures and submitted to the data bank as
part of clinical trial results information. (See also the discussion in
Sections IV.B.4 and IV.C.4 of this preamble regarding primary outcome
measure as a clinical trial registration information data element in
Sec. 11.28(a)(2)(i)(W) and as a clinical trial results information
data element in Sec. 11.48(a)(3).) We received one comment in support
of the proposed definition. We maintain the definition in the final
rule, except, for greater clarity about the definition's scope, we add
the phrase ``for purposes of this part.''
Principal Investigator
In the NPRM, we defined ``principal investigator'' in Sec. 11.10
to mean ``the individual who is responsible for the scientific and
technical direction of the study.'' As we explained, ``principal
investigator'' is a term used in the definition of ``responsible
party'' in section 402(j)(1)(A)(ix) of the PHS Act and in the
description of the Certain Agreements results data element in section
402(j)(3)(C)(iv) of the PHS Act, but the term itself is not defined in
section 402(j) of the PHS Act (79 FR 69607). The definition uses
terminology derived from 42 CFR 52.2, which defines ``principal
investigator'' in the context of an NIH grant as ``the individual(s)
judged by the applicant organization to have the appropriate level of
authority and responsibility to direct the project or program supported
by the grant and who is or are responsible for the scientific and
technical direction of the project.'' We did not include the phrases
``applicant organization'' and ``project or program supported by the
grant,'' which are specific to NIH-funded grants, because these
references would not necessarily apply to applicable clinical trials
that are funded by industry or other non-governmental organizations. We
used the term ``study'' in place of ``project'' because the projects of
relevance to this rule would be clinical studies, whether clinical
trials or pediatric postmarket surveillances of a device. We also made
it clear that the definition applies to only a single individual. This
is consistent with our interpretation that there cannot be more than
one responsible party for a clinical trial that is subject to section
402(j) of the PHS Act. We would expect a principal investigator to have
full responsibility for the treatment and evaluation of human subjects
in the study and for the integrity of the research data for the full
study. In keeping with this approach, an investigator for an individual
site in a multi-site clinical trial would not be considered the
principal investigator unless he or she also has overall responsibility
for the clinical trial at all sites at which it is being conducted.
[[Page 65026]]
This interpretation is consistent with the requirement in section
402(j)(1)(A)(ix) of the PHS Act that a principal investigator may be
designated by the sponsor as a responsible party only if he or she is
responsible for conducting the trial, has access to and control over
the data from the clinical trial, has the right to publish the clinical
trial results, and has the ability to meet all the requirements for the
submission of clinical trial information under section 402(j) of the
PHS Act and this part.
We received comments on this proposed definition. Commenters
requested that we make the proposed definition of ``principal
investigator'' consistent with relevant FDA definitions. ``Principal
investigator'' is not defined in FDA regulations or HHS ``Common Rule''
regulations (45 CFR part 46). However, FDA regulations in 21 CFR part
312 define ``investigator'' as ``an individual who actually conducts a
clinical investigation (i.e., under whose immediate direction the drug
is administered or dispensed to a subject). In the event an
investigation is conducted by a team of individuals, the investigator
is the responsible leader of the team'' (see 21 CFR 312.3(b)). Other
FDA regulations in 21 CFR parts 50, 56, and 812 define ``investigator''
similarly. The commenters noted that for large academic consortium
studies, there may be an investigator who is responsible for the
study's scientific and technical direction and who is commonly referred
to as the ``overall principal investigator'' or ``study director.'' As
the commenters noted, FDA regulations do not define ``principal
investigator,'' and our proposed definition is for the purposes of this
rule.
We do not believe that the proposed definition is inconsistent with
FDA's definition of an ``investigator.'' As we explained above, the
definition is based on the NIH regulation applying to grants (42 CFR
52.2), with which academic medical centers should be familiar. We
clarify that in the commenters' examples, the ``overall principal
investigator'' or ``study director'' responsible for the study's
overall scientific and technical direction would be considered the
``principal investigator'' for the purpose of this part. If there are
clinical trials for which there is more than one individual whom the
sponsor considers to be a principal investigator for the overall study,
the sponsor may designate only one of these principal investigators as
the responsible party. Another commenter also stated that the
definition should include a qualifier to designate the principal
investigator for the overall study (with multiple sites) or an
individual site.
After considering these comments, we modify the definition of
``principal investigator'' to clarify that the principal investigator
is responsible for the overall study (as distinguished from the
individual study sites). The definition of ``principal investigator''
in the final rule means ``the individual who is responsible for the
overall scientific and technical direction of the study.'' We note that
the principal investigator of a grant awarded by a Federal Government
agency that funds a clinical trial may not necessarily be the principal
investigator for that clinical trial for the purposes of this part. For
example, for the purposes of grant funding, NIH defines ``program
director/principal investigator'' in part as ``[t]he individual(s)
designated by the applicant organization to have the appropriate level
of authority and responsibility to direct the project or program to be
supported by the award.'' [Ref. 87a]. Such an individual may or may not
be ``the individual who is responsible for the overall scientific and
technical direction of the study'' as defined in Sec. 11.10(a) of this
regulation.
In addition, the principal investigator on a Federal grant who has
responsibility for only one site of a multi-site clinical trial (see,
for example, 42 CFR 52.2) would neither have the requisite
responsibility for conducting the entire trial nor the requisite access
to data from all sites involved in the clinical trial, both of which
are required by section 402(j) of the PHS Act and this part in order to
meet the definition of ``responsible party.'' Accordingly, the
principal investigator on such a grant could not be designated by the
sponsor to be the responsible party for the purposes of registering a
clinical trial and submitting clinical trial results information under
section 402(j) of the PHS Act and this part.
Protocol
In the NPRM, we defined ``protocol'' in Sec. 11.10(a) to mean
``the written description of the clinical trial, including
objective(s), design, and methods. It may also include relevant
scientific background and statistical considerations.'' As we explained
in the NPRM, the protocol is the document that describes the design of
a clinical trial. It may be, and frequently is, amended after a
clinical trial has begun (79 FR 69607). This definition is derived from
ICH E6(R1): Good Clinical Practice: Consolidated Guideline [Ref. 81]
which defines the term as ``[a] document that describes the
objective(s), design, methodology, statistical considerations, and
organization of a trial. The protocol usually also gives the background
and rationale for the trial, but these could be provided in other
protocol referenced documents.'' The protocol generally addresses major
statistical considerations, such as the number of human subjects
required to provide adequate statistical power, but it may or may not
include detailed information about the specific statistical analyses to
be performed as part of the clinical trial. Such information may be
contained in a separate SAP. We received no comments on this
definition, and we maintain it in the final rule. We note, for the
purposes of this part, that the written description may vary in the
degree of detail, structure, or format. This clarification is relevant
for other definitions in this part that include the ``protocol''
component, including the definitions for ``clinical trial'' and
``interventional.''
Responsible Party
In the NPRM, we defined ``responsible party'' in Sec. 11.10(a) to
mean ``with respect to a clinical trial, (i) the sponsor of the
clinical trial, as defined in 21 CFR 50.3 (or any successor
regulation); or (ii) the principal investigator of such clinical trial
if so designated by a sponsor, grantee, contractor, or awardee, so long
as the principal investigator is responsible for conducting the trial,
has access to and control over the data from the clinical trial, has
the right to publish the results of the trial, and has the ability to
meet all of the requirements under this part for the submission of
clinical trial information. For a pediatric postmarket surveillance of
a device that is not a clinical trial, the responsible party is the
entity whom FDA orders to conduct the pediatric postmarket surveillance
of a device.'' As we explained, ``responsible party'' is the term
defined in section 402(j)(1)(A)(ix) of the PHS Act and used in section
402(j) of the PHS Act to refer to the entity or individual who is
responsible for registering a clinical trial or a pediatric postmarket
surveillance of a device that is not a clinical trial, for submitting
clinical trial results information to ClinicalTrials.gov, and for
updating all submitted clinical trial information (79 FR 69607). We
received no comments on this definition, and we maintain it in the
final rule. We have, however, made a minor formatting change and
grammatical correction (changing ``whom'' to ``who''). As we have
elsewhere, we also now use the term ``device product.'' The procedures
for determining which individual or entity meets the definition of
[[Page 65027]]
``responsible party'' are specified in Sec. 11.4(c) and described in
Section IV.A.2 of this preamble. We address the comments on these
procedures in that section.
Secondary Outcome Measure(s)
In the NPRM, we defined ``secondary outcome measure'' in Sec.
11.10(a) to mean ``an outcome measure that is of lesser importance than
a primary outcome measure, but is part of a pre-specified plan for
evaluating the effects of the intervention or interventions under
investigation in a clinical trial.'' As we explained in the NPRM, a
``clinical trial may have more than one secondary outcome measure'' (79
FR 69607). We also noted that for the purpose of this part, ``secondary
outcome'' has the same meaning as ``secondary outcome measure.''
``Secondary outcome measure'' is a term used, but not defined, in
section 402(j) of the PHS Act. Section 402(j)(2)(A)(ii)(I)(ll) of the
PHS Act expressly requires secondary outcome measures to be submitted
as a clinical trial registration information data element, as a
component of the outcome measures data element. In addition, secondary
outcome measure(s) is also expressly required as a clinical trial
results information data element by section 402(j)(3)(C)(ii) of the PHS
Act. As we said, we believe this structure enables users of
ClinicalTrials.gov to identify the pre-specified secondary outcome
measures for the clinical trial submitted as part of the clinical trial
registration information and to examine the results data collected for
those outcome measures and submitted to the data bank as part of
clinical trial results information. We also pointed out that the
definition is consistent with the WHO Trial Registration standard and
ICMJE registration policies [Ref. 2, 73].
We received comments on this definition. One commenter supported
this definition. We also heard from others that we should clarify
whether any outcomes that are not part of the SAP, or are indicated to
be tertiary or exploratory, are secondary outcome measures. We consider
secondary outcome measures to be those outcome measures (other than the
primary outcome measures) that are not considered exploratory or
tertiary and for which there is a specific analysis plan. In general,
the analysis plan would be specified in the protocol or SAP, but
protocols do not always contain detailed information about statistical
analyses, and SAPs may not be complete at the time a trial is
registered. Therefore, the plan to analyze the secondary outcome
measures may only be expressed in other formal trial documentation
(e.g., a grant application, contract, or published journal article).
Therefore, in response to these comments, we confirm that outcome
measures that are not part of an analysis plan, or are indicated to be
exploratory or tertiary, are lower-level outcome measures and not
secondary outcome measures. These lower-level outcome measures are not
required to be submitted to ClinicalTrials.gov, but the information may
be submitted voluntarily. (See the discussions in Sections IV.B.4 and
IV.C.3 of this preamble, respectively, regarding secondary outcome
measure(s) as a clinical trial information data element to be submitted
at the time of registration, pursuant to Sec. 11.28(a)(2)(i)(X), and
at the time of results information submission, pursuant to Sec.
11.48(a)(3).) After consideration of these comments, we clarify that a
pre-specified exploratory or tertiary measure is not considered a
secondary outcome. The definition of ``secondary outcome measure(s)''
in Sec. 11.10(a) of this final rule is ``an outcome measure that is of
lesser importance than a primary outcome measure, but is part of a pre-
specified analysis plan for evaluating the effects of the intervention
or interventions under investigation in a clinical trial and is not
specified as an exploratory or other measure. A clinical trial may have
more than one secondary outcome measure.'' For the purpose of this
part, ``secondary outcome'' has the same meaning as ``secondary outcome
measure.'' We include the phrase ``and is not specified as an
exploratory or other measure'' to be clear that a pre-specified
exploratory or other measure is not considered a secondary outcome
measure.
Secretary
In the NPRM, we defined ``Secretary'' in Sec. 11.10(a) to mean
``the Secretary of Health and Human Services or any other official(s)
to whom the Secretary delegates authority contained in 42 U.S.C.
282(j)'' (see 79 FR 69669). We received no comments on this definition.
We maintain it, except that we make clear that that the Secretary's
authority is contained in ``section 402(j) of the Public Health Service
Act (42 U.S.C. 282(j).''
Serious Adverse Event
In the NPRM, we defined ``serious adverse event'' in Sec. 11.10(a)
to mean ``an adverse event that results in any of the following
outcomes: Death, a life-threatening adverse event as defined in 21 CFR
312.32 (or any successor regulation), inpatient hospitalization or
prolongation of existing hospitalization, a persistent or significant
incapacity or substantial disruption of the ability to conduct normal
life functions, or a congenital anomaly/birth defect. Important medical
events that may not result in death, be life-threatening, or require
hospitalization may be considered serious when, based upon appropriate
medical judgment, they may jeopardize the human subject and may require
medical or surgical intervention to prevent one of the outcomes listed
in this definition. Examples of such medical events include allergic
bronchospasm requiring intensive treatment in an emergency room or at
home, blood dyscrasias or convulsions that do not result in inpatient
hospitalization, or the development of a substance use disorder.'' As
we explained in the NPRM, ``serious adverse event'' is a term used, but
not defined, in section 402(j)(3)(I) of the PHS Act (79 FR 69608).
Section 402(j)(3)(I)(iii)(I) of the PHS Act requires the submission to
ClinicalTrials.gov of specific information about ``anticipated and
unanticipated serious adverse events'' for applicable clinical trials
of drugs as well as devices.
We received comments on this definition. Commenters suggested that
the adverse event reporting requirements for devices should be
consistent with the definition of ``serious adverse event'' used by the
international standard for clinical investigations of medical devices
in human subjects (ISO 14155) [Ref. 88]. As we noted in our discussion
of the term in the NPRM, the definition is consistent with established
FDA standards, and we drew on the FDA definition of ``serious adverse
event'' in 21 CFR 312.32(a) for IND applications in developing the
definition because that FDA definition more fully characterizes the
criteria for ``other serious problems'' as well as ``any life-
threatening problem'' or ``[d]eath.'' In defining the term ``serious
adverse event'' in its IND Safety Reporting regulations in 21 CFR
312.32(a), FDA considers an adverse event to be ``serious'' when, in
the view of either the sponsor or the investigator, it ``results in any
of the following outcomes: Death, a life-threatening adverse event,
inpatient hospitalization or prolongation of existing hospitalization,
a persistent or significant incapacity or substantial disruption of the
ability to conduct normal life functions, or a congenital anomaly/birth
defect. Important medical events that may not result in death, be life-
threatening, or require hospitalization may be considered serious when,
based upon appropriate
[[Page 65028]]
medical judgment, they may jeopardize the patient or subject and may
require medical or surgical intervention to prevent one of the outcomes
listed in this definition. Examples of such medical events include
allergic bronchospasm requiring intensive treatment in an emergency
room or at home, blood dyscrasias or convulsions that do not result in
inpatient hospitalization, or the development of drug dependency or
drug abuse.'' The other points we made in the NPRM are also relevant,
and we reiterate them here to explain why we are not adopting the
commenters' suggestion. A ``serious adverse event,'' as defined in 21
CFR 312.32(a), applies only in the context of drugs (including
biological products). No fully equivalent term is defined in FDA
regulations for medical devices. In 21 CFR 812.3(s), FDA defines an
``unanticipated adverse device effect'' as, in part, ``any serious
adverse effect on health or safety or any life-threatening problem or
death caused by, or associated with, a device'' that ``was not
previously identified . . . in the investigational plan or application
. . . or any other unanticipated serious problem associated with a
device that relates to the rights, safety, or welfare of subjects.''
However, we did not consider this definition to be sufficient to meet
the statutory requirement in section 402(j)(3)(I)(iii) of the PHS Act
for submission of serious adverse event information that encompasses
both anticipated and unanticipated events because it is restricted to
unanticipated effects.
After considering the comments, we maintain the NPRM definition of
``serious adverse event'' in Sec. 11.10(a) to mean ``an adverse event
that results in any of the following outcomes: Death, a life-
threatening adverse event as defined in 21 CFR 312.32, inpatient
hospitalization or prolongation of existing hospitalization, a
persistent or significant incapacity or substantial disruption of the
ability to conduct normal life functions, or a congenital anomaly/birth
defect. Important medical events that may not result in death, be life-
threatening, or require hospitalization may be considered serious when,
based upon appropriate medical judgment, they may jeopardize the human
subject and may require medical or surgical intervention to prevent one
of the outcomes listed in this definition. Examples of such medical
events include allergic bronchospasm requiring intensive treatment in
an emergency room or at home, blood dyscrasias or convulsions that do
not result in inpatient hospitalization, or the development of a
substance use disorder.'' Although we adopted terms from an FDA drug
regulation, we emphasize that ``serious adverse event,'' as defined for
the purposes of this part, applies to both drugs and devices. Further,
and as explained more fully in section IV.C.4. of this preamble, the
rule does not require investigators or responsible parties to collect
information that is not specified in the clinical trial protocol.
We use the phrase ``a substance use disorder'' instead of the
phrase ``drug dependency or drug abuse,'' which is used in the FDA
definition, for consistency with the latest version (fifth edition) of
the Diagnostic and Statistical Manual of Mental Disorders [Ref. 89]. By
referring to adverse events (and thus the definition of that term in
this part), our definition of ``serious adverse event'' is broader than
the FDA definition of ``serious adverse event'' in 21 CFR 312.32(a)
because it encompasses any untoward or unfavorable medical occurrences
associated with any intervention included in a clinical trial (not just
the use of the FDA-regulated product), including any intervention(s) in
any arm of the clinical trial that does not involve FDA-regulated
products. In addition, as with our definition of ``adverse event,'' our
definition of ``serious adverse event'' encompasses both anticipated
and unanticipated effects regardless of attribution or association with
the intervention.
Sponsor
In the NPRM, we defined ``sponsor'' in Sec. 11.10(a) to mean
``either a `sponsor' or `sponsor-investigator,' as each is defined 21
CFR 50.3 or any successor regulation.'' As we explained, ``[s]ponsor''
is a term used in section 402(j) of the PHS Act to define responsible
party (79 FR 69608). Section 402(j)(1)(A)(ix)(I) of the PHS Act
explicitly defines ``sponsor'' as such term is defined at 21 CFR 50.3
or any successor regulation. Two types of sponsors are defined in 21
CFR 50.3, both of which, we noted, meet the definition of ``sponsor''
for the purposes of this part. The first type is a ``sponsor,'' defined
in 21 CFR 50.3 as ``a person who initiates a clinical investigation but
who does not actually conduct the investigation, i.e., the test article
is administered or dispensed to or used involving, a subject under the
immediate direction of another individual. A person other than an
individual (e.g., corporation or agency) that uses one or more of its
own employees to conduct a clinical investigation it has initiated is
considered to be a sponsor (not a sponsor-investigator), and the
employees are considered to be investigators.'' The second type is a
``sponsor-investigator,'' defined in 21 CFR 50.3 as ``an individual who
both initiates and actually conducts, alone or with others, a clinical
investigation, i.e., under whose immediate direction the test article
is administered or dispensed to, or used involving, a subject. The term
does not include any person other than an individual, e.g., corporation
or agency.'' As we noted, we believe that the definition of ``sponsor''
used in this part must encompass both a sponsor and a sponsor-
investigator because both terms are relevant in determining who
initiates the clinical trial.
We did not receive any comments on this definition, and we maintain
it in the final rule to mean ``either a `sponsor' or `sponsor-
investigator', as each is defined 21 CFR 50.3.'' Procedures for
determining which individual or entity would be considered the sponsor
of an applicable clinical trial or other clinical trial subject to this
part are specified in Sec. 11.4(c) and described in Section IV.A.2 of
this preamble. As those sections explain, the individual or entity that
is the sponsor is considered to be the responsible party of an
applicable clinical trial or other clinical trial, unless and until
that responsibility is delegated to the principal investigator,
consistent with the requirements of section 402(j)(1)(A)(ix) of the PHS
Act and this part.
Study Completion Date
The NPRM did not use the term ``study completion date'' or propose
either a definition of it in Sec. 11.10(a) or a data element for it in
Sec. 11.28, but we are including the term and data element in this
final rule. We define the term ``study completion date'' in Sec.
11.10(a) to mean ``for a clinical trial, the date the final subject was
examined or received an intervention for purposes of final collection
of data for the primary and secondary outcome measures and adverse
events (e.g., last subject's last visit), whether the clinical trial
concluded according to the pre-specified protocol or was terminated.''
Section 402(j)(2)(A)(ii) of the PHS Act specifies the clinical trial
registration information that must be submitted, although study
completion date is not included. However, section 402(j)(2)(A)(iii) of
the PHS Act permits the Secretary to ``modify the requirements for
clinical trial [registration] information'' by regulation, provided
that ``such a modification improves and does not reduce such clinical
trial information.''
[[Page 65029]]
As discussed in Section IV.B.4, we believe that the study completion
date is helpful in indicating when all primary and secondary outcome
measures and the collection of all adverse event information, as
specified in the protocol, will be completed and when final data
collection has occurred. Therefore, we believe that requiring the
submission of the study completion date improves and does not reduce
clinical trial information.
Section 11.64(a)(3) describes when a responsible party's obligation
to submit updates ends. Our definition of ``study completion date''
identifies the final date of data collection for the study, including
for any primary and secondary outcomes and for adverse events. For
adverse events, the last date of data collection is the end of the
adverse event collection period specified by the protocol. The study
completion date will be the end of this adverse event collection period
if this period ends later than the last subject's last visit for the
primary and secondary outcomes. As discussed in other sections of this
preamble, the study completion date is relevant in determining the
obligations for responsible parties to submit registration and results
information. As described in Section IV.C.3 for partial results
information deadlines under Sec. 11.44(d), clinical trial results
information specified in Sec. 11.48 must be submitted no later than
one year after the study completion date. In addition, the Study
Completion Date,'' which is a registration data element, will be
displayed on the posted record.
Although we did not receive any specific comments about adding a
Study Completion Date data element, commenters did request that a
mechanism be included in the PRS to make clear to responsible parties
when they have fulfilled all obligations to update the study record,
and when no further updates are required. A responsible party can use
the ``study completion date'' definition and related data element in
determining various obligations under this part, such as the deadlines
for submitting partial results information under Sec. 11.44(d). The
``study completion date'' is distinct from ``completion date,'' which,
as discussed above, we refer to as the ``primary completion date.''
U.S. FDA-Regulated Device Product
In the NPRM, we defined ``FDA-regulated device'' in Sec. 11.10(a)
to mean ``for purposes of this part, a device subject to section
510(k), 515, 520(m), or 522 of the Federal Food, Drug, and Cosmetic
Act.'' As we explained, this term and its definition are based on
section 402(j)(1)(A)(ii) of the PHS Act, which defines ``applicable
device clinical trial'' as including studies of a ``device subject to
section 510(k), 515, or 520(m) of the Federal Food, Drug, and Cosmetic
Act.'' We did not receive any comments on this definition and maintain
it in Sec. 11.10(a) of the final rule. However, because ``FDA'' is a
term used by similar regulatory agencies in other countries, we have
changed the term ``FDA-regulated device'' to ``U.S. FDA-regulated
device product'' for clarity. As we have elsewhere, we now also use the
term ``device product.'' A responsible party must submit information,
in accordance with Sec. 11.28, about whether the trial ``studies a
U.S. FDA-regulated device product.'' We explain further whether a trial
studies a U.S. FDA-regulated device product in Section IV.B.2 of this
preamble in our elaboration on the meaning of an ``applicable device
clinical trial.'' We also include the applicable U.S.C. statutory
citations in the definition.
U.S. FDA-Regulated Drug Product
In the NPRM, we defined ``FDA-regulated drug'' in Sec. 11.10(a) to
mean ``for purposes of this part, a drug subject to section 505 of the
Federal Food, Drug, and Cosmetic Act or a biological product subject to
section 351 of the Public Health Service Act.'' As we explained, this
term and its definition are based on section 402(j)(1)(A)(iii) of the
PHS Act, which defines ``applicable drug clinical trial'' as including
studies of a ``drug subject to section 505 of the Federal Food, Drug,
and Cosmetic Act or to section 351 of the [Public Health Service
Act].'' We did not receive any comments on this definition and maintain
it in Sec. 11.10(a) of the final rule. However, because ``FDA'' is a
term used by similar regulatory agencies in other countries, we have
changed the term ``FDA-regulated drug'' to ``U.S. FDA-regulated drug
product'' for further clarity. Additionally, for clarity, we now use
the term ``drug product'' rather than ``drug.'' A responsible party
must submit information in accordance with Sec. 11.28 about whether
the trial ``studies a U.S. FDA-regulated drug product.'' We explain
further whether a trial studies a U.S. FDA-regulated drug product in
Section IV.B.2 of this preamble in our elaboration on the meaning of an
``applicable drug clinical trial''. We also include the applicable
U.S.C. statutory citations in the definition.
Section 11.10(b) defines certain data elements that are part of the
clinical trial registration information that must be submitted to
ClinicalTrials.gov under this part. The data elements defined in Sec.
11.10(b) are enumerated in Sec. 11.28(a).
B. Subpart B--Registration
1. 11.20--Who must submit clinical trial registration information?
Overview of Proposal
Proposed Sec. 11.20 required that ``[t]he responsible party for an
applicable clinical trial specified in Sec. 11.22 must register the
applicable clinical trial by submitting clinical trial registration
information specified in Sec. 11.28 for that clinical trial.'' As we
explained in the NPRM, this approach is consistent with section
402(j)(2)(C) of the PHS Act, which states that the ``responsible party
for an applicable clinical trial . . . shall submit to the Director of
NIH for inclusion in the registry data bank the [clinical trial
registration information]'' (79 FR 69609).
Comments and Response
There were no comments received on this section.
Final Rule
The final rule maintains Sec. 11.20 as proposed, except clarifies
the wording for consistency with Sec. 11.40. Section 11.20 requires
that ``[t]he responsible party for an applicable clinical trial
specified in Sec. 11.22 must submit clinical trial registration
information for that clinical trial.''
2. 11.22--Which applicable clinical trials must be registered?
Overview of Proposal
In proposed Sec. 11.22(a), the Agency interpreted section
402(j)(2)(C) of the PHS Act to specify which applicable clinical trials
must be registered with ClinicalTrials.gov. As we explained in the
NPRM, proposed Sec. 11.22(b) set forth an approach for determining
whether or not a clinical trial meets the statutory definitions of an
applicable device clinical trial and an applicable drug clinical trial,
as established in section 402(j)(1) of the PHS Act (79 FR 69610). The
proposed approach used a series of specific registration data elements
and corresponding criteria to determine whether a clinical trial or
study meets the definition of an applicable clinical trial (i.e., Study
Type of the trial is ``interventional,'' Study Phase is other than
``Phase 1,'' etc.). We also pointed out that ``algorithms'' following
the approach outlined in the regulations would also be made available
outside the registration process (e.g., online at http://prsinfo.clinicaltrials.gov/fdaaa.html), and study sponsors could use
such algorithms to evaluate whether a particular trial meets the
definition of
[[Page 65030]]
applicable clinical trial (79 FR 69610). The NPRM invited public
comment on the approach proposed in Sec. 11.22(b) for determining
whether a clinical trial or study is an applicable clinical trial. It
also requested comments on whether there are any types of applicable
clinical trials that would be misidentified by this approach.
Comments and Response
Commenters addressed the NPRM's approach for facilitating the
determination of which clinical trials or studies are applicable
clinical trials that must be registered with ClinicalTrials.gov.
Several commenters supported the proposed approach for determining
whether a study is an applicable clinical trial, with a few commenters
suggesting that the rationale and approach would likely reduce
administrative burden for stakeholders. One suggested that the data
elements required for the determination process be made available to
sponsors outside of the registration process and that
ClinicalTrials.gov issue dated receipts to provide an audit trail
detailing whether or not a clinical trial was determined to be an
applicable clinical trial. In order to assist users in evaluating,
prior to beginning the registration process, whether their clinical
trial or study is an applicable clinical trial and potentially subject
to the requirements of the statute and the final rule, a checklist-
based tool will be made available at https://prsinfo.clinicaltrials.gov
(or successor site) for sponsors and others before the effective date
of the rule. Although proposed Sec. 11.22(b) included the criteria for
determining whether a trial is an applicable clinical trial, the
checklist tool is external to the ClinicalTrials.gov PRS and separate
from the registration process. The outcome generated by the checklist
tool will not be retained by the Agency and will not be binding on
either the user or any government Agency in any future actions. While
the tool is intended to be useful, it is not intended to be
determinative of the applicability of the statute or this rule. Thus,
we do not agree that a dated receipt for the outcome is necessary.
A few commenters opposed the overall proposed approach. One stated
that it would be neither helpful nor appropriate and requested that
study sponsors be allowed to make the determination rather than respond
to each specific element. As noted, the Agency is not making the
checklist tool available within the internal PRS system. The proposed
approach provides responsible parties or other users with a method to
help evaluate whether a particular clinical trial is an applicable
clinical trial prior to data submission. Since 2009, a draft
Elaboration of Definitions, which expounds on the definition of
applicable clinical trial [Ref. 90], and ClinicalTrials.gov
registration data elements have been available to allow sponsors to
indicate whether a clinical trial or study is an applicable clinical
trial (i.e., ``Section 801 Clinical Trial'') [Ref. 85]. However, based
on requests for clarification we have received to date, some users have
found application of these definitions and data elements difficult to
implement in practice. Building on our experience in responding to such
requests and the comments received, breaking the definition of
applicable clinical trial into components that can be explained in
terms of objective data elements has often facilitated understanding of
the applicable clinical trial definition and the user's evaluation
process for their particular clinical trial or study. Other than
comments on the interpretation of the definition of applicable clinical
trial and its components (e.g., definition of ``controlled,''
application to studies of ``combination products''), which are
discussed elsewhere in the preamble (see Section IV.A.5), we did not
receive any specific examples, as invited, of situations in which the
proposed approach would misidentify an applicable clinical trial.
However, as addressed below, other commenters offered suggestions or
raised questions about our proposal.
Some commenters observed that the data elements used for the
Applicable Clinical Trial assessment checklist were either too broadly
or too poorly defined. One commenter suggested that additional data
elements be added to determine whether a study is interventional. We
clarify or provide elaboration on the definitions (see Sec. 11.10) for
a number of data elements, such as ``interventional,'' used to
determine whether a study is an applicable clinical trial. In addition,
we are committed to providing additional guidance as needed when new
issues with interpretation are raised. The Agency believes that this
data element-based approach provides an objective, transparent set of
criteria for responsible parties and other users to evaluate, prior to
registering a trial, whether a clinical trial or study is an applicable
clinical trial and for such users of ClinicalTrials.gov to understand
the data elements used in evaluating whether a clinical trial or study
is an applicable clinical trial. Prior to registration a sponsor or
other user will be able to use the external checklist tool, which will
be based on the set of data elements identified in Sec. 11.22(b), to
assess whether a clinical trial or study is considered an applicable
clinical trial. Once clinical trial registration information has been
submitted, the Agency will be able to identify applicable clinical
trials based on the set of data elements identified in Sec. 11.22(b).
Public users of ClinicalTrials.gov, other than responsible parties,
should be able to understand whether a registered trial is an
applicable clinical trial. Although we have not conducted a formal
pilot study, as suggested by a commenter, the approach is responsive to
the challenges users have experienced in the past while trying to
determine whether their clinical trial or study meets the definition of
applicable clinical trial.
Commenters requested that the Agency provide examples of clinical
trials that do not fulfill the proposed criteria for applicable
clinical trials, and a couple of commenters observed that case studies
would be helpful for clarification purposes. The Agency intends to
continue making explanatory documents and other materials available,
including examples, case studies, and a publicly-accessible checklist-
based tool (described above) consisting of the relevant data elements
and detailed explanation of each criterion at https://prsinfo.clinicaltrials.gov (or successor stite). Finally, the Agency
believes that it has identified the minimum set of criteria
(corresponding to the registration data elements) needed to identify
applicable clinical trials, which should minimize burden on the
responsible parties.
Several commenters recommended that the Agency provide responsible
parties with a mechanism to explain why a clinical trial is not an
applicable clinical trial and/or to appeal the outcome of the proposed
approach. However, although we specifically asked in the NPRM for
examples of cases in which the approach outlined in the NPRM and
discussed above would lead to a misclassification of a clinical trial
(i.e., either by inappropriately including a trial that is not an
applicable clinical trial or excluding a trial that is), no examples
were submitted. Further, as mentioned previously, the checklist will be
available as a tool separate from the ClinicalTrials.gov registration
process in the PRS. By having each criterion correspond to one or more
standard data elements, the evaluation and assessment process follows a
checklist approach based on factual information (e.g.,
[[Page 65031]]
whether or not the Study Type is ``interventional'' as defined; whether
a drug is regulated by the U.S. FDA under section 505 of the FD&C Act
or section 351 of the PHS Act). Responsible parties or other users who
use the checklist tool are responsible for using accurate data about a
clinical trial or study and for conducting the evaluation. Since the
outcome is dependent on the factual data relied on by a responsible
party or other user, and the outcome of the assessment will not be
binding on either the user or any government Agency in any future
actions, we do not see a need for a mechanism for responsible parties
or other users to comment on a particular outcome of the external
checklist tool or an appeal process to dispute the outcome. The Agency
will provide contact information for obtaining assistance with
questions that arise about the interpretation of a criterion or a
relevant data element definition for which answers cannot be found in
Agency documents or other existing materials.
Another commenter requested that the ClinicalTrials.gov Web site
remove the ``late'' status and ``problems'' designation for trials that
do not meet the definition of ``applicable clinical trial'' under the
regulation. It is our understanding that this comment refers to an
online tool that is currently available to help responsible parties
manage their study records when using the PRS. Since all of the data
elements needed to evaluate whether a clinical trial or study is an
applicable clinical trial are not yet available, the current online
tool only approximates which submissions may be ``late'' and which
trials are ``probable applicable clinical trials.'' The Agency used the
term ``probable applicable clinical trials'' (pACTs) to refer to the
estimated number of clinical trials subject to section 402(j) of the
PHS Act prior to the effective date of the rule. This approach relied
on the set of clinical trial registration data elements available prior
to enactment of the final rule, but did not include all of the data
elements necessary to determine which studies are applicable clinical
trials as specified in Sec. 11.22(b) of the final rule. The pACTs were
defined as records listing an ``interventional'' Study Type; with at
least one Intervention Type as ``Biological,'' ``Drug,'' ``Device,''
``Genetic,'' or ``Radiation;'' a Study Phase other than ``Phase 0'' or
``Phase 1;'' a Primary Completion Date on or after January 2008 or, if
the Primary Completion Date was missing, a Study Completion Date on or
after January 2008, or any record for which both the Primary Completion
Date and the Study Completion Date are missing; an Overall Recruitment
Status other than ``Withdrawn,'' and at least one Facility Location
Country in the ``United States'' or if none, indication that the study
is conducted under an FDA IND or IDE.
Promulgation of the final rule and implementation of several new
data elements (e.g., Studies an FDA-regulated Drug [or Device]),
enables the Agency to be better able to identify applicable clinical
trials more accurately in the PRS and on the public Web site. In
addition, it enables the Agency to create other tools within the PRS to
assist responsible parties with managing their responsibilities.
Misidentified trials, as referred to in the comments, should be able to
be addressed.
Final Rule
Taking into consideration the submitted comments, as well as the
statutory definitions of the terms, ``applicable device clinical
trial'' and ``applicable drug clinical trial,'' the rule retains the
proposed scope for required registration of applicable clinical trials,
but modifies the approach for evaluating whether a study is an
applicable clinical trial as specified in Sec. 11.22(b) based on the
Agency's revised interpretation of ``control or controlled,'' as
described elsewhere in the preamble (Section IV.A.5). Additionally, the
final rule clarifies that ``device'' means ``device product'' and
``drug'' means ``drug product.'' The final rule also clarifies that the
approach in Sec. 11.22(b) for evaluating whether a study is an
applicable clinical trial applies to trials initiated on or after the
effective date of the final rule.
Section 11.22(a)(1) and (2) state that registration is required
for: (1) ``[a]ny applicable clinical trial that is initiated after
September 27, 2007;'' and (2) ``[a]ny applicable clinical trial that is
initiated on or before September 27, 2007 and is ongoing on December
26, 2007 [ . . . ].'' Section 11.22(a)(3) provides clarification for
determining the date on which an applicable clinical trial is
initiated, stating that ``[a]n applicable clinical trial, other than a
pediatric postmarket surveillance of a device product that is not a
clinical trial, is considered to be initiated on the date on which the
first human subject is enrolled.''
Based on the Agency's interpretation of the term ``applicable
device clinical trial'' as defined in section 402(j)(1) of the PHS Act,
Sec. 11.22(b)(1) states that a clinical trial is considered an
applicable device clinical trial if (1) it is a pediatric postmarket
surveillance of a device product required by FDA under section 522 of
the FD&C Act (regardless of whether the pediatric postmarket
surveillance is a clinical trial), or (2) it is a clinical trial with
one or more arms that meets all of the following criteria: (a) The
Study Type is interventional; (b) the Primary Purpose selected is any
other than feasibility; (c) the clinical trial Studies a U.S. FDA-
regulated Device; and, (d) one or more of the following applies: At
least one Facility Location is within the U.S. or one of its
territories, the device under investigation is a Product Manufactured
in and Exported from the U.S. or one of its territories for study in
another country, or the clinical trial has a U.S. Food and Drug
Administration IDE Number. We also note that the final rule does not
include the proposed criterion regarding the Number of Arms and Single
Arm Controlled data elements in Sec. 11.22(b)(1)(ii)(C) and
(b)(2)(iii) of the NPRM because the Agency considers all clinical
trials with one or more arms and pre-specified primary or secondary
outcome measures controlled for purposes of the final rule (see
discussion of ``control or controlled'' in Section IV.A.5 of this
preamble).
Based on the Agency's interpretation of the term ``applicable drug
clinical trial'' as defined in section 402(j)(1) of the PHS Act, Sec.
11.22(b)(2) states that a clinical trial with one or more arms is
considered an applicable drug clinical trial if it meets all of the
following: (1) The Study Type is interventional; (2) the Study Phase is
other than phase 1; (3) the clinical trial Studies a U.S. FDA-regulated
Drug Product; and, (4) one or more of the following applies: At least
one Facility Location is within the U.S. or one of its territories, the
drug product under investigation is a Product Manufactured in and
Exported from the U.S. for study in another country, or the clinical
trial has a U.S. Food and Drug Administration IND Number.
With respect to Study Phase and the determination process, we do
not consider a phase 1/phase 2 trial (i.e., a trial with
characteristics of both phase 1 and phase 2 studies trials) to be a
phase 1 trial. If a clinical trial is initially registered as phase 1/
phase 2 trial, it is considered to be a phase 2 trial. If the trial
subsequently proceeds through only the phase 1 stage and/or is
terminated before reaching phase 2, the Study Phase data element may be
updated to indicate that the trial is a phase 1 trial, in which case it
would not be considered an applicable drug clinical trial and would not
be subject to the requirements for results information submission
specified in subpart C. However, submitted registration information
would continue
[[Page 65032]]
to be posted in the ClinicalTrials.gov data bank.
While most applicable clinical trials will meet the definition of
either an applicable device clinical trial or an applicable drug
clinical trial, some applicable clinical trials that study multiple
intervention types (e.g., in different arms of the clinical trial)
could meet both definitions. For example, a clinical trial with
facility locations in the U.S. that studies a U.S. FDA-regulated drug
product in one arm, studies a U.S FDA-regulated device product in
another arm, and compares outcomes of the two arms would meet both
definitions. If the U.S. FDA-regulated device product studied in such
an applicable clinical trial is not approved or cleared by FDA for any
use, we will not post clinical trial registration information for that
applicable clinical trial prior to the date of approval or clearance of
the device product, consistent with Sec. 11.35(b)(2)(i), unless the
responsible party indicates, pursuant to Sec. 11.35(b)(2)(ii), that it
authorizes such posting.
3. 11.24--When must clinical trial registration information be
submitted?
Overview of Proposal
Proposed Sec. 11.24 specified the deadlines by which a responsible
party must submit clinical trial registration information for an
applicable clinical trial to ClinicalTrials.gov, implementing section
402(j)(2)(c) of the PHS Act. As explained in the NPRM, proposed Sec.
11.24(a) specified the general registration deadline requiring
submission by the later of December 26, 2007, or 21 calendar days after
enrollment of the first human subject in a clinical trial, as specified
in section 402(j)(2)(C)(i) and (ii) (79 FR 69611). Proposed Sec.
11.24(b) implemented two exceptions: (1) For applicable clinical trials
that are not for a serious or life-threatening disease or condition and
that were initiated on or before enactment of FDAAA, the registration
deadline is not later than September 27, 2008, or 21 calendar days
after the first human subject is enrolled, whichever date is later,
consistent with section 402(j)(2)(C)(iii) of the PHS Act, and (2) for a
pediatric postmarket surveillance of a device product that is not a
clinical trial, which is defined as an applicable device clinical trial
in section 402(j)(1)(A)(ii)(II) of the PHS Act, the registration
deadline is not later than December 26, 2007, or 21 calendar days after
FDA approves the postmarket surveillance plan, whichever date is later
(79 FR 69611).
Comments and Response
Commenters addressed the registration submission deadlines in
proposed Sec. 11.24. The commenters suggested that the final rule
require general registration prior to enrollment of the first human
subject, rather than allow up to an additional 21 calendar days as
proposed. One commenter noted that such a deadline would be consistent
with requirements specified in the EU Clinical Trials Regulation as
well as the Declaration of Helsinki. Another commenter also requested
that the final rule omit the exception to the general deadline for
registering applicable clinical trials not for a serious or life-
threatening disease or condition specified in proposed Sec.
11.24(b)(1). The Agency is not revising proposed Sec. 11.24 as
suggestedby the comments. Section 11.24 accurately reflects the
statutory requirements for submission of registration information.
Final Rule
Taking into consideration the commenters' suggestions and the
statutory requirements for registration information submission
deadlines, the final rule maintains the approach proposed in Sec.
11.24(a) and (b) except that it clarifies that ``device'' means
``device product.'' In addition, we have clarify that the clinical
trial registration information that must be submitted will either be
the information specified in section 402(j)(2)(A)(ii) of the PHS Act or
in Sec. 11.28(a). Consistent with the discussion in section IV.F., the
requirements for applicable clinical trials will differ based on the
initiation date of the applicable clinical trial. Final Sec. 11.24(a)
generally requires a responsible party to submit clinical trial
registration information 21 calendar days after the first human subject
is enrolled in the clinical trial. Final Sec. 11.24 also provides
exceptions to this general registration submission deadline for
applicable clinical trials that are clinical trials and were (1)
initiated on or before September 27, 2007, and (2) ongoing as of
December 26, 2007. For applicable clinical trials for a serious or
life-threatening disease or condition, responsible parties were
required to submit registration information by December 26, 2007, under
Sec. 11.24(a). Examples of serious or life-threatening diseases or
conditions include acquired immunodeficiency syndrome, all other stages
of human immunodeficiency virus (HIV), Alzheimer's disease, cancer, or
heart failure [Ref. 78, 79]. For applicable clinical trials not for a
serious or life-threatening disease or condition, responsible parties
were required to submit registration information by September 27, 2008,
under Sec. 11.24(b)(1).
4. Sec. 11.28--What constitutes clinical trial registration
information?
Sec. 11.28--Overall
Overview of Proposal
Proposed Sec. 11.28 identified the structured information, or data
elements, that constitute clinical trial information that a responsible
party must submit in order to register an applicable clinical trial.
Section 402(j)(2)(A)(ii) of the PHS Act specifies a number of data
elements that must be submitted to ClinicalTrials.gov for registration.
In general, the proposed data elements in Sec. 11.28 conformed to the
items enumerated in section 402(j)(2)(A)(ii) of the PHS Act. In many
instances, the Agency, through the proposed rulemaking, had restated or
clarified the registration data elements required by section
402(j)(2)(A)(ii) of the PHS Act. In addition, section 402(j)(2)(A)(iii)
of the PHS Act expressly authorizes the Secretary to modify the
registration data elements, by regulation, if a rationale is provided
as to why such a modification ``improves and does not reduce'' such
information. In developing the proposed set of data elements for
registration, we carefully considered the items enumerated in section
402(j)(2)(A)(ii) of the PHS Act, the mandate in section 402(j)(2)(A)(i)
to ``expand'' the existing registration data bank, and the intent to
expand the data bank ``to enhance patient enrollment and provide a
mechanism to track subsequent progress of clinical trials'' (see
section 402(j)(2)(A)(i) of the PHS Act). We also took into
consideration the WHO Trial Registration Data Set and have sought to
maintain consistency with the clinical trial registration requirements
of ICMJE [Ref. 73, 2].
As we noted in the NPRM, careful consideration was given to the
data elements that were part of the data bank prior to passage in 2007
of section 402(j) of the PHS Act, some of which are not expressly
required under section 402(j)(2)(A)(ii) of the PHS Act, but which we
considered necessary to fulfill both the purpose of the expansion of
registration information contained in ClinicalTrials.gov and certain
other requirements of section 402(j) of the PHS Act. We later consulted
with a wide range of groups, including the NLM Board of Directors
Working Group on Clinical Trials, internal NIH and joint NIH-FDA
working groups and committees, the FDA Risk Communication Advisory
Committee, the HHS Secretary's Advisory
[[Page 65033]]
Committee on Human Research Protections, the Drug Information
Association Clinical Trial Disclosure Special Interest Area Community,
and a Clinical and Translational Science Awards ClinicalTrials.gov Task
Force [Ref. 72, 91, 91]. We believe, in general, that maintaining
consistency with the pre-existing ClinicalTrials.gov data elements is
consistent with the intent of section 402(j) of the PHS Act. Not only
do we presume that Congress was familiar with those existing
definitions when it developed and passed section 402(j) of the PHS Act,
we also believe that maintaining consistency achieves several important
goals. It is intended to minimize confusion for those who submitted
registration information to ClinicalTrials.gov prior to enactment of
section 402(j) of the PHS Act as well as minimize the level of effort
required by those who previously established automated computer-based
processes for submitting and updating registration data in
ClinicalTrials.gov, rather than entering the data manually into the
data bank. We believe that maintaining consistency serves the public by
facilitating cross-comparison of entries made before and after
enactment of section 402(j) of the PHS Act and that it also ensures
that the proposed clinical trial registration information requirements
would not have the effect of reducing the amount of information
available for newly registered clinical trials as compared to those
registered prior to the passage in 2007 of section 402(j) of the PHS
Act, a result that we believe would be contrary to the intent of
section 402(j) of the PHS Act. For these reasons, we believe that
requiring the submission of data elements that were expected to be
submitted to ClinicalTrials.gov prior to the passage in 2007 of section
402(j) of the PHS Act in order to register a clinical trial improves
and does not reduce the clinical trial information submitted to
ClinicalTrials.gov.
While developing our proposed set of data elements for clinical
trial registration information for the NPRM, we decided to exercise our
authority under section 402(j)(2)(A)(iii) of the PHS Act to modify the
section 402(j)(2)(A)(ii) requirements for registration information in
order to achieve the following objectives:
(1) Specify a particular structure for submitting certain clinical
trial registration information in order to (a) help the public use the
data bank more easily and be able to compare entries, consistent with
section 402(j)(2)(B)(iv) of the PHS Act; (b) enable searching of the
data bank using criteria listed in sections 402(j)(2)(B)(i) and (ii) of
the PHS Act; and (c) facilitate the submission of complete and accurate
information by responsible parties.
(2) Enable effective implementation of, or compliance with, other
provisions of section 402(j) of the PHS Act and this part, e.g.,
proposed adding data elements to indicate whether a product under study
in a clinical trial is manufactured in the United States and whether a
study is a pediatric postmarket surveillance of a device product, both
of which are important to help determine whether a study meets the
definition of an applicable clinical trial.
(3) Improve the quality and consistency of clinical trial
registration information, e.g., proposed adding the Other Intervention
Name(s) and Intervention Description data elements to help users
identify and differentiate among similar interventions studied in
registered clinical trials.
(4) Demonstrate whether clinical trials registered in the data bank
have complied with ethical and scientific review procedures in
accordance with applicable statutes and regulations, e.g., proposed
adding the Human Subjects Protection Review Board Status data element
to indicate to potential human subjects and other users whether an
applicable clinical trial has received needed approvals or is not
subject to such requirements (79 FR 69611).
Several commenters supported the additional registration data
elements proposed in the NPRM. An additional commenter requested that
the final rule minimize the number of required registration data
elements to provide more flexibility for the reporting of different
types of trials. In developing the proposed registration data elements,
the Agency carefully considered the statutory provisions and additional
requirements in order to carry out those mandates. We believe that the
data elements proposed in the NPRM represent a ``minimum'' data set of
the information required to describe and understand key information
about a clinical trial. Nevertheless, we have modified some of the
proposed definitions and requirements for particular data elements in
the final rule in response to public comments as well as on our own
initiative (e.g., for clarity or consistency).
Sec. 11.28(a)--Clinical Trial
Overview of Proposal
Proposed Sec. 11.28(a) specified the data elements that a
responsible party would be required to submit to ClinicalTrials.gov to
register an applicable clinical trial other than a pediatric postmarket
surveillance of a device that is not a clinical trial. As we described
in the NPRM, the clinical trial registration information data elements
are grouped into the four categories used in section 402(j)(2)(A)(ii)
of the PHS Act: (1) Descriptive information, (2) recruitment
information, (3) location and contact information, and, (4)
administrative data. Additional data elements that the Agency proposed
were listed in the categories in which they best fit. The proposed
clinical trial registration information data elements, grouped by
category, were described in detail in the NPRM. See Section IV.B.4(a)
of the NPRM for details about the data elements under proposed Sec.
11.28(a) (79 FR 69612).
For each data element defined in proposed Sec. 11.28(a), we
describe the following: (1) The proposed definition, (2) any specific
public comment(s) we received about the data element and our
response(s), and (3) the definition used in Sec. 11.28(a) of the final
rule. The information about each data element is ordered by section
number as assigned in the codified section of the final rule, which
also parallels section 402(j)(2)(A)(ii) of the PHS Act. We note that in
the final rule some of the names of the data elements, as well as their
numbers, differ from those assigned in the NPRM because of
modifications to the data elements, all of which are described in the
context of each specific data element. After discussing the last
registration data element listed under Sec. 11.28(a) of the final rule
(i.e., Responsible Party Contact Information in Sec.
11.28(a)(2)(iv)(F)), we address data elements that were suggested in
the public comments but were not added in the final rule.
We have made one overall change to the structure of Sec. 11.28(a)
and (b). In light of our determination that the registration
requirements that apply to an applicable clinical trial are determined
by the date on which the trial is initiated, i.e., the actual Study
Start Date, as defined in Sec. 11.10(b)(16) (see discussion below in
section IV.F.), we have indicated in both Sec. 11.28(a) and (b) that
for applicable clinical trials that must be registered with
ClinicalTrials.gov as specified in section 402(j)(2)(C) of the PHS Act
or Sec. 11.22, the responsible party must submit the information
specified in section 402(j)(2)(A)(ii) of the PHS Act or the data
elements listed in Sec. 11.28, as applicable.
Based on this modification, Sec. 11.28(a)(1) requires that ``[f]or
such applicable clinical trials that were initiated before January 18,
2017, the responsible party must submit the
[[Page 65034]]
information specified in section 402(j)(2)(A)(ii) of the Public Health
Service Act (42 U.S.C. 282(j)(2)(A)(ii)).'' Section 11.28(a)(2)
requires the data elements described below for such applicable clinical
trials that are initiated on or after January 18, 2017.
(i) Descriptive Information
(A) Brief Title. In Sec. 11.10(b)(1) of the NPRM, Brief Title was
defined as ``a short title of the clinical trial written in language
intended for the lay public, including any acronym or abbreviation used
publicly to identify the clinical trial.'' Section
402(j)(2)(A)(ii)(I)(aa) of the PHS Act specifically requires the
submission of a brief title as part of the clinical trial information
submitted at registration, but it does not define the term, other than
to indicate that the title is ``intended for the lay public.'' As
explained in the NPRM, we interpreted this requirement to mean that
potential human subjects should be able to understand, from the brief
title, the general purpose of the clinical trial and distinguish it
from others listed in the data bank. Additionally, based on our
experience to date with ClinicalTrials.gov, we recognized that acronyms
are frequently used to refer to clinical trials (e.g., ``ACCORD'' for
the Action to Control Cardiovascular Risk in Diabetes trial or
``STAR*D'' for the Sequenced Treatment Alternatives to Relieve
Depression trial), and we believe that it is important for such
acronyms to be included in the registry to enable users of the data
bank to identify clinical trials that they may see referenced in other
media (e.g., news reports, journal articles). As such, we considered an
acronym used to identify a clinical trial to be part of the brief title
(79 FR 69612). We received no comments on this description and
therefore maintain the proposed description in the final rule. We note
that a Brief Title intended for the lay public should include, where
possible, information on the participants, condition being evaluated,
and intervention(s) studied.
(B) Official Title. In Sec. 11.10(b)(2) of the NPRM, we defined
Official Title as ``[t]he title of the clinical trial, corresponding to
the title of the protocol.'' As described in the NPRM, while not
explicitly required in section 402(j)(2)(A)(ii)(I) of the PHS Act, we
used the authority in section 402(j)(2)(A)(iii) of the PHS Act to
propose to require a responsible party to submit an official title as
part of clinical trial information when registering an applicable
clinical trial on ClinicalTrials.gov. We expressed our belief that the
Official Title will complement the Brief Title that is intended for the
lay public by providing a technical title that will help researchers
understand the general purpose of the study. The official title would
also be helpful in associating the clinical trial on ClinicalTrials.gov
with information about the clinical trial contained in other sources,
such as scientific publications, regulatory submissions, and media
reports, which often use the official title of the study protocol (79
FR 69612). We received no comments on this description and therefore
maintain the proposed description in the final rule. We note that
Official Title is also consistent with the WHO Trial Registration Data
Set (version 1.2.1) (WHO data item #10) and ICMJE registration
policies, which require the submission of a ``scientific title'' [Ref.
73, 2].
(C) Brief Summary. In Sec. 11.10(b)(3) of the NPRM, Brief Summary
was described as ``a short description of the clinical trial, including
a brief statement of the clinical trial's hypothesis, written in
language intended for the lay public.'' As noted in the NPRM, section
402(j)(2)(A)(ii)(I)(bb) of the PHS Act expressly requires a ``brief
summary'' to be submitted as clinical trial registration information,
but it does not define the term other than to indicate that the brief
summary is ``intended for the lay public'' (79 FR 69612). We received
no comments on this description and therefore maintain the proposed
description in the final rule.
(D) Primary Purpose. Under Sec. 11.10(b)(4) of the NPRM, Primary
Purpose referred to ``the main objective of the intervention(s) being
evaluated by the clinical trial.'' We noted in the NPRM that section
402(j)(2)(A)(ii)(I)(cc) of the PHS Act expressly requires the ``primary
purpose'' of the intervention(s) to be submitted as clinical trial
registration information, but it does not define the term (79 FR
69612). We received no comments on this description and maintain the
proposed definition in the final rule.
In the NPRM, we stated that we would require a responsible party to
provide a response selected from the following set of options:
``Treatment,'' ``prevention,'' ``diagnostic,'' ``supportive care,''
``screening,'' ``health services research,'' ``basic science,''
``feasibility,'' or ``other'' (79 FR 69612) We are modifying the name
of one of these options, from ``feasibility'' to ``device
feasibility.'' This change helps responsible parties more easily
recognize that the option is intended to be limited to the type of
feasibility study of a device that is described as being excluded from
the definition of an applicable device clinical trial as specified in
section 402(j)(1)(A)(ii) of the PHS Act and defined in Sec. 11.10(a)
of this part. ``Device feasibility'' is distinguished from the general
term ``feasibility,'' which is sometimes used in research to describe a
study that is performed to determine the practicality of conducting a
full clinical trial. We also note that a responsible party may
nevertheless voluntarily register a clinical trial that is a
feasibility study of a device. Such registration would be a voluntary
submission of clinical trial information under section 402(j)(4)(A) of
the PHS Act and Sec. 11.60 of the final rule.
In addition, we would like to provide additional clarification for
responsible parties regarding the options available under Primary
Purpose. These clarifications are as follows: ``Treatment'' should be
selected when one or more interventions are being evaluated for
treating a disease, syndrome, or condition; ``prevention'' should be
selected when one or more interventions are being assessed for
preventing the development of a specific disease or health condition;
``diagnostic'' should be selected when one or more interventions are
being evaluated for identifying a disease or health condition;
``supportive care'' should be selected when one or more interventions
are being evaluated for maximizing comfort, minimizing side effects, or
mitigating against a decline in the subject's health or function;
``screening'' should be selected when one or more interventions are
being assessed or examined for identifying a condition, or risk factors
for a condition, in people who are not yet known to have the condition
or risk factor; ``health services research'' should be selected when
one or more interventions are being evaluated for the delivery,
processes, management, organization or financing of health care;
``basic science'' should be selected when one or more interventions are
being used for examining the basic mechanism of action (e.g.,
physiology, biomechanics), of an intervention or disease process;
``device feasibility'' should be selected when a device product is
being evaluated for the feasibility of the product or of a test
prototype device and not health outcomes; and ``other'' should be
selected when none of the other options apply.
(E) Study Design. Proposed Sec. 11.10(b)(5) defined Study Design
as ``a description of the manner in which the clinical trial will be
conducted'' and required information about the following important
aspects of a clinical
[[Page 65035]]
trial: Interventional study model, number of arms, arm information,
allocation, masking, and whether a single-armed clinical trial is
controlled. As we noted in the NPRM, this proposed definition of Study
Design, including the key attributes, conforms to ICH Guidelines [Ref.
56] and is consistent with ``study type'' of the WHO Trial Registration
Data Set (version 1.2.1) (WHO data item #15) and ICMJE registration
policies [Ref. 2, 73]. Section 402(j)(2)(A)(ii)(I)(dd) of the PHS Act
expressly requires ``study design'' to be submitted as part of clinical
trial registration information, but it does not define the term.
Because there are many important aspects of a study design, and
information about each is relevant to ensuring that the descriptions of
study designs are complete and comparable across clinical trials, we
proposed to require that several components of study design be
submitted, as described below. Although none of these terms is used in
section 402(j) of the PHS Act, we pointed out that we believe that each
is a key component of study design (79 FR 69613). We received no
comments on the overall definition and therefore generally maintain the
proposed definition of Study Design in the final rule, with one
exception.
The final rule does not include the proposed Single Arm Controlled?
data item of the Study Design data element, which was defined in Sec.
11.10(b)(5)(vi) of the NPRM as ``[f]or a single-armed clinical trial
only, whether or not the clinical trial is controlled, as specified by
the protocol or statistical analysis plan.'' This data item of the
Study Design data element was proposed in the NPRM to assist the
Agency, responsible parties, and users of the data bank in determining
whether a clinical trial with only one arm meets the definition of an
applicable clinical trial because it includes a control or is
controlled. However, as described in Section IV.A.5, the Agency has
clarified its interpretation of ``control or controlled'' to make clear
that all single-arm interventional studies or clinical trials with pre-
specified primary or secondary outcome measures are considered to be
``controlled'' for purposes of this part. As such, the proposed Single
Arm Controlled? component of the Study Design data element is not
necessary and has been removed from Sec. Sec. 11.10(b) and 11.22(b) of
the final rule.
Interventional Study Model. In Sec. 11.10(b)(5)(i) of the NPRM,
this data item was defined as ``[t]he strategy for assigning
interventions to human subjects.'' As stated in the NPRM, responsible
parties would be required to select an entry from the following limited
set of proposed options: ``single group'' (i.e., clinical trials with a
single arm), ``parallel'' (i.e., participants are assigned to one of
two or more groups in parallel for the duration of the study), ``cross-
over'' (i.e., participants receive one of two alternative interventions
during the initial phase of the study and receive the other
intervention during the second phase of the study), and ``factorial''
(i.e., two or more interventions, each alone and in combination, are
evaluated in parallel against a control group). No ``other'' option was
proposed. To address situations in which a clinical trial might use a
modified version of one of these models, or the responsible party might
wish to provide more information about the specific implementation of
the model, we proposed that responsible parties also be able to provide
an optional additional free-text description containing more specific
details about the interventional study model. We invited public comment
on this proposed definition and approach (79 FR 69613). A few
commenters recommended that the final rule add an ``other'' option for
Interventional Study Model, with one commenter suggesting ``enrichment
designs'' and ``adaptive borrowing of historical data'' as examples. We
note that these examples do not appear to represent interventional
study models that differ conceptually from those proposed in the NPRM.
For example, even though ``enrichment designs'' involve prespecified
study periods that allow researchers to select subsets of enrolled
participants who are likely to be particularly sensitive to the studied
intervention (e.g., to demonstrate the effect of a drug), we believe
that the underlying interventional study model involves at least one of
the suggested options (i.e., ``single-group,'' ``parallel,'' ``cross-
over,'' or ``factorial''). The fact that a study involves an enrichment
design could be noted in the proposed optional additional free-text
description field. The final rule retains the name and definition of
Interventional Study Model as proposed in the NPRM. In reviewing this
proposed data item, however, we identified two modifications to the set
of proposed options. First, based on our experience in operating
ClinicalTrials.gov, we add the option of ``sequential'' as we believe
that it represents an Interventional Study Model that is fundamentally
different from the other options available for selection under
Interventional Study Model and is fairly common among drug studies
(e.g., dose escalation). Thus, we have added ``sequential'' as an
option under the Interventional Study Model data item; responsible
parties would select this option to indicate that groups of
participants are assigned to receive interventions based on prior
milestones being reached in the study, such as in some dose escalation
and adaptive design studies. Second, we have also modified the
description of the ``cross-over'' option to clarify that this term
refers to study designs in which participants are assigned to receive
one of two (or more) alternative interventions during the initial phase
of the study followed by the other intervention(s) during subsequent
phase(s) of the study. This modification clarifies that cross-over
studies are not restricted to just two interventions, but may involve
two (or more) interventions [Ref. 84].
Number of Arms. In Sec. 11.10(b)(5)(ii) of the NPRM, this data
item was defined as ``[t]he number of arms in the clinical trial. For a
trial with multiple periods or phases that have different numbers of
arms, the maximum number of arms during any period or phase.'' We noted
that the term ``arm'' was defined in proposed Sec. 11.10(a) and that
some clinical trials contain multiple periods or phases, each of which
might use different numbers of arms. We also clarified in the NPRM that
we do not consider historical controls to be an ``arm'' of a clinical
trial for the purposes of this part, therefore, they would not be
counted in the number of arms (79 FR 69613). One commenter suggested
that, for reporting trials with ``mutually reporting arms,'' the
maximum number of arms listed should be inclusive of all arms from all
periods. This commenter also suggested that historical controls not be
counted in the Number of Arms data item of the Study Design data
element, which is specified in proposed Sec. 11.28(a)(1)(v) and
defined in proposed Sec. 11.10(b)(5)(ii). We interpreted this comment
to refer to ``mutually exclusive reporting arms,'' agree with the
commenter, and note that the definition in Sec. 11.10(b)(5)(ii)
specifies that ``[f]or a trial with multiple periods or phases that
have different numbers of arms, it means the maximum number of arms
during all periods or phases.'' We also reiterate, as stated in the
preamble of the NPRM, that ``historical controls are not considered to
be an `arm' of a clinical trial and thus are not counted in the number
of arms'' (79 FR 69613). After considering this comment, we maintain
the proposed definition in the final rule, except the definition
clarifies that for a trial with multiple periods or phases
[[Page 65036]]
that have different numbers of arms, the ``number of arms'' means the
maximum number of arms during ``all periods or phases''.
Arm Information. In Sec. 11.10(b)(5)(iii) of the NPRM, this data
item was defined as ``[a] description of each arm of the clinical trial
that indicates its role in the clinical trial, provides an informative
title, and, if necessary, additional descriptive information to
differentiate each arm from other arms in the clinical trial.'' As
stated in the NPRM, responsible parties would be required to select
from the following list of options for describing the role of each arm
in the clinical trial: ``Experimental,'' ``active comparator,''
``placebo comparator,'' ``sham comparator,'' ``no intervention,'' or
``other.'' The informative title would consist of a label or short name
to identify the arm in the clinical trial record (e.g., the name of the
experimental intervention used in the arm or placebo). Additional
descriptive information would be required if the informative title does
not sufficiently differentiate among arms in the clinical trial (e.g.,
in a clinical trial that compares two different dosages of the same
investigational drug, the descriptive information would have to
indicate which is the higher dose arm versus the lower dose arm). Even
if the informative title and/or additional descriptive information vary
sufficiently among the arms of the clinical trial, responsible parties
may voluntarily include additional details about the interventions or
the arms in this field (79 FR 69613). We received a few comments about
Arm Information. One commenter requested that the final rule clarify
that a historical-control arm be considered ``other'' from the list of
options available for Arm Information. Another commenter asked for a
way to distinguish between study designs that incorporate
``concurrent'' and ``nonconcurrent'' controls, which are described in
the preamble discussion of the term ``controlled'' in the NPRM. As
noted in the preamble of the NPRM, we do not consider historical
controls or other types of non-concurrent controls to be arms for the
purposes of the Number of Arms data item defined in proposed Sec.
11.10(b)(5)(ii) (79 FR 69613). Because Arm Information is used to
describe each arm identified by Number of Arms, the need to identify an
arm as ``historical'' or ``nonconcurrent'' should not arise when
submitting Arm Information in ClinicalTrials.gov. However, if a
responsible party wishes to identify and/or describe a historical or
non-concurrent control used in the study, we note that such information
could be submitted using an optional data item such as Detailed
Description. After consideration of these comments, we generally are
maintaining the proposed definition in the final rule. However, we are
revising it slightly to specify that if more than one arm is specified
for the clinical trial, the responsible party must designate the listed
intervention(s) to the arm in which they are administered. Therefore,
``arm information'' is defined as ``[a] description of each arm of the
clinical trial that indicates its role in the clinical trial, provides
an informative title, and, if necessary, additional descriptive
information (including which interventions are administered in each
arm) to differentiate each arm from other arms in the clinical trial.''
This designation approach (currently implemented using the ``[Arm or
Group]/Intervention Cross-Reference'' data element) will allow for
continuing to display on ClinicalTrials.gov arm and intervention
information as a table, helping users understand the relationship
between arm information and intervention information.
Allocation. In Sec. 11.10(b)(5)(iv) of the NPRM, this data item
was defined as ``[t]he method by which human subjects are assigned to
arms in a clinical trial.'' As stated in the NPRM, responsible parties
would be required to select from the following limited set of options:
``randomized'' (participants are assigned to intervention groups by
chance), or ``nonrandomized'' (participants are expressly assigned to
intervention groups through a non-random method, such as physician
choice), or ``not applicable'' (for a single-arm study). No ``other''
option was proposed (79 FR 69613). We invited public comment, but did
not receive any, therefore, we maintain the proposed definition and
approach in the final rule.
Masking. In Sec. 11.10(b)(5)(v) of the NPRM, this data item was
defined as ``[t]he party or parties, if any, involved in the clinical
trial who are prevented from having knowledge of the interventions
assigned to individual human subjects.'' As stated in the NPRM,
responsible parties would be required to select from the following
limited set of choices for describing which party(ies) is/are masked:
``human subject,'' ``care provider,'' ``investigator,'' and/or an
``outcomes assessor'' (i.e., the individual who evaluates the
outcome(s) of interest). No ``other'' option was proposed, but
responsible parties would have the ability to provide additional,
optional free-text information about other parties who may be blinded
in the clinical trial (79 FR 69614). We received no comments, however,
for clarity, we are adding to the limited menu of choices ``no
masking'' for the responsible party to indicate that the study design
does not include masking (e.g., open-label). We otherwise maintain the
proposed definition in the final rule.
Single Arm Controlled. In Sec. 11.10(b)(5)(vi) of the NPRM, this
data item was defined as ``for a single arm clinical trial only,
whether or not the clinical trial is controlled, as specified by the
protocol or statistical analysis plan.'' We have deleted this data item
in the final rule because the information is no longer necessary to
determine whether a clinical trial is ``controlled'' under the
definition in Sec. 11.10(a) and therefore an ``applicable drug
clinical trial'' or ``applicable device clinical trial'' under the
regulations, as discussed in the preamble for Sec. 11.22.
(F) Study Phase. In Sec. 11.10(b)(6) of the NPRM, this data
element was defined as ``for a clinical trial of a drug, the numerical
phase of such clinical trial, consistent with terminology in 21 CFR
312.21, or any successor regulation, such as phase 2 or phase 3, and in
21 CFR 312.85, or any successor regulation, for phase 4 studies.''
Section 402(j)(2)(A)(ii)(I)(ee) of the PHS Act expressly requires, for
an applicable drug clinical trial, the ``study phase'' to be submitted
as a clinical trial registration information data element, but it does
not define the term. As stated in the NPRM, responsible parties would
be required to select one response from a limited list of options that
includes phases 1, 2, 3, and 4, consistent with the terminology in 21
CFR 312.21 and 21 CFR 312.85. In addition, responsible parties would be
able to select from other options that are commonly used in practice:
Phase 1/phase 2 (for trials that are a combination of phases 1 and 2;
as discussed previously, phase 1/phase 2 studies are not considered
phase 1 studies and may be applicable drug clinical trials) and phase
2/phase 3 (for trials that are a combination of phases 2 and 3). No
``other'' option was proposed. Although we are aware that the term
``phase 0'' is used in practice (e.g., to refer to clinical trials that
are exploratory in nature and are not designed to evaluate therapeutic
or diagnostic intent), any trial that would be referred to as ``phase
0'' meets the definition of a phase 1 trial under FDA regulations (21
CFR 312.21). Therefore, we did not propose to include ``phase 0'' as an
option for the Study Phase data element, and responsible parties
registering a clinical trial that might be referred to as ``phase 0''
would select ``phase 1'' for the Study Phase (79 FR 69614). We received
no comments on
[[Page 65037]]
this description and therefore maintain the proposed description in the
final rule except that we clarify that ``drug'' means ``drug product.''
We note that study phases are not intended for use in describing
clinical trials of devices; therefore, consistent with section
402(j)(2)(A)(ii)(I)(ee) of the PHS Act, responsible parties for
applicable device clinical trials would not be required to submit this
data element.
(G) Study Type. In Sec. 11.10(b)(7) of the NPRM, we defined this
data element as ``the type of study for which clinical trial
information is being submitted.'' Section 402(j)(2)(A)(ii)(I)(ff) of
the PHS Act expressly requires ``study type'' to be submitted as
clinical trial information at the time of registration, but it does not
define the term. Consistent with practice prior to FDAAA, we stated in
the NPRM that responsible parties would be required to select one of
the following limited set of options: ``Interventional,''
``observational,'' or ``expanded access program.'' No ``other'' option
was proposed. We expressed our belief that all applicable clinical
trials and all other clinical studies that might be registered
voluntarily on ClinicalTrials.gov could be accurately characterized as
either ``interventional'' or ``observational,'' depending on whether
human subjects studied are assigned to interventions based on a
research protocol (interventional) or whether patients receive
interventions as part of routine medical care, and a researcher studies
the effect of the intervention (observational). We indicated that we
would consider observational studies to include a wide range of non-
interventional studies, including retrospective reviews of patient
records or relevant literature (79 FR 69614). (See the elaboration of
the terms ``applicable device clinical trial'' and ``applicable drug
clinical trial'' in Section IV.A.5 of this preamble). We received one
comment requesting that we provide clarification by either providing
examples or modifying the definition so that it does not use the term
being defined. We believe ``type of study'' in the proposed definition
is sufficiently clear, particularly with the three options described
for the Study Type data element. In addition, the elaboration of the
terms ``applicable device clinical trial'' and ``applicable drug
clinical trial'' in Section IV.A.5 of this preamble provide further
details about interventional and observational studies. We also plan to
provide additional guidance, including examples, as needed.
After considering the comments, we maintain the NPRM definition in
the final rule, except we clarify that Study Type means ``the nature of
the investigation or investigational use for which clinical trial
information is being submitted, e.g., interventional, observational.''
We note that a study that is designated ``interventional,'' as that
term is defined in this part, may or may not be an applicable clinical
trial, depending on whether it meets the other criteria for an
applicable clinical trial that are specified in this part. A study that
is designated ``observational'' would be an applicable clinical trial
only if it is a pediatric postmarket surveillance of a device product
as defined in this part. (See the definition of ``pediatric postmarket
surveillance of a device product'' in Sec. 11.10, the discussion of
Sec. 11.28(b), and the discussion of observational studies in Section
IV.A.5 of this preamble). Conversely, any applicable clinical trial
other than a pediatric postmarket surveillance of a device product must
have a Study Type of ``interventional.'' An applicable clinical trial
that is a pediatric postmarket surveillance of a device product could
have a Study Type of ``interventional'' or ``observational.'' The term
``expanded access'' is provided as an option for Study Type because
responsible parties who are both manufacturers of an investigational
drug product (including a biological product) that is available for
expanded access use and sponsors of an applicable clinical trial of the
investigational product are required to create an expanded access
record for the investigational drug product (including a biological
product) if such a record does not already exist at the time the
applicable clinical trial is registered. As discussed in section IV.A.5
of this preamble, expanded access use is not considered to be an
applicable clinical trial. Therefore, the Study Type for all expanded
access use is ``expanded access'' (see the discussion of Sec.
11.28(c)).
(H) Pediatric Postmarket Surveillance of a Device Product. In Sec.
11.10(b)(8) of the NPRM, we defined the Whether the Study is a
Pediatric Postmarket Surveillance of a Device data element to mean
``for a study that includes a device as an intervention and is a
pediatric postmarket surveillance of a device, an affirmation that the
study is a pediatric postmarket surveillance of a device.'' Although
this data element is not explicitly listed in section 402(j) of the PHS
Act as part of clinical trial information, we proposed it to identify a
subset of applicable device clinical trials. As we noted in the NPRM,
the term ``applicable device clinical trial'' is defined, in part, as
``a pediatric postmarket surveillance as required under section 522 of
the Federal Food, Drug, and Cosmetic Act'' (see section
402(j)(1)(A)(ii)(II) of the PHS Act). A responsible party would be
required to provide this data element only if the study is a pediatric
postmarket surveillance of a device product; a responsible party would
not be required to submit this data element if the device study is not
a pediatric postmarket surveillance of a device product (79 FR 69615).
We received no comments addressing this data element. In the final
rule, we modify the name of the data element to ``Pediatric Postmarket
Surveillance of a Device Product'' to clarify that ``device'' means
``device product'' and modify the definition to clarify that the term
refers only to ``a clinical trial or study that includes a U.S. FDA-
regulated device product as an intervention'' and is a pediatric
postmarket surveillance of a device product ``ordered under section 522
of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 369l).'' In the
final rule, we also removed from the definition the requirement for an
affirmation that the study is a pediatric postmarket surveillance of a
device. By indicating that a study is a pediatric postmarket
surveillance of a device product, users of the data bank and the Agency
will be able to confirm that the study is an applicable device clinical
trial. In addition, by combining this information with other submitted
clinical trial registration information (e.g., the Study Type data
element), the Agency could confirm whether the pediatric postmarket
surveillance of a device product is a clinical trial and indicate which
other data elements must be submitted at the time of registration. If a
pediatric postmarket surveillance of a device product is a clinical
trial, the clinical trial registration information data elements set
forth in Sec. 11.28(a) will be required to be submitted. If a
pediatric postmarket surveillance of a device product is not a clinical
trial (i.e., it is a form of observational study, including a
retrospective review of patient records or relevant literature), then
the clinical trial registration information data elements specified in
Sec. 11.28(b) will be required to be submitted.
(I) Primary Disease or Condition Being Studied in the Trial, or the
Focus of the Study. In Sec. 11.10(b)(9) of the NPRM, we defined this
data element as ``the name(s) of the disease(s) or condition(s) studied
in the clinical trial, or the focus of the clinical trial, using, if
available, appropriate descriptors from the NLM's
[[Page 65038]]
MeSH controlled vocabulary thesaurus http://www.nlm.nih.gov/mesh/, or
terms from another vocabulary, such as the SNOMED CT, that has been
mapped to MeSH within the UMLS Metathesaurus, https://uts.nlm.nih.gov.'' As we noted in the NPRM, section
402(j)(2)(A)(ii)(I)(gg) of the PHS Act expressly requires ``the primary
disease or condition being studied, or the focus of the study'' to be
submitted as part of clinical trial registration information, but it
does not define the term. Section 402(j)(2)(B)(i)(I) of the PHS Act
further requires the data bank to be searchable by one or more of eight
listed criteria, including ``the disease or condition being studied in
the clinical trial, using Medical Subject Headers (MeSH) descriptors.''
To support searching using MeSH descriptors, the primary disease or
condition being studied in the clinical trial, or the focus of the
study, must be described using either MeSH terminology (http://www.nlm.nih.gov/mesh/) or another terminology that has been mapped to
MeSH, when available (if the other terminology is mapped to MeSH, the
data bank can be searched using MeSH terms and retrieve the correct
record(s)) (79 FR 69615). We received no comments on this proposed data
element, but we slightly modify the proposed description in the final
rule for clarity as follows: ``the name(s) of the disease(s) or
condition(s) studied in the clinical trial, or the focus of the
clinical trial. Use, if available, appropriate descriptors from NLM's
Medical Subject Headings (MeSH) controlled vocabulary thesaurus, or
terms from another vocabulary, such as the Systematized Nomenclature of
Medicine--Clinical Terms (SNOMED CT), that has been mapped to MeSH
within the Unified Medical Language System (UMLS) Metathesaurus.'' We
note that this definition is consistent with ``health condition(s) or
problem(s) studied'' of the WHO Trial Registration Data Set (version
1.2.1) (WHO data item #12) and ICMJE registration policies [Ref. 2,
73].
(J) Intervention Name(s). Under Sec. 11.10(b)(10) of the NPRM,
Intervention Name was specified as ``a brief descriptive name used to
refer to the intervention(s) studied in each arm of the clinical trial.
A non-proprietary name of the intervention must be used, if available.
If a non-proprietary name is not available, a brief descriptive name or
identifier must be used.'' Section 402(j)(2)(A)(ii)(I)(hh) of the PHS
Act expressly requires ``intervention name'' to be submitted as part of
clinical trial information at the time of registration, but it does not
define the term. As we explained in the NPRM, we believe the purpose of
this data element is to enable interested parties to readily identify
the intervention(s) being studied in each arm of a clinical trial and
compare clinical trials by intervention. While some clinical trials
compare a single intervention against a placebo, many compare multiple
interventions (e.g., a newly developed drug product versus standard
treatment, or different dosages of the same drug product). We believe
it is important for the names of all interventions studied in a
clinical trial to be submitted to the data bank (79 FR 69616). We
received no comments on this proposed data element and therefore are
maintaining it in the final rule, although we slightly modify its name
to ``Intervention Name(s)'' and specify in the definition that ``it''
refers to ``the intervention'' for clarity. Based on our experience in
operating ClinicalTrials.gov, we recognize that there are inherent
difficulties in determining the level of detail that should be required
for naming interventions, especially those without non-proprietary
(i.e., generic) names [Ref. 23]. We believe that non-proprietary names
must be provided for interventions (e.g., drug products (including
biological products) and device products) when available. For
interventions for which a non-proprietary name is not available, our
prior experience suggests that a brief descriptive name can suffice. In
either case, additional descriptive information is often needed to
distinguish the intervention(s) under study from other, similar
interventions used in practice or studied in the same or other clinical
trials. Examples of a brief descriptive name or identifier include a
chemical name, company code, or serial number. We note that this
description of Intervention Name(s) is consistent with the
``intervention(s)'' of the WHO Trial Registration Data Set (version
1.2.1) (WHO data item #13) and ICMJE registration policies [[Ref. 2,
73].
(K) Other Intervention Name(s). In Sec. 11.10(b)(11) of the NPRM,
this term was defined as ``other current and former name(s) or
alias(es), if any, different from the Intervention Name(s), that the
sponsor has used publicly to identify the intervention, including, but
not limited to, past or present names such as brand name(s), serial
numbers, or chemical descriptions.'' As noted in the NPRM, ``other
intervention name(s)'' is a term that is not used in section 402(j) of
the PHS Act, but it is proposed as a data element that responsible
parties must submit if the sponsor has used more than one name publicly
to identify the intervention under study in a clinical trial. Based on
our experience operating ClinicalTrials.gov, we are aware that
interventions often have multiple names, including, for example, a
sponsor code name, brand name(s), or a name or identifier from a
standard vocabulary, such as RxNorm for drugs (http://www.nlm.nih.gov/research/umls/rxnorm/index.html). Accordingly, providing only a single
name for each intervention (as is required under the Intervention
Name(s) data element) does not necessarily provide enough information
to allow users to find and compare all clinical trials in
ClinicalTrials.gov that involve a specific intervention, as a different
clinical trial with the same intervention may have been registered by
another responsible party under a different intervention name.
Therefore, we noted that we believe that adding a requirement to submit
Other Intervention Name(s) improves and does not reduce the clinical
trial information available in the data bank. We also noted that this
requirement could mean that, in some circumstances (e.g., when the
responsible party is a designated principal investigator), the
responsible party would need to communicate with the sponsor or the
manufacturer of the intervention(s) to determine whether another name
has been used publicly. We indicated that we do not believe such
additional communication would be frequent or onerous. The proposal
would not have required a responsible party to submit names that have
not been used publicly because users of ClinicalTrials.gov would be
unlikely to search for a clinical trial using such names. We asked for
comment on this approach (79 FR 69616) and some commenters addressed
the Other Intervention Name(s) data element. A few commenters suggested
requiring the use of a universally recognized standard, such as the WHO
International Nonproprietary Names (INN) or the FDA unique device
identifier (UDI). While we agree that the Other Intervention Name(s)
data element includes all standardized names, we note that the data
element is not limited to only those intervention names that are
compliant with a particular naming standard or convention. As stated in
the proposed definition, this data element is intended to broadly
capture all ``other current and former name(s) or alias(es) . . . that
the sponsor has used publicly to identify the intervention.''
Therefore, we clarify that all names, including internationally
recognized standard names, must be
[[Page 65039]]
submitted for the Other Intervention Name(s) data element.
One commenter indicated that displaying other intervention names
would be confusing to the public and suggested that the final rule
remove Other Intervention Name(s) as a required data element. Another
commenter requested that only the U.S. generic and proprietary names be
required for submission. We disagree with both commenters. Because
users of ClinicalTrials.gov may encounter a number of names for an
intervention depending on the source or context (e.g., drug code name),
we believe that providing access to all the different public names of
an intervention would help users find potentially relevant information.
Additionally, requiring responsible parties to provide all public names
for an intervention allows the ClinicalTrials.gov system to identify
and retrieve clinical studies records listing any of the relevant
intervention names. After consideration of these comments, we generally
maintain this data element as proposed in the final rule. We modify the
definition by deleting the phrase ``chemical descriptions'' to avoid
any suggestion that chemical descriptions are required to be submitted.
Chemical descriptions are, however, an example of another type of name
that would be appropriate to include for Other Intervention Name(s).
(L) Intervention Description. In Sec. 11.10(b)(12) of the NPRM, we
defined this term to mean ``details that can be made public about the
intervention, other than the Intervention Name and Other Intervention
Name(s), sufficient to distinguish it from other, similar interventions
studied in the same or another clinical trial.'' As we described in the
NPRM, while this term is not used in section 402(j) of the PHS Act, we
proposed it as an additional data element to be submitted as clinical
trial information at the time of registration. Based on prior
experience, we recognize that the Intervention Name(s) and Other
Intervention Name(s) data elements, whether providing information on
brand or non-proprietary names, do not always provide enough
information to allow potential human subjects or other
ClinicalTrials.gov users to differentiate among similar interventions
used in different arms of a clinical trial, distinguish the
intervention used in one clinical trial from a similar intervention
used in another clinical trial, or understand the differences between
interventions studied in a clinical trial and those used in routine
medical practice. For example, a clinical trial might compare two or
more dosages of the same drug or two different clinical trials might
examine drug-eluting stents that are similar to those used in standard
medical practice. To reduce this ambiguity, additional descriptive
information about the intervention is needed, such as information about
the dosage, dosage form, frequency of administration, route of
administration, and/or duration of administration of a drug, or a
general description of the device, including how the device functions;
the scientific concepts that form the basis for the device; and the
significant physical and performance characteristics of the device,
such as its key components and the general types of materials used. The
submission of such information would enable users (whether subjects,
patients, physicians, researchers, or others) to understand key
elements of a clinical trial, and compare information among clinical
trials. For these reasons, requiring the submission of an intervention
description would improve but not reduce the clinical trial information
available in the data bank (79 FR 69616). A few commenters suggested
that the Agency consider making optional some of the details required
to be submitted for the Intervention Description data element; other
commenters recommended that the entire data element be considered
optional in the final rule. The reasons provided were that such
detailed information may contain confidential commercial information
and providing such details would be burdensome. The Agency disagrees
with these commenters and continues to believe that users of the public
site must be able to understand the interventions that are being
compared in a trial and how the comparators differ from each other and/
or other similar interventions. For example, the Consolidated Standards
Of Reporting Trials (CONSORT) guidelines recommend that each
intervention, including control interventions, be described thoroughly
so that published studies may be understood more clearly [Ref. 93]. The
submission of these details at study registration could also give
earlier insight to the problem of study sponsors choosing
inapprorpriate comparison groups, which can bias study results [Ref.
94]. As specified in the NPRM, the Agency also believes that
sufficiently detailed information could be made public without
including information that the sponsor may consider sensitive or
proprietary (79 FR 69616). While the final rule retains the name of the
proposed data element, we have modified the proposed definition by
adding an example for clarity as a second sentence. Thus, the final
rule defines the term to mean ``details that can be made public about
the intervention, other than the Intervention Name(s) and Other
Intervention Name(s), sufficient to distinguish it from other, similar
interventions studied in the same or another clinical trial. For
example, interventions involving drugs may include dosage form, dosage,
frequency and duration.'' We clarify that Intervention Description
should be sufficiently detailed to differentiate the specified
intervention from other similar interventions, but should not include
information that the responsible party cannot make public. For example,
if the specific dosage of a drug being studied cannot be divulged, a
responsible party could instead indicate whether the dosage is higher
or lower than that used in an approved or licensed drug or in another
arm of the study. If an experimental device uses different material
than previous versions of the device, or than other marketed devices,
the responsible party could provide a general description of the new
material without including its specific formulation.
(M) Intervention Type. In Sec. 11.10(b)(13) of the NPRM,
Intervention Type was defined as ``for each intervention studied in the
clinical trial, the general type of intervention.'' As we pointed out
in the NPRM, section 402(j)(2)(A)(ii)(I)(hh) of the PHS Act expressly
requires ``intervention type'' to be submitted as part of clinical
trial information at the time of registration, but it does not define
the term. We further proposed that responsible parties would be
required to select one of the following options for each intervention
studied: ``drug'' (including placebo), ``device'' (including sham),
``biological/vaccine,'' ``procedure/surgery,'' ``radiation,''
``behavioral'' (e.g., psychotherapy, lifestyle counseling), ``genetic''
(including gene transfer, stem cell and recombinant DNA), ``dietary
supplement'' (e.g., vitamins, minerals), ``combination product''
(combining a drug and device, a biological product and device; a drug
and biological product; or a drug, biological product, and device),
``diagnostic test'' (e.g., imaging, in-vitro), and ``other.'' We noted
that when the intervention used is a combination product (e.g., drug-
eluting stent), the responsible party must select ``combination
product'' as the Intervention Type (79 FR 69617). We received one
comment requesting clarification by either providing examples or
modifying the definition so that it does not use the term being
defined. We believe ``type of intervention'' in the proposed definition
[[Page 65040]]
is sufficiently clear, particularly with the options described for the
Intervention Type data element. We also plan to provide additional
guidance as needed.
After considering the comments, we maintain the NPRM definition in
the final rule, except that we add ``e.g., drug, biological/vaccine, or
device'' as examples for clarification. Note that, as specified in
Sec. 11.28(a)(2)(i)(M) of the final rule, selection of an Intervention
Type is required for each intervention studied in each arm of the
clinical trial. Some clinical trials will therefore include multiple
intervention types. As discussed in Section IV.B.2 of this preamble, a
clinical trial that studies a drug and a device as separate,
independent interventions would list both ``drug'' and ``device'' as
Intervention Types and may meet the definitions of both an applicable
device clinical trial and an applicable drug clinical trial. If the
U.S. FDA-regulated device product studied in such an applicable
clinical trial is not approved or cleared by FDA for any use, we would
not post clinical trial registration information for that applicable
clinical trial prior to the date of approval or clearance of the device
product, consistent with Sec. 11.35(b)(2)(i), unless the responsible
party indicates, pursuant to Sec. 11.35(b)(2)(ii), that it authorizes
such posting. In addition, if the Intervention Type is specified as a
``drug,'' ``biological/vaccine,'' or ``device,'' but both the Studies a
U.S. FDA-regulated Device Product and Studies a U.S. FDA-regulated Drug
Product data elements are specified as ``no,'' the clinical trial would
not be an applicable clinical trial under the definition in Sec.
11.10(a). For this reason, we note that the Intervention Type data
element is not used in determining whether a clinical trial is an
applicable clinical trial as specified in Sec. 11.22(b).
(N) Studies a U.S. FDA-regulated Device Product. In Sec.
11.10(b)(39) of the NPRM, we defined this data element to mean ``a
clinical trial that studies a device subject to section 510(k), 515, or
520(m) of the Federal Food, Drug, and Cosmetic Act.'' As we described
in the NPRM, although section 402(j) of the PHS Act does not explicitly
require submission of such a clinical trial registration information
data element, we proposed to require such a data element using our
authority under section 402(j)(2)(A)(iii) of the PHS Act, to assist
responsible parties, users of ClinicalTrials.gov, and the Agency in
determining whether a clinical trial is an applicable device clinical
trial, using the approach specified in proposed Sec. 11.22(b)(1). As
specified in the elaboration of the definition of an ``applicable
device clinical trial'' in Section IV.A.5 of this preamble, one
criterion for an applicable device clinical trial is that the clinical
trial studies a device product ``subject to section 510(k), 515, or
520(m) of the [FD&C Act].'' It is possible that a clinical trial with
an Intervention Type of ``device'' would not be an applicable device
clinical trial because the device is not subject to section 510(k),
515, or 520(m) of the FD&C Act. Conversely, it is possible that a
clinical trial could be an applicable device clinical trial even if
none of the specified Intervention Types is a ``device.'' For example,
a clinical trial for which a responsible party indicates the
Intervention Type is ``radiation,'' ``genetic,'' or ``procedure'' could
in fact be an applicable device clinical trial studying a device
product subject to section 510(k), 515, or 520(m) of the FD&C Act
(e.g., an x-ray device, a genetic test, or a surgical instrument). If
the responsible party has obtained an IDE and submitted an IDE number
to ClinicalTrials.gov, the clinical trial is considered an applicable
device clinical trial as defined in this part. If the responsible party
does not submit an IDE number, however, ambiguity would arise because
the lack of an IDE number (or an IDE) does not necessarily indicate
that a clinical trial is not an applicable device clinical trial. We
proposed requiring the Studies an FDA-regulated Device data element in
the NPRM to avoid this ambiguity and help ensure that applicable
clinical trials can be properly identified. Consistent with the
elaboration of the term applicable device clinical trial in Section
IV.A.4 of this preamble, we interpreted this definition to mean that
the clinical trial studies a device that would require any of the
following before it may be legally marketed in the United States: (1) A
finding of substantial equivalence under section 510(k) of the FD&C
Act, (2) an order under section 515 of the FD&C Act approving a
premarket approval application (PMA) for the device, or (3) an HDE
under section 520(m) of the FD&C Act. We believe that submission of
this information would improve and not reduce the clinical trial
information submitted at the time of registration by making it clear to
the responsible party, the Agency, and users of ClinicalTrials.gov
whether a clinical trial without an IDE studies an FDA-regulated
device. This information would, in turn, be used in determining whether
a clinical trial meets the definition of an applicable device clinical
trial, following the approach specified in proposed Sec. 11.22(b)(1).
We also noted that, to reduce the data entry burden on responsible
parties, ClinicalTrials.gov could automatically pre-populate this data
field to indicate ``yes'' if a responsible party submits an IDE number
as part of the FDA IND or IDE Number data element specified in proposed
Sec. 11.10(b)(35) (79 FR 69617).
We received no comments addressing the proposed data element and
therefore retain the proposed definition in the final rule, except that
the definition clarifies that ``device'' is ``device product'' and
includes the applicable U.S.C. statutory citations in the final rule.
The name has also been changed from the proposed ``Studies an FDA-
regulated Device'' to ``Studies a U.S. FDA-regulated Device Product''
in the final rule for clarity. We also note that we are aware that
device products may be used in clinical trials even though they are not
the intervention studied in the clinical trial or the experimental
variable of interest in the study. For example, clinical trials of
procedures involving surgical device products may not be designed to
study the effect of those device products. Therefore, when considering
whether a clinical trial Studies a U.S. FDA-regulated Device Product a
responsible party should consider whether (a) the study is designed to
examine the effect or performance of an FDA-regulated device product or
differences in the intended use, for example, variations in frequency
of use, method of administration, design specifications, and other
characteristics (e.g., used in one or more, but not all, arms in a
multi-arm study); and/or (b) at least one pre-specified primary or
secondary outcome measure reflects a characteristic, effect, or
performance of an FDA-regulated device product (e.g., need for
replacement or maintenance of the device). As described in the preamble
discussion of an applicable device clinical trial in Sec. 11.10(a), a
clinical trial of a combination product with a device primary mode of
action that otherwise meets the definition of an ``applicable clinical
trial'' will be considered an applicable device clinical trial. We note
that for such trials, the responsible party must indicate that the
trial Studies a U.S. FDA-regulated Device Product.
(O) Studies a U.S. FDA-regulated Drug Product. In Sec.
11.10(b)(40) of the NPRM, we defined this data element to mean ``a
clinical trial that studies a drug subject to section 505 of the
Federal Food, Drug, and Cosmetic Act or to section 351 of the Public
Health Services Act.'' As we described in the NPRM, section 402(j) of
the PHS Act does not explicitly require submission of such a clinical
trial registration
[[Page 65041]]
information data element. We proposed to require this data element,
however, using our authority under section 402(j)(2)(A)(iii) of the PHS
Act to assist responsible parties, users of ClinicalTrials.gov, and the
Agency in determining whether or not a clinical trial is an applicable
drug clinical trial using the approach specified in proposed Sec.
11.22(b)(2). As specified in the elaboration of the definition of an
``applicable drug clinical trial'' in Section IV.A.5 of this preamble,
one criterion for an applicable drug clinical trial is that the
clinical trial studies a drug ``subject to section 505 of the [FD&C]
Act or [a biological product subject] to section 351 of [the PHS]
Act.'' We noted that it is possible that a clinical trial with an
Intervention Type of ``drug'' or ``biological/vaccine'' would not be an
applicable drug clinical trial because the drug product is not subject
to section 505 of the FD&C Act (e.g., a non-prescription drug product
that is marketed under an over-the-counter drug monograph) and/or the
biological product is not subject to section 351 of the PHS Act.
Conversely, we indicated that it is possible that a clinical trial
could be an applicable drug clinical trial even if the responsible
party does not select ``drug'' or ``biological/vaccine'' as the
Intervention Type. A clinical trial for which the responsible party
indicates the Intervention Type to be ``dietary supplement'' or
``genetic'' or ``procedure'' could in fact be an applicable drug
clinical trial studying a drug product subject to section 505 of the
FD&C Act or a biological product subject to section 351 of the PHS Act.
For example, a product otherwise marketed as a dietary supplement could
be studied for the treatment of cancer, or a genetic trial could study
a gene therapy. If the responsible party has obtained an IND and
submitted an IND number to ClinicalTrials.gov, the clinical trial would
generally be an applicable drug clinical trial as defined in the NPRM.
If the responsible party does not submit an IND number, however,
ambiguity would arise because the lack of an IND number (or an IND)
does not necessarily indicate that a trial is not an applicable drug
clinical trial. To avoid this ambiguity and help ensure that applicable
clinical trials can be properly identified, we proposed to require a
responsible party to specifically indicate whether a clinical trial
studies an FDA-regulated drug by submitting the Studies an FDA-
regulated Drug data element. Consistent with the elaboration of the
term ``applicable drug clinical trial'' in the NPRM, we interpreted
this definition to mean that the clinical trial studies a drug that is
the subject of an approved NDA or BLA or that would require an approved
NDA or BLA to be legally marketed in the United States. We noted in the
NPRM our belief that submission of this information would improve, and
not reduce, the clinical trial information submitted at the time of
registration by making it clear to the responsible party, the Agency,
and users of ClinicalTrials.gov whether a clinical trial without an IND
studies an FDA-regulated drug product (including a biological product).
This information would, in turn, be used in determining whether a
clinical trial meets the definition of an ``applicable drug clinical
trial,'' following the approach specified in proposed Sec.
11.22(b)(2). To reduce the data entry burden on responsible parties, we
noted that ClinicalTrials.gov could automatically pre-populate this
data field to indicate ``yes'' if a responsible party submits an IND
number as part of the FDA IND or IDE Number data element specified in
proposed Sec. 11.10(b)(35) (79 FR 69618).
We received no comments addressing the proposed data element and
therefore retain the proposed definition in the final rule, except that
the definition clarifies that ``drug'' is ``drug product'' and includes
the applicable U.S.C. statutory citations in the final rule. However,
the name has been changed from ``Studies an FDA-regulated Drug'' in the
NPRM to ``Studies a U.S. FDA-regulated Drug Product'' in the final rule
for clarity. We also note that we are aware that a clinical trial may
include an FDA-regulated drug product even though the drug product is
not a variable of interest. For example, a clinical trial of a device
product may involve the surgical insertion of the device product under
anesthesia, but the anesthesia drug product is not studied in the
clinical trial. In determining whether a clinical trial studies a U.S.
FDA-regulated drug product, a responsible party should consider whether
(a) the clinical trial is designed to examine the effect of the FDA-
regulated drug product(s) or of differences in the intended use,
including differences in dosing, frequency of use, or route of
administration; and/or (b) at least one of the pre-specified primary or
secondary outcome measures reflects a characteristic or effect of the
FDA-regulated drug product(s). As described in the preamble discussion
of applicable drug clinical trial in Sec. 11.10(a), a clinical trial
of a combination product with a drug primary mode of action will be
considered an applicable drug clinical trial. We note that for such
trials, the responsible party must indicate that the trial Studies a
U.S. FDA-regulated Drug Product.
(P) Device Product Not Approved or Cleared by U.S. FDA. In proposed
Sec. 11.10(b)(14), we defined U.S. FDA Approval, Licensure, or
Clearance Status to mean ``for each drug or device studied in the
clinical trial, whether that drug or device is approved, licensed, or
cleared by the U.S. Food and Drug Administration for any use.''
Although section 402(j) of the PHS Act does not explicitly require that
such a data element be submitted as part of clinical trial information,
we proposed it to help ensure that the data bank operates in compliance
with statutory requirements, e.g., knowledge of the approval or
clearance status of a device is necessary to determine when clinical
trial registration information submitted for an applicable device
clinical trial may be posted publicly in the data bank (see section
402(j)(2)(D)(ii) of the PHS Act.) We indicated that this information
would also be helpful for users of ClinicalTrials.gov, including
potential participants, who may wish to know whether or not the
product(s) under study have been approved, licensed, or cleared for the
use studied in the clinical trial. Requiring submission of the
approval, licensure, or clearance status for each drug or device
studied in an applicable clinical trial would therefore improve and not
reduce the clinical trial information available in the data bank,
consistent with section 402(j)(2)(A)(iii) of the PHS Act for proposed
modifications to clinical trial registration information. We also
stated in the NPRM that we would require responsible parties to select
a response from the following limited list of choices: ``for studied
use(s)'' (the drug, biological product, or device is approved,
licensed, or cleared for the use studied in the clinical trial), ``for
other use(s)'' (the drug, biological product, or device is approved,
licensed, or cleared for use(s) other than those studied in the
clinical trial, e.g., the clinical trial studies a new use of the
product), or ``No'' (the product has not been approved, licensed, or
cleared for any use). No ``other'' option was proposed, but a
responsible party would also be able to provide additional, optional
free-text information to further describe the approval, licensure, or
clearance status (e.g., to indicate that the product has been approved
in another dose or dosage form, or to list the indications for which it
has been approved). We invited public comment
[[Page 65042]]
on whether the set of proposed options is sufficient (79 FR 69618).
Some commenters addressed the proposed U.S. FDA Approval,
Licensure, or Clearance Status data element. One commenter requested
clarification on whether more information than the FDA approval,
licensure, or clearance status would be required for this data element,
while another commenter recommended that the Agency itself submit
information for this data element. In reviewing these comments and
assessing ways to reduce reporting burden where possible, we
reconsidered the proposed approach of requiring the FDA approval,
licensure, or clearance status information for each product studied in
the clinical trial. A separate data element about the approval,
licensure, or clearance status for each drug product, biological
product, or device product studied in an applicable clinical trial is,
for the most part, not necessary to implement these regulations,
because that information is provided via other data elements, when
necessary. For example, responsible parties will notify the Agency that
they are seeking ``initial'' approval, licensure or clearance of a
product or approval, licensure, or clearance of a ``new use'' for a
product studied in the trial by submitting a certification for delayed
submission of results information in accordance with Sec. 11.44(b) and
11.44(c), respectively. A key exception, however, is the need for
ClinicalTrials.gov to identify applicable device clinical trials that
study a device product that has not been previously approved or cleared
in order to delay public posting of the submitted clinical trial
registration information, as specified in Sec. 11.35(b)(2)(i).
Therefore, the final rule replaces the proposed U.S. FDA Approval,
Licensure, or Clearance Status data element with the Device Product Not
Approved or Cleared by U.S. FDA data element in Sec.
11.28(a)(2)(i)(P), which is defined in Sec. 11.10(b)(14) of the final
rule to mean ``that at least one device product studied in the clinical
trial has not been previously approved or cleared by FDA for one or
more uses.'' As discussed below, this data element must be updated not
later than 15 calendar days after a change in approval or clearance
status of one or more of the device products studied in the applicable
clinical trial.
A responsible party would only be required to complete this data
element for a record in which ``Yes'' is selected as the response to
the Studies a U.S. FDA-regulated Device Product data element in Sec.
11.28(a)(2)(i)(N). We would require responsible parties to select a
response from the following limited list of choices: ``Yes'' (at least
one studied FDA-regulated device product has not been previously
approved or cleared by FDA for one or more uses and therefore the
applicable device clinical trial may be subject to the delayed posting
requirements specified in Sec. 11.35(b)(2)(i)) or ``No'' (all studied
FDA-regulated device products have been previously approved or cleared
by FDA for at least one use and therefore the applicable device
clinical trial is not subject to the delayed posting requirement
specified in Sec. 11.35(b)(2)(i)).
We included the word ``product'' in the name of the Device Product
Not Approved or Cleared by U.S. FDA data element in Sec.
11.28(a)(2)(i)(P) to clarify that, as explained in Section IV.C.3, the
Agency in the final rule is focusing on the device ``product'' rather
than the device ``type'' when determining which PMA approvals or 510(k)
clearances are considered ``initial'' approvals or clearances versus
approvals or clearances of a ``new use.'' For example, with respect to
510(k) clearances, the Agency is interpreting ``initial clearance'' in
the final rule to pertain to the clearance of a manufacturer's original
510(k) submission for a particular device product whereas ``clearance
of a new use'' of a device pertains to the clearance of the same
manufacturer's subsequent 510(k) submission for an additional use for
the same device product. The term ``manufacturer'' means a manufacturer
who is the sponsor of the applicable clinical trial.
This interpretation subjects clinical trial registration
information for more devices to delayed posting under section
402(j)(2)(D)(ii)(I) of the PHS Act as compared with the NPRM approach,
because each individual device manufacturer seeking initial clearance
of its device product would be subject to delayed posting of its
clinical trial registration information, as specified in Sec.
11.35(b)(2)(i) of the final rule, rather than only the first
manufacturer to obtain clearance for the device type. Consistent with
this interpretation, under the definition of ``Device Product Not
Approved or Cleared by U.S. FDA,'' if a manufacturer's original 510(k)
submission for its particular device product has not been previously
cleared, then that manufacturer's device product would be considered a
``device product not cleared by FDA,'' even if another manufacturer has
already obtained 510(k) clearance of its device product within the same
product type.
A few commenters suggested that the final rule include an option
for providing information about the use for which the product has been
approved, and additional commenters requested the addition of the
option ``Approved but not for use being studied.'' We agree that
choices other than the three proposed in the NPRM (i.e., ``for studied
uses(s),'' ``for other uses,'' and ``no'') could provide other useful
information about a product's approval status. However, because of
changes to the data element in the final rule (to indicate ``whether at
least one device product studied in the clinical trial has not been
previously approved or cleared by FDA for one or more uses,'' as
described below) the options proposed by the commenters for specifying
the approval, licensure, or clearance status of each studied drug
product or device product will no longer be necessary. Another
commenter requested that the final rule require the submission of
information about the particular approved, licensed, or cleared uses of
each product using a standardized terminology to ensure the usefulness
and consistency of this information within and across study records. We
note that section 402(j)(3)(A)(ii) of the PHS Act requires
ClinicalTrials.gov to link to information about approved, licensed, or
cleared products available on the FDA Web site (e.g., FDA advisory
committee meeting summaries, public health advisories, and action
package for approval documents) as well as citations from the published
literature and structured product labels in NLM's PubMed (http://www.ncbi.nlm.nih.gov/pubmed/) and DailyMed (https://dailymed.nlm.nih.gov/dailymed/) databases, respectively.
(Q) Post Prior to U.S. FDA Approval or Clearance. This data element
was neither specified as clinical trial registration information in
section 402(j)(2)(A)(ii) of the PHS Act nor proposed in the NPRM. We
define the term in Sec. 11.10(b)(40) of the final rule to mean ``for
an applicable device clinical trial of a device product that has not
been previously approved or cleared, the responsible party indicates to
the Director that it is authorizing the Director, in accordance with
Sec. 11.35(b)(2)(ii), to publicly post its clinical trial registration
information, which would otherwise be subject to delayed posting, as
specified in Sec. 11.35(b)(2)(i), prior to the date of FDA approval or
clearance of its device product.'' We also list the data element as a
component of clinical trial registration information in Sec.
11.28(a)(2)(i)(Q) in accordance with the statutory authority in section
402(j)(2)(A)(iii) of the PHS Act, which
[[Page 65043]]
permits the Secretary to ``modify the requirements for clinical trial
[registration] information'' by regulation, provided that ``such a
modification improves and does not reduce such clinical trial
information.'' The Post Prior to U.S. FDA Approval or Clearance data
element is needed to allow a responsible party for an applicable
clinical trial of a device product that is unapproved or uncleared to
indicate to the Director that it is authorizing the Director to
publicly post on ClinicalTrials.gov its clinical trial registration
information, which would otherwise be subject to delayed posting as
specified in Sec. 11.35(b)(2)(i), prior to the date of approval or
clearance of the product, pursuant to Sec. 11.35(b)(2)(ii). Otherwise,
all such trials are subject to the posting deadline specified in Sec.
11.35(b)(2)(i), which states that the Director will post publicly the
clinical trial registration information, except for certain
administrative data, not earlier than the date of FDA approval or
clearance of the device product (see the preamble discussion of Sec.
11.35 for further details). To reduce data submission burden, a
responsible party would have this option if the Studies a U.S. FDA-
regulated Device Product and the Device Product Not Approved or Cleared
by U.S. FDA data elements indicate that at least one studied device
product has not been approved or cleared by FDA.
(R) Product Manufactured in and Exported from the U.S. In Sec.
11.10(b)(15) of the NPRM, we proposed the following definition for the
Product Manufactured in the U.S. data element: ``For a drug or device
studied in a clinical trial, whether or not the drug or device is
manufactured in the U.S. or one of its territories.'' Although section
402(j) of the PHS Act does not explicitly require that such a data
element be submitted as part of clinical trial information, we proposed
to include it, using our authority under section 402(j)(2)(A)(iii) of
the PHS Act to allow users to determine whether a registered clinical
trial is an applicable clinical trial. As explained in the definitions
of ``applicable device clinical trial'' and ``applicable drug clinical
trial,'' the NPRM noted that even if a clinical trial is being
conducted entirely outside of the United States or one of its
territories, it is still an applicable clinical trial when the drug
product or device product is manufactured in the United States or one
of its territories. We noted that a drug product or device product
manufactured in the United States or one of its territories is subject
to regulation under the FD&C Act, even if it is exported for study in
another country (see, for example, 21 CFR 312.110 and section 802 of
the FD&C Act). Therefore, we proposed that information indicating
whether each intervention studied in a clinical trial is manufactured
in the United States or one of its territories would be essential in
some situations for determining whether such trial is subject to FDA
jurisdiction and meets the definition of an ``applicable clinical
trial.'' We indicated that including this information in the data bank
would improve and not reduce clinical trial information by publicly
providing data necessary to determine whether such trial is an
applicable clinical trial (79 FR 69618). We did not receive any public
comments on this proposed data element, but we have modified the
definition in the final rule. In assessing ways to reduce reporting
burden where possible, we reconsidered the proposed requirement for
United States product manufacturing information for each drug product
(including a biological product) or device product studied in a
clinical trial. To determine whether a clinical trial that is not
conducted under an IND or IDE and that does not have any study
facilities in the United States or its territories meets the definition
of an ``applicable clinical trial,'' the Agency, responsible parties,
and the public only need information about whether at least one drug
product (including biological product) or device product was
manufactured in the United States and exported for research. Therefore,
we renamed the data element ``Product Manufactured in and Exported from
the U.S.'' in Sec. 11.28(a)(2)(i)(R) to clarify that the intent is to
identify a U.S.-manufactured product that is exported for research
purposes. Additionally, we clarify that ``drug'' means ``drug product''
and ``device'' means ``device product.'' In Sec. 11.10(b)(15) of the
final rule, we define this data element to mean ``that any drug product
(including a biological product) or device product studied in the
clinical trial is manufactured in the United States or one of its
territories and exported for study in a clinical trial in another
country.'' To reduce data submission burden, a responsible party would
be required to complete this data element only if the entry submitted
for the U.S. Food and Drug Administration IND or IDE Number data
element indicates that there is no IND or IDE for the clinical trial,
and the entry(ies) for the Facility Information data element include no
facility locations in the United States or its territories.
(S) Study Start Date. In Sec. 11.10(b)(16) of the NPRM, we defined
Study Start Date to mean: ``the estimated date on which the clinical
trial will be open to enrollment of human subjects. If the clinical
trial has enrolled the first human subject, the actual date on which
the first human subject was enrolled.'' Section 402(j)(2)(A)(ii)(I)(ii)
of the PHS Act expressly requires ``study start date'' to be submitted
as clinical trial information at the time of registration, but it does
not define the term. Section 402(j)(2)(C)(ii) of the PHS Act and
proposed Sec. 11.24(a) generally required that clinical trial
registration information be submitted to ClinicalTrials.gov not later
than 21 calendar days after the first human subject is enrolled in the
clinical trial. In practice, however, many responsible parties submit
clinical trial registration information to ClinicalTrials.gov before
the first subject is enrolled. In some cases, at the time the clinical
trial is registered, the responsible party may not have information
about when the first subject will be enrolled or was enrolled (e.g., in
a large multi-site trial) but may only know when the clinical trial was
or will be opened for enrollment. To account for these potential
scenarios, we proposed that responsible parties be required to provide
an estimated study start date (i.e., the estimated date on which the
clinical trial will be open to enrollment of human subjects), unless
and until the responsible party knows the actual study start date
(i.e., the actual date on which the first human subject is enrolled).
The responsible party would be required to update the Study Start Date
data element to reflect the actual study start date not later than 30
calendar days after the first human subject is enrolled, consistent
with proposed Sec. 11.64. We suggested in the NPRM that providing the
estimated study start date to the public, even before the first subject
is enrolled, has important benefits to potential human subjects because
it will allow them to know when a clinical trial will likely be open to
enrollment. We clarified that the Study Start Date must include the
day, month, and year (79 FR 69619).
We received comments on this definition. Several commenters
requested that we change the term ``Study Start Date'' to ``Date of
First Enrolled Participant'' to avoid confusion with other contexts,
such as those related to human subjects protection and IRB oversight,
in which the study start date is considered to be when the study is
first approved by the IRB and is recruiting. Another comment stated
[[Page 65044]]
that the WHO Trial Registration Data Set, defines study start date as
the date of first enrollment. One commenter requested that we change
the definition of ``Study Start Date'' to ``date of first enrollment''
for consistency with these other policies. Another comment asserted
that ICMJE, WHO, FDA, and EMA consider the study start date to be the
``First-Patient-First-Visit,'' which is the first participant's
anticipated or actual enrollment date, rather than when the trial is
first opened to enrollment. Another commenter acknowledged that our
definition requires the Study Start Date to be updated with the
``First-Patient-First-Visit'' (i.e., actual enrollment date) but stated
that the other, estimated date on which the clinical trial will be open
to enrollment is inconsistent with these other study start date
definitions. The commenter requested that we change the definition to
``First-Patient-First-Visit.'' After considering these comments, we
maintain the proposed definition for Study Start Date in Sec.
11.10(b)(16) of the final rule, with slight modifications for
consistency of phrasing with similar data elements concerning when the
responsible party would update the data element with the actual
enrollment date. As such, we define Study Start Date as ``the estimated
date on which the clinical trial will be open for recruitment of human
subjects, or the actual date on which the first human subject was
enrolled.'' If the estimated date is used, the responsible party must
update the Study Start Date data element to the actual date on which
the first human subject was enrolled. We also decline to define Study
Start Date as only the ``First-Patient-First-Visit'' or actual
enrollment date. The definition already incorporates the actual
enrollment date, which the responsible party will use when the first
subject has been enrolled. By including the date when recruitment opens
and the date of first enrollment, we believe the definition maintains
consistency with prior practice at ClinicalTrials.gov and addresses
commenters' request to document the date of first human subject
enrollment as in the WHO Trial Registration Data Set. As stated in the
NPRM, we believe that providing the estimated study start date to the
public, even before the first subject is enrolled, has important
benefits to potential human subjects because it will provide them with
the date on which a clinical trial will likely be open to enrollment.
To minimize the burden associated with this requirement and to reflect
that it is an estimated date, the date may be provided as ``month,
year'' when estimated and updated to ``day, month, year'' when actual.
We also note that, as discussed above, the final rule modifies the
proposed definition of ``enroll or enrolled,'' a component of the
definition of Study Start Date (see Section IV.A.5 of this preamble).
We note that if a clinical trial is registered with an estimated study
start date but the clinical trial is then halted before enrolling the
first subject (e.g., because of difficulties in recruitment or loss of
funding), the responsible party would not be expected to update the
study start date. Instead, the responsible party would be expected to
update the Overall Recruitment Status data element defined in Sec.
11.10(b)(25) and specified in Sec. 11.28(a)(2)(ii)(E) to indicate that
the clinical trial has been ``withdrawn,'' as such term is used for the
purpose of this regulation, and update the Why Study Stopped data
element defined in Sec. 11.10(b)(26) and specified in Sec.
11.28(a)(2)(ii)(F).
We note that, as stated in Sec. 11.22(a)(3), an applicable
clinical trial, other than a pediatric postmarket surveillance of a
device product that is not a clinical trial, is considered to be
initiated on the date on which the first human subject is enrolled.
Therefore, we consider the actual Study Start Date to be the date of
initiation for an applicable clinical trial other than a pediatric
postmarket surveillance of a device product that is not a clinical
trial.
(T) Primary Completion Date. In Sec. 11.28(a)(1)(xiv) of the NPRM,
we proposed that when registering a clinical trial, a responsible party
must submit the Completion Date for the clinical trial, which was
defined in proposed Sec. 11.10(b)(17) of the NPRM as ``the estimated
completion date. Once the clinical trial has reached the completion
date, the responsible party must update the Completion Date data
element to reflect the actual completion date.'' Section
402(j)(2)(A)(ii)(I)(jj) of the PHS Act requires the responsible party
to submit information on the ``expected completion date'' of an
applicable clinical trial when registering a clinical trial. We noted
in the NPRM that the public availability of information about the
expected primary completion date (i.e., the expected completion date)
is important for an ongoing clinical trial because it provides an
indication of the relative progress of the clinical trial and the
expected date on which results information may be submitted to the data
bank because section 402(j)(3)(c)(i) of the PHS Act requires that, in
general, clinical trial results information be submitted not later than
1 year after the earlier of the estimated completion date of the
applicable clinical trial or the actual completion date of the
applicable clinical trial. We note that certain exceptions apply to
this general deadline for the submission of clinical trial results
information (see discussion of Sec. 11.44). In addition, we
interpreted the phrase ``estimated completion date,'' as such term is
used in section 402(j)(3)(c)(i)(I) of the PHS Act, to have the same
meaning as ``expected completion date,'' as such term is used in
section 402(j)(2)(A)(ii)(I)(jj) of the PHS Act, because both indicate
the date on which the responsible party anticipates that the clinical
trial will be completed in relation to the primary outcome measures. In
addition, we expressed our belief that it is important for users to
have information about the actual completion date of a clinical trial,
so they know when clinical trial results information would ordinarily
be due under section 402(j)(3)(c)(i) of the PHS Act and proposed Sec.
11.44(a), absent certain specified circumstances in which the
submission of clinical trial results information may be delayed.
Because clinical trial results information generally is required under
section 402(j)(3)(c)(i) of the PHS Act and under proposed Sec. 11.44
to be submitted not later than 1 year after the estimated or actual
completion date, whichever is earlier, we expressed our belief that it
is important for the Completion Date data element to be updated
promptly after the completion date is reached. We proposed to require
the responsible party to take the following steps with regard to the
Completion Date data element: (1) Provide a reasonable estimated
completion date at the time of registration; (2) update the estimated
completion date at least once every 12 months during the course of the
clinical trial, in accordance with proposed Sec. 11.64(a)(2), if the
estimate changes; and (3) update the Completion Date information to
indicate the actual completion date not later than 30 calendar days
after the clinical trial reaches its completion date, in accordance
with proposed Sec. 11.64(b)(1)(viii) (79 FR 69619).
Commenters expressed concern about possible confusion and
misinterpretation among responsible parties and the public resulting
from the proposed data element name and uniformly suggested replacing
``completion date'' with ``primary completion date'' or ``primary
outcome measure completion date,'' with several noting that
ClinicalTrials.gov has used the term ``primary completion date'' since
the enactment of FDAAA. We
[[Page 65045]]
agree with these comments and note that the Primary Completion Date
data element was created in response to section 402(j) of the PHS Act
to avoid confusion with the Study Completion Date data element, which
existed prior to the law and is currently an optional data element.
Furthermore, the final rule in Sec. 11.28(a)(2)(i)(U) adds the Study
Completion Date data element as a component of clinical trial
registration information. In response to these comments and taking into
consideration statutory requirements, we rename the Completion Date
data element ``Primary Completion Date'' in Sec. 11.28(a)(2)(i)(T) of
the final rule and use the term ``Primary Completion Date'' throughout
the final rule for clarity. Primary Completion Date is defined in Sec.
11.10(b)(17) of the final rule to mean ``the estimated or actual
primary completion date. If an estimated primary completion date is
used, the responsible party must update the Primary Completion Date
data element once the clinical trial has reached the primary completion
date to reflect the actual primary completion date.'' We also note that
the term ``completion date'' in Sec. 11.10(a) of the final rule
states, in part, that ``[f]or purposes of this part, completion date is
referred to as `primary completion date.'''
(U) Study Completion Date. This data element was neither specified
as clinical trial registration information in section 402(j)(2)(A)(ii)
of the PHS Act nor proposed in the NPRM. We define the term ``study
completion date'' in Sec. 11.10(a) of the final rule to mean ``for a
clinical trial, the date the final subject was examined or received an
intervention for purposes of final collection of data for the primary
and secondary outcome measures and adverse events (e.g., last subject's
last visit), whether the clinical trial concluded according to the pre-
specified protocol or was terminated.'' The final rule also lists Study
Completion Date as a required registration data element under Sec.
11.28(a)(2)(i)(U) and specifies the data element definition in Sec.
11.10(b)(41) as ``the estimated or actual study completion date. Once
the clinical trial has reached the study completion date, the
responsible party must update the Study Completion Date data element to
reflect the actual study completion date in accordance with Sec.
11.64(a)(1)(ii)(J).'' We have included the study completion date as a
component of clinical trial registration information in accordance with
the statutory authority in section 402(j)(2)(A)(iii) of the PHS Act,
which permits the Secretary to ``modify the requirements for clinical
trial [registration] information'' by regulation, provided that ``such
a modification improves and does not reduce such clinical trial
information.'' We believe that Study Completion Date is helpful to
indicate to the Agency, responsible parties, and the public when all
primary and secondary outcome measures and collection of all adverse
event information, as specified in the protocol, will be completed and
when final data collection for all primary and secondary outcomes and
all adverse events has occurred. Some commenters requested that a
mechanism be included in the PRS to make clear to responsible parties
when they have fulfilled all obligations to update the study record as
specified in proposed Sec. 11.64(a)(3) and that no further updates are
required. Several other commenters suggested that ``completion date,''
defined in proposed Sec. 11.10(a), be redefined to mean ``final visit/
final patient'' or ``final visit/final patient for all outcome
measures.'' Following an internal review of the proposed rule, we also
note that while proposed Sec. 11.44(d) described the procedure for
submitting partial results information, it did not specify how to
determine when the responsible party's obligation under subpart C is
fulfilled. While the Study Completion Date does not specify when these
obligations are fulfilled per se, it does provide the minimum amount of
information needed to make such a determination based on when all of
the data for a trial is to be collected. Note that Sec.
11.64(a)(1)(ii)(J) of the final rule requires the responsible party to
update the Study Completion Date within 30 calendar days after the
clinical trial reaches its actual study completion date.
(V) Enrollment. We defined this data element in Sec. 11.10(b)(18)
of the NPRM as ``the estimated total number of human subjects to be
enrolled or target number of human subjects in the clinical trial.''
Section 402(j)(2)(A)(ii)(I)(kk) of the PHS Act expressly requires
submission of ``the target number of subjects'' to be enrolled in an
applicable clinical trial, but this phrase is not defined. We expressed
our belief that this data element is intended to describe the intended
or estimated size of the clinical trial, in terms of the estimated
total number of human subjects (including healthy volunteers) or target
number of human subjects to be enrolled in the clinical trial. We
therefore proposed in Sec. 11.28(a)(1)(xx) of the NPRM to require the
submission of enrollment information at the time of registration (79 FR
69620). We received a few comments addressing the Enrollment data
element. One commenter suggested that the final rule require submission
of information about target enrollment goals by gender, age, and race/
ethnicity during registration but did not provide any specific
justification or evidence that such information is necessary for
registration. We note that the clinical trials results information
submission requirements under Demographic and baseline characteristics
in proposed Sec. 11.48(a)(2)(iii) included the reporting of ``age,
gender, and any other measure(s) that were assessed at baseline . . .''
and the final rule further requires the submission of baseline measure
information by race and ethnicity, if collected during the clinical
trial. ClinicalTrials.gov also provides pre-formatted categories that
enable responsible parties to submit common demographic
characteristics, including age, sex/gender, race, ethnicity, and region
of enrollment (if assessed at baseline), to facilitate comparison
across study records. Another commenter suggested requiring the listing
of the targeted and actual numbers of subjects enrolled in each trial.
Two specific required registration data elements proposed in the NPRM,
and combined in the final rule, address this comment. The Enrollment
data element specified in proposed Sec. 11.28(a)(1)(xx) is defined in
proposed Sec. 11.10(b)(18) as ``the estimated total number of human
subjects to be enrolled or target number of human subjects in the
clinical trial,'' and the Actual Enrollment data element specified in
proposed Sec. 11.28(a)(2)(vii) is defined as ``for a clinical trial
for which recruitment of human subjects has terminated or completed,
the actual number of human subjects enrolled in the clinical trial'' in
proposed Sec. 11.10(b)(27). After consideration of these comments, we
maintain the proposed name of the Enrollment data element in the final
rule, but we combine it with the proposed Actual Enrollment data
element for convenience and consistency with the format on
ClinicalTrials.gov prior to this rule. We clarify that with the
approach in the final rule, the estimated number of human subjects to
be enrolled will be retained, to allow for later display of both the
estimated and actual total number of human subjects enrolled in the
clinical trial. We have therefore changed the definition of Enrollment
to ``the estimated total number of human subjects to be enrolled
(target number) or the actual total number of human subjects that are
enrolled in the clinical
[[Page 65046]]
trial. Once the trial has reached the primary completion date, the
responsible party must update the Enrollment data element to reflect
the actual number of human subjects enrolled in the clinical trial.''
We expect that the estimated or target enrollment for a clinical trial
may change before or during the clinical trial (e.g., as recruitment
continues). Consistent with section 402(j)(4)(C) of the PHS Act and
Sec. 11.64(a)(1), a responsible party would be required to update the
Enrollment data element not less than once every 12 months, if the
anticipated or target enrollment for the clinical trial changes. This
update would be in addition to the requirement in Sec. 11.64(a),
described in Section IV.D.3, that a responsible party submit the actual
enrollment when the clinical trial has reached its primary completion
date, i.e., when the Primary Completion Date of the trial is changed to
``actual.'' This requirement is intended to provide users of
ClinicalTrials.gov with additional information on the total number of
participants enrolled in the clinical trial, which may differ from the
target enrollment. (See Sec. 11.64(a) and the discussion of Primary
Completion Date'' for a discussion of this requirement.) We also note
that ``enrolled,'' as defined in Sec. 11.10(a) of the final rule,
means ``a human subject's, or their legally authorized
representative's, agreement to participate in a clinical trial
following completion of the informed consent process, as required in 21
CFR part 50 and/or 45 CFR part 46, as applicable. For the purposes of
this part, potential subjects who are screened for the purpose of
determining eligibility for a trial, but do not participate in the
trial, are not considered enrolled, unless otherwise specified by the
protocol.'' In addition, we note that in response to comments on the
update requirements in Sec. 11.64, the Enrollment data element must be
updated at the time the Primary Completion Date data element is updated
to ``actual'' instead of at the time after enrollment closes.
(W) Primary Outcome Measures and (X) Secondary Outcome Measures are
data elements expressly required by section 402(j)(2)(A)(ii)(I)(ll) of
the PHS Act to be submitted as part of clinical trial information at
the time of registration. Definitions of the terms ``outcome measure'',
``primary outcome measure'', and ``secondary outcome measure'' are
provided and elaborated on in the preamble and subpart A of the final
rule. However, section 402(j) of the PHS Act does not specify what
specific information about primary and secondary outcome measures must
be submitted to ClinicalTrials.gov at the time of registration. Under
proposed Sec. 11.28(a)(1)(xxi) and (xxii) of the NPRM, responsible
parties would be required to submit the information specified in
proposed Sec. 11.10(b)(19) and (20) for each primary or secondary
outcome measure in their clinical trials, namely the following: (1) The
name of the specific outcome measure (e.g., systolic blood pressure),
(2) a description of the metric used to characterize the specific
outcome measure (e.g., mean value of systolic blood pressure), and (3)
the time point(s) at which the measurement is assessed for the specific
metric used (e.g., 24 weeks after initiation of treatment). We noted in
the NPRM that these requirements are consistent with the WHO Trial
Registration Data Set (version 1.2.1), which specifies that each
outcome include the name of the outcome, the metric or method of
measurement used, and the time point(s) of primary interest.
Furthermore, based on our experience in operating ClinicalTrials.gov,
we expressed our belief that these three elements are key attributes of
an outcome measure. Not only may certain outcome measures be assessed
in different ways (e.g., systolic blood pressure can be measured as a
mean value at a specific time point or as a change from baseline), but
also a single clinical trial may assess a single attribute at multiple
points in time (e.g., systolic blood pressure may be measured 3 months,
6 months, and 12 months after beginning treatment). Each of these would
be considered a different outcome measure. We noted that ensuring that
the primary and secondary outcome measures include descriptions of the
measures and the time points of assessment is therefore necessary for
differentiating between similar measures and for subsequently ensuring
that results information is provided for all of them and in a manner
that is consistent with the way in which they were pre-specified in the
registry. This approach would also ensure that any changes in the
outcome measure are recorded as updates to the registration
information, consistent with the purpose of the data bank ``to track
subsequent progress of clinical trials,'' section 402(j)(2)(A)(i) of
the PHS Act (79 FR 69620).
One commenter cited findings of that commenter's research [Ref. 14]
and recommended that the final rule require responsible parties to
submit information on whether each outcome measure is defined in terms
of a noninferiority, superiority, or equivalence hypothesis and
associated information about the noninferiority or equivalence margin
with relevant calculations and justification of margin selection as
free-text descriptions in a new sub-element associated with each
reported outcome measure. While we agree with the commenter on the
potential value of this information, we note that the information
should be available with the reporting of outcomes with results
information under Sec. 11.48. We do not believe that the benefits of
reporting this information at registration outweighs the burden on
responsible parties for reporting these details at that time. We will
continue, however, to evaluate ways to accommodate this and other
information related to the SAP as optional structured data elements in
ClinicalTrials.gov. Responsible parties are able to submit this
information voluntarily during registration as part of the Detailed
Description data element. We also note that, during results reporting
for any statistical analysis that is considered scientifically
appropriate, the following information is required to be submitted:
``for a non-inferiority or equivalence test, a description of the
analysis that includes, at minimum, the power calculation and non-
inferiority or equivalence margin'' (see Sec. 11.48(a)(3)(v)). After
considering this comment, we maintain the proposed definition in the
final rule.
(ii) Recruitment Information
(A) Eligibility Criteria. In Sec. 11.10(b)(21) of the NPRM,
Eligibility Criteria was described as ``a limited list of criteria for
selection of human subjects to participate in the clinical trial,
provided in terms of inclusion and exclusion criteria and suitable for
assisting potential human subjects in identifying clinical trials of
interest.'' Section 402(j)(2)(A)(ii)(II)(aa) of the PHS Act expressly
requires ``eligibility criteria'' to be submitted for registration on
ClinicalTrials.gov, but it does not define the term. In the NPRM we
expressed our belief that the purpose of this data element is to enable
users of the data bank to determine key characteristics of potential
participants in the clinical trial and assist prospective participants
in identifying clinical trials that may be of interest. Consistent with
the stated objective of section 402(j)(2)(A)(i) of the PHS Act to
``enhance patient enrollment,'' we interpreted the requirement to
include an ``Eligibility Criteria'' data element as part of clinical
trial registration information to refer to information that can be of
practical use to prospective participants who wish to determine if they
potentially qualify to participate in
[[Page 65047]]
a clinical trial and who may be interested in seeking additional
information about a clinical trial. We noted that our proposed
definition of ``eligibility criteria'' was consistent with ``key
inclusion and exclusion criteria'' of the WHO Trial Registration Data
Set (version 1.2.1) (WHO data item #14) and ICMJE registration policies
[Ref. 2, 73] (79 FR 69621). A few commenters addressed the proposed
Eligibility Criteria data element. One commenter agreed with the
proposal that only ``a limited list of criteria'' be provided but
suggested the need for a disclaimer on the posted record that the data
element is not intended to represent all eligibility criteria. Although
we do not believe that a disclaimer about the eligibility criteria data
element on the record is necessary, particularly because there may be
cases in which the criteria listed do represent the complete list, we
will consider displaying on the public record an explanation that the
listed eligibility criteria represent ``key'' or ``selected'' criteria
to minimize the potential for confusion. Another commenter suggested
requiring the use of standardized terminology for describing the
eligibility criteria to facilitate automated, machine-based screening
and matching with potential participants. While this is an active area
of ongoing research, we are not aware of any widely-accepted data
standards for representing eligibility criteria and the commenter did
not reference any. Therefore, the final rule does not require the
submission of eligibility criteria using any particular standardized
terminology, although we encourage responsible parties to submit such
information in as structured and standardized a fashion as possible to
facilitate data reuse. After considering these comments, we maintain
the proposed definition in the final rule. For submission of
eligibility criteria information, responsible parties must provide a
list of inclusion and exclusion criteria (e.g., Inclusion Criteria:
Clinical diagnosis of Alzheimer's Disease, must be able to swallow
tablets; Exclusion Criteria: Insulin dependent diabetes, thyroid
disease). We note that clinical trial protocols typically contain
lengthy, detailed descriptions of inclusion and exclusion requirements
for participants, including, for example, specific laboratory test
result values. The requirements are often complex and must be assessed
by a clinician or researcher involved in the clinical trial. We believe
that the submission of all eligibility criteria would be burdensome for
responsible parties and, instead of helping prospective participants,
would prove confusing or overwhelming to them. We believe that
prospective participants are better served by a more limited list of
inclusion and exclusion criteria in the data bank to assist in
identifying clinical trials of possible interest. Prospective
participants who believe they meet the criteria listed in the data bank
could discuss the clinical trial with their physician or other
healthcare advisor and contact the facility-specific contact or central
contact for the clinical trial for more information and a more complete
assessment of eligibility. We note that for users of the data bank who
want more detailed information about eligibility criteria for the
purposes of interpreting clinical trial results information and better
understanding the population of human subjects studied, the final rule
requires responsible parties to submit protocols as part of the
clinical trial results information (see Section III.D. of this
preamble).
(B) Sex/Gender. In Sec. 11.10(b)(22) of the NPRM, we defined the
term ``gender'' to mean, ``the biological sex of the human subjects who
may participate in the clinical trial.'' Section
402(j)(2)(A)(ii)(II)(bb) of the PHS Act expressly requires ``gender''
to be submitted as clinical trial information at the time of
registration, but it does not define this term. We also proposed that
responsible parties would select from the following limited set of
choices: ``male,'' ``female,'' or ``both.'' Although no ``other''
option was proposed, the NPRM explained that responsible parties would
be able to provide additional, optional free-text information about the
gender of participants who may participate in the clinical trial (79 FR
69621).
Several commenters addressed this data element. A few requested
that the final rule change the term to ``sex.'' Others stated that use
of the term ``sex'' would be consistent with FDA's guidance,
``Evaluation of Sex-Specific Data in Medical Device Clinical Studies,''
in which ``sex'' refers to classification by reproductive organ, and
``gender'' refers to a person's self-representation as male or female
[Ref. 95]. They also noted that FDA's guidance is based on an IOM
report, ``Exploring the Biological Contributions to Human Health: Does
Sex Matter?'' [Ref. 96].
We agree with the commenters that the proposed definition of
``gender'' does not align with the cited definitions and usage of the
distinct terms ``gender'' and ``sex.'' The commenters further suggested
that we change the data element name from ``Gender'' to ``Sex'' to
better align with the proposed definition. Although not mentioned
specifically by commenters, we also note that the WHO Trial
Registration Data Set (version 1.2.1) describes inclusion and exclusion
criteria for participant selection, including age and ``sex.''
To further consider how the terms ``gender'' and ``sex'' are used
to define recruitment/eligibility criteria in protocols, we evaluated a
convenience sample of 80 study protocols made available online with
publication in the Journal of the American Medical Association and the
New England Journal of Medicine. Our observations suggest that although
protocols use the terms ``gender'' and/or ``sex,'' it was generally not
possible to determine whether the usage was appropriate, as definitions
of those terms were not typically included. Among the protocols
examined, 23 (29 percent) used the term ``gender'' only, 11 (14
percent) used ``sex'' only, 32 (40 percent) appeared to use the terms
``gender'' and ``sex'' interchangeably, and 14 (17 percent) did not use
either term. We believe it is important for the information on
ClinicalTrials.gov to accurately represent the individuals who may
participate in the clinical trial, based on information specified in
the trial protocol. Based on our evaluation of this sample of protocols
and the comments received on the NPRM, we have concluded that the data
element needs to be sufficiently flexible to allow responsible parties
to submit information about both sex and gender, if those terms are
applicable to the trial being registered. We have therefore modified
the proposed name of the data element to ``Sex/Gender'' in Sec.
11.28(a)(2)(ii)(B) of the final rule to accommodate studies that base
eligibility on sex (meaning, for purposes of this part, a person's
classification as male or female based on biological distinctions) and
gender (meaning, for purposes of this part, a person's self-
representation of gender identity). Similarly, to reflect both terms,
we have updated the definition of ``Sex/Gender'' to be ``the sex and,
if applicable, gender of the human subjects who may participate in the
clinical trial'' in Sec. 11.10(b)(22). The responsible party must
indicate the sex of the individuals who may participate in the clinical
trial using the following options available on ClinicalTrials.gov for
this data element: ``male,'' which indicates that only male
participants are being studied, ``female,'' which indicates that only
female participants are being studied, and ``all'' which indicates that
the recruitment
[[Page 65048]]
criteria do not limit eligibility based on the sex of participants. In
addition, if eligibility for the clinical trial is based on gender, the
responsible party may also select from the following options to provide
details about gender: ``yes'' (meaning eligibility is based on gender)
or ``no'' (meaning eligibility is not based on gender). If the
responsible party selects ``yes,'' descriptive information about gender
criteria may be provided in the optional, additional, free-text
element. Information on gender is required to be submitted only if
gender is used as an eligibility/recruitment criterion for the clinical
trial. We further note that we consider the Sex/Gender data element
complementary to the limited list of criteria submitted as part of the
Eligibility Criteria data element, but provision of information on sex/
gender in that data element does not substitute for the requirement to
provide the Sex/Gender data element.
(C) Age Limits. In Sec. 11.10(b)(23) of the NPRM, we defined this
term to mean, ``the minimum and maximum age of human subjects who may
participate in the clinical trial, provided in relevant units of
time.'' Section 402(j)(2)(A)(ii)(II)(cc) of the PHS Act expressly
requires ``age limits'' to be submitted as clinical trial information
at the time of registration, but it does not define the term (79 FR
69621). We received no comments and therefore retain the proposed data
element and definition in the final rule. We clarify, however, that the
responsible party selects the unit of time from the following limited
set of choices: ``years,'' ``months,'' ``weeks,'' ``days,'' ``hours,''
``minutes,'' and ``N/A'' (i.e., no limit). These structured choices are
consistent with current practice on ClinicalTrials.gov and facilitates
more specific searches by age limits (e.g., finding studies recruiting
children aged 24 to 36 months versus adults aged 24 to 36 years).
(D) Accepts Healthy Volunteers. In Sec. 11.10(b)(24) of the NPRM,
we defined the Accepts Healthy Volunteers data element to mean
``whether human subjects who do not have a disease or condition, or
related conditions or symptoms, under study in the clinical trial are
permitted to participate in the clinical trial.'' Section
402(j)(2)(A)(ii)(II)(dd) of the PHS Act requires the submission of
information about ``whether the trial accepts healthy volunteers.'' (79
FR 69621) We received no comments and therefore retain the proposed
data element and definition in the final rule, except we delete the
word ``whether'' in the definition for additional clarity. We note that
we consider any human participant in a clinical trial to be a human
subject regardless of whether he or she is a healthy volunteer.
(E) Overall Recruitment Status. Under Sec. 11.10(b)(25) of the
NPRM, we defined the Overall Recruitment Status data element as ``the
recruitment status for the clinical trial as a whole, based upon the
status of the individual sites. If at least one facility in a multi-
site clinical trial has an individual site status of `recruiting,' then
the overall recruitment status for the trial must be `recruiting.' ''
Section 402(j)(2)(A)(ii)(II)(ee) of the PHS Act requires ``overall
recruitment status'' to be submitted as clinical trial information at
the time of registration, but it does not define the term. To
facilitate searching for clinical trials by recruitment status and to
allow information to be compared across clinical trials, we also stated
in the NPRM that responsible parties would be required to select from
the following limited set of choices: ``Not yet recruiting''
(participants are not yet being recruited); ``Recruiting''
(participants are currently being recruited, whether or not any
participants have yet been enrolled); ``Enrolling by invitation''
(participants are being, or will be selected from a predetermined
population); ``Active, not recruiting'' (study is ongoing, meaning
participants are being treated or examined, but new participants are
not currently being recruited or enrolled); ``Completed'' (the study
has concluded normally; participants are no longer being examined or
treated, i.e., last patient's last visit has occurred); ``Suspended''
(recruiting or enrolling participants has halted prematurely but
potentially will resume), ``Terminated'' (recruiting or enrolling
participants has halted prematurely and will not resume; participants
are no longer being examined or treated), and ``Withdrawn'' (study
halted prematurely, prior to enrollment of first participant). No
``other'' option was proposed. We invited public comment on whether the
proposed options are sufficient to accurately describe the overall
recruitment status of clinical trials subject to the proposed rule. We
also noted that the proposed definition of ``overall recruitment
status'' is consistent with ``recruitment status'' in the WHO Trial
Registration Data Set (version 1.2.1) (WHO data item #18) and ICMJE
registration policies [Ref. 2, 73] (79 FR 69621).
We received no comments and therefore retain the proposed
definition in the final rule. The final rule requires responsible
parties to provide and update information for the Overall Recruitment
Status data element. Such a requirement will provide users of
ClinicalTrials.gov with an effective means of tracking the progress of
clinical trials, as required by section 402(j)(2)(A)(i) of the PHS Act.
However, we clarify the descriptions for the following four choices
identified in the NPRM for the Overall Recruitment Status data element:
``Active, not recruiting'' indicates that a ``study is continuing,
meaning that participants are receiving an intervention or being
examined, but new participants are not currently being recruited or
enrolled;'' ``Completed'' indicates that ``the study has concluded
normally; participants are no longer receiving an intervention or being
examined, i.e., the last patient's last visit has occurred;''
``Suspended'' indicates that a ``study halted prematurely but
potentially will resume;'' and ``Terminated'' indicates that a ``study
halted prematurely and will not resume; participants are no longer
being examined or receiving an intervention.'' These descriptions are
clearer and more accurate for the data element choices. We remove the
term ``treated'' from the description of these options and instead use
the phrase ``receiving an intervention'' for greater accuracy because
not all clinical trials are conducted to evaluate whether interventions
are efficacious for the treatment of the disease or condition that is
the focus of the study. We note that ``receiving an intervention''
includes receiving a placebo or receiving no intervention, as assigned
in the study protocol. The other modifications clarify that the status
relates to the entire study, not just the aspect of the study that
involves recruitment. We also note that if a clinical trial is
registered before it is open to recruitment, we would expect the
Overall Recruitment Status to be ``Not yet recruiting.'' When the
clinical trial opens for enrollment, we would expect the Overall
Recruitment Status to be ``Enrolling by invitation'' if human subjects
are selected from a predetermined population or ``Recruiting'' if the
study is open to volunteers who meet the study's eligibility criteria.
As indicated in the discussion of the Study Start Date data element,
for this rule, if a clinical trial is registered prior to enrollment of
the first subject and the clinical trial is subsequently halted before
the first subject is enrolled, we would expect the responsible party to
update the Overall Recruitment Status data element to ``Withdrawn.''
We believe that updating the Overall Recruitment Status data
element will provide users of ClinicalTrials.gov with
[[Page 65049]]
an effective means of tracking the progress of clinical trials, as the
data bank is intended to do (see section 402(j)(2)(A)(i) of the PHS
Act). In the case of a clinical trial that is halted before the first
subject is enrolled (i.e., a status of Withdrawn), this information
will explain why no results information can be expected or is required
to be submitted. In the case of a clinical trial for which recruitment
is prematurely halted (i.e., a status of Suspended or Terminated), this
information will allow potential human subjects to determine whether
enrollment is likely to resume. Such information will also assist in
the interpretation of results information, for example, by providing an
explanation of why some clinical trial outcomes were not achieved and/
or enrollment was significantly below the target. We note that when a
study has reached its study completion date, as defined in Sec.
11.10(a), the Overall Recruitment Status would be Completed, unless the
responsible party terminates the study, which would be reflected in a
status of Terminated.
(F) Why Study Stopped. Proposed Sec. 11.10(b)(26) of the NPRM
defined the Why Study Stopped? data element to mean ``for a clinical
trial that is suspended or terminated or withdrawn prior to its
completion as anticipated by the protocol, a brief explanation of the
reason(s) why such clinical trial was stopped.'' We proposed allowing
responsible parties to enter this information as a free-text response,
to provide them with the flexibility to explain the reason(s) why a
clinical trial stopped prematurely. While this information is not
required for submission by section 402(j) of the PHS Act, we indicated
that it is important to communicate to users of the data bank why a
clinical trial was suspended, terminated, or withdrawn (e.g., safety
concerns, difficulties in recruitment, financial reasons). Such
information also furthers the statutory objective stated in section
402(j)(2)(A)(i) of the PHS Act to enable users ``to track subsequent
progress of clinical trials.'' As we stated in the NPRM, for these
reasons requiring this information improves and does not reduce the
clinical trial information available in the data bank, consistent with
the authority granted to the Agency under section 402(j)(2)(A)(iii) of
the PHS Act. We also indicated our concern that if such information
were not required in each instance in which a clinical trial is stopped
prematurely (i.e., not according to the protocol), it might be
submitted only for some trials, resulting in inconsistencies in the
information available for registered clinical trials (79 FR 69622).
Two commenters requested that for this data element the final rule
require only the submission of reasons for stopping a study that are
directly related to safety. These commenters asserted that any other
reasons would be business reasons, which would be confidential
commercial information prohibited from disclosure. As we explained in
the NPRM, we believe it is important for responsible parties to provide
any reasons for stopping a study, whether or not they relate to safety.
This increased transparency will assist the public, including patients,
in understanding the reasons why a trial was stopped. We also note that
this proposed definition specifies that any explanation provided be
brief; therefore, we do not believe that a responsible party will need
to provide any confidential commercial or proprietary information when
submitting the information for this data element. However, even if the
summary results information required to be submitted and posted does
include such proprietary information, as discussed above, section
402(j) of the PHS Act and this final rule constitute authorization by
law to disclose the information.
After considering the comments, we are maintaining the NPRM
definition in the final rule. We note that Sec. Sec. 11.10(b)(26) and
11.64(a)(1) specify that a brief explanation for why the clinical trial
was stopped must be submitted if the Overall Recruitment Status is
``Suspended,'' ``Terminated,'' or ``Withdrawn.'' In most cases, the
Overall Recruitment Status of a clinical trial would be other than
Suspended, Terminated, or Withdrawn at the time of registration (e.g.,
a status of ``Not yet recruiting'' or ``Recruiting''). The responsible
party would not be required to complete the Why Study Stopped data
element unless and until there is a change in the Overall Recruitment
Status to Suspended, Terminated, or Withdrawn. (The Why Study Stopped
data element would not be available to a responsible party during the
registration process nor to the public in the posted clinical trial
record, unless and until the Overall Recruitment Status indicates that
the clinical trial is Suspended, Terminated, or Withdrawn.) However, if
a clinical trial is suspended, terminated, or withdrawn, the
responsible party would be required to update the Overall Recruitment
Status data element and, consistent with Sec. 11.64(a)(1), submit the
Why Study Stopped data element not later than 30 calendar days after
the date of the suspension, termination, or withdrawal of the clinical
trial to explain why the study stopped.
(G) Individual Site Status. In proposed Sec. 11.10(b)(28) of the
NPRM, we defined this data element as ``the recruitment status of each
participating facility in a clinical trial.'' Section
402(j)(2)(A)(ii)(II)(ff) of the PHS Act expressly requires ``individual
site status'' to be submitted as a clinical trial information at the
time of registration, but it does not define the term. To be consistent
with the proposed Overall Recruitment Status data element, we also
stated in the NPRM that responsible parties would be required to
indicate the individual site status by selecting from the following
limited set of choices: ``Not yet recruiting,'' ``Recruiting,''
``Enrolling by invitation,'' ``Active, not recruiting,'' ``Completed,''
``Suspended,'' ``Terminated,'' and ``Withdrawn.'' No ``other'' option
was proposed. We invited public comment on whether the proposed options
were sufficient to accurately describe the individual site status of
clinical trials that would be subject to the proposed rule (79 FR
69623). Two commenters suggested that the final rule remove the
proposed requirement for registering and updating the Individual Site
Status data element for each participating facility in the trial. The
Individual Site Status data element is required by section
402(j)(2)(A)(ii)(II)(ff) of the PHS Act. Furthermore, such information
supports the purpose of ClinicalTrials.gov to enhance patient
enrollment by assisting potential human subjects who search for
clinical trials by location and wish to retrieve information about only
those trials that are open to recruitment in specified locations. We
clarify that when the Overall Recruitment Status is a status other than
Recruiting, the Individual Site Status data element no longer needs to
be updated because the Overall Recruitment Status would apply to each
individual site. We also note that the update burden for responsible
parties is reduced by tools available in the PRS that allow the
Individual Site Status data element to be easily changed (e.g., from
Recruiting to Active, not recruiting) for many sites at once. After
considering the comments, we retain the proposed definition in the
final rule. However, we clarify these descriptions as described for the
Overall Recruitment Status data element. Specifically, we modify the
following four choices for the Individual Site Status data element from
the limited set described in the NPRM: ``Active, not recruiting''
indicates that a study is continuing, meaning that participants are
receiving
[[Page 65050]]
an intervention or being examined, but new participants are not
currently being recruited or enrolled; ``Completed'' indicates that the
study has concluded normally and that participants are no longer
receiving an intervention or being examined, i.e., the last patient's
last visit has occurred; ``Suspended'' indicates that a study halted
prematurely but potentially will resume; and ``Terminated'' indicates
that a study halted prematurely and will not resume and that
participants are no longer being examined or receiving an intervention.
We note that when a study has reached its study completion date, as
defined in Sec. 11.10(a), the Individual Site Status would be
Completed, unless the responsible party terminates the study, which
would be reflected as a status of Terminated.
(H) Availability of Expanded Access. Section
402(j)(2)(A)(ii)(II)(gg) of the PHS Act specifies that if a drug
(including a biological product) being studied in an applicable
clinical trial is not approved under section 505 of the FD&C Act or
licensed under section 351 of the PHS Act, the responsible party must
specify (1) ``whether or not there is expanded access to the drug under
section 561 of the [FD&C Act] for those who do not qualify for
enrollment in the clinical trial'' and, if so, (2) ``how to obtain
information about such access.'' As we expressed in the NPRM, we
believe the purpose of this requirement is to allow prospective human
subjects and other users of the data bank to readily identify
unapproved drugs that are available through expanded access under
section 561 of the FD&C Act and to direct these users to additional
information about the expanded access. Therefore, we proposed that
responsible parties meet the requirements of section
402(j)(2)(A)(ii)(II)(gg) of the PHS Act by indicating in the clinical
trial record whether expanded access is available for the drug under
study (i.e., either ``yes'' or ``no'') and, if yes, submitting the
additional information about the expanded access in the form of an
expanded access record under proposed Sec. 11.28(c) and including the
NCT number for the expanded access record in the record of a clinical
trial that studies the drug.
In the NPRM, we proposed to require the submission of information
to create an expanded access record using the statutory authority at
section 402(j)(2)(A)(iii) of the PHS Act, which allows the Secretary by
regulation to modify the requirements for clinical trial registration
information if the Secretary provides a rationale for why such a
modification ``improves and does not reduce such clinical trial
information.'' Information about the availability of expanded access
would be a data element that a responsible party is required to submit
under section 402(j)(2)(A)(ii)(II) of the PHS Act and, therefore, would
meet the definition of ``clinical trial information'' in section
402(j)(1)(A)(iv) of the PHS Act. We indicated that the additional data
elements describing expanded access availability would improve, and not
reduce, this clinical trial information by providing users with more
complete and consistent information about expanded access programs for
drugs studied in applicable clinical trials than would be available
pursuant to section 402(j)(A)(ii)(II)(gg) of the PHS Act alone. We
further concluded that we have the authority to require that the
clinical trial information required under proposed Sec. 11.28(c) be
submitted by creating a separate expanded access record in
ClinicalTrials.gov under section 402(j)(2)(B)(iv) of the PHS Act, as
the expanded access record would ensure that the public may more easily
use the data bank to determine whether there is expanded access to a
drug and compare different expanded access programs.
The approach we proposed is similar to the one used to submit a
description of whether, and through what procedure, the manufacturer or
sponsor will respond to requests for protocol exception, with
appropriate safeguards, for single-patient and expanded access use of
the investigational drug, particularly in children, prior to the
enactment of FDAAA [Ref. 78, 79]. Proposed Sec. 11.28(a)(2)(ix) would
require the responsible party for an applicable clinical trial of a
drug that is not approved under section 505 of the FD&C Act to submit
the Availability of Expanded Access data element, which was defined in
proposed Sec. 11.10(b)(29) to include ``[a]n indication of whether
there is expanded access to the drug under section 561 of the [FD&C
Act] (21 U.S.C. 360bbb) for those who do not qualify for enrollment in
the applicable clinical trial,'' and, if expanded access is available,
``the NCT number of the expanded access record.'' The availability of
expanded access would be indicated by a yes/no designation in
ClinicalTrials.gov. In addition, if the drug studied in the clinical
trial is available through expanded access under section 561 of the
FD&C Act and an expanded access record has not been created, under the
NPRM the responsible party would be required to create an expanded
access record consisting of the information specified in proposed Sec.
11.28(c). The posted expanded access record would be assigned its own
NCT number and thus would be searchable and retrievable independent of
the record(s) for the applicable clinical trial(s) of the
investigational product for which expanded access is available.
Under the proposed approach, we stated that we would expect the
sponsor of the expanded access program to be responsible for (1)
informing the responsible party(ies) for any applicable clinical trials
that study the drug available under expanded access of the creation of
an expanded access record and (2) providing them with the NCT number
for the expanded access record. The responsible party(ies) would be
required to update the related clinical trial record under proposed
Sec. 11.64(b) to include the NCT number for the expanded access record
within 30 calendar days of receipt. Accordingly, a single expanded
access record could be linked, via the expanded access record NCT
number, to several applicable clinical trials that study the drug that
is available via expanded access. If an expanded access record has
already been completed at the time of registration of an applicable
clinical trial (e.g., to fulfill the registration or updating
requirements for a previously registered applicable clinical trial),
the responsible party would be required to submit the NCT number for
that expanded access record as part of the Availability of Expanded
Access data element. The NPRM also noted that expanded access is
available via treatment INDs, which provide widespread access; expanded
access for intermediate-size patient populations; and expanded access
for individual patients (79 FR 69624). As we stated in the NPRM,
because requests for individual patient access are generally handled on
a case-by-case basis, a responsible party likely would not be able to
provide detailed information describing individual patient access at
the time of registering an applicable clinical trial. For cases in
which expanded access is only available for individual patients on a
case-by-case basis, we stated that we would not require the responsible
party to submit the elements of the expanded access record, as
described below, and we would expect that users of ClinicalTrials.gov
would direct inquiries regarding individual patient access to the
facility contact.
Commenters addressed issues related to the Availability of Expanded
Access data element in proposed Sec. 11.28(a)(2)(ix) and its
definition in proposed Sec. 11.10(b)(29). A few commenters expressed
support for the
[[Page 65051]]
proposed data element and its definition. A few commenters supported,
in particular, the proposed requirement that responsible parties for
applicable clinical trials of drugs available through expanded access
provide the NCT number for the expanded access record to permit linking
from clinical trial records to additional information about the
expanded access program. One commenter opposed the proposed requirement
for creating expanded access records because of concerns that such
records may (1) mislead patients into believing that no other
opportunities to obtain expanded access exist beyond what is described
in expanded access records because the proposal does not require the
submission of information about individual patient access and/or (2)
confuse patients regarding the distinction between clinical trials and
expanded access programs. We agree with the commenter that requiring
the submission of registration information for only certain types of
available expanded access programs, as proposed, could be problematic.
In addition, section 402(j)(2)(A)(ii)(II)(gg) of the PHS Act broadly
requires ``specify[ing] whether or not there is expanded access to the
drug under section 561 of the Federal Food, Drug, and Cosmetic Act''
and does not explicitly exclude individual patient expanded access.
After considering these comments and the statutory provision, in
the final rule we have revised the requirements regarding the
information to be submitted about the availability of expanded access
to investigational drug products (including biological products). We
have also clarified that ``drug'' means ``drug product.'' Therefore,
under the final rule, if an investigational drug product (including a
biological product) is available for any type of expanded access, and
the responsible party for an applicable clinical trial of that product
is both the manufacturer of the product and the sponsor of the
applicable clinical trial, the responsible party must create an
expanded access record for the investigational product by submitting
the expanded access data elements specified in Sec. 11.28(c) of the
final rule. We note that only one expanded access record should be
created for any given investigational product, even if the
investigational product is being made available for individual patient
expanded access (i.e., the responsible party should not create an
expanded access record for each instance of individual patient access).
This approach permits users of ClinicalTrials.gov to identify the full
range of expanded access availability under section 561 of the FD&C Act
by searching posted expanded access records.
Another commenter requested that posted clinical trial records be
made ``separate and distinct'' from expanded access records to avoid
confusion and suggested that ClinicalTrials.gov provide sponsors with
the ability to link to their expanded access policy and contact Web
pages. We recognize the potential for confusion between expanded access
records and clinical trial records and have sought to help users
distinguish between them (e.g., prominently displaying Study Type of
``Expanded Access'' versus ``Interventional Study,'' and Overall
Recruitment Status displayed as ``Expanded access is currently
available for this treatment'' versus ``This study is currently
recruiting participants''). We will continue to explore ways to
differentiate between the two types of records. With regard to the
second comment, we note that ClinicalTrials.gov currently permits
responsible parties to submit URLs of Web sites through the optional
Links data element.
One commenter requested that the final rule define ``expanded
access program'' and clarify for which expanded access programs the
data elements specified in proposed Sec. 11.28(c) would be required
under the final rule. In particular, although the preamble of the NPRM
stated that responsible parties would not be required to create
expanded access records when expanded access is available only through
individual patient access, this distinction was not specified in the
codified section of the NPRM. The commenter suggested that the final
rule state explicitly which types of expanded access programs require
the creation of expanded access records, such as by adding a definition
of expanded access in Sec. 11.10 of the final rule. Another commenter
suggested that the final rule narrow the proposed definition of
Availability of Expanded Access to section 561(c) of the FD&C Act,
thereby limiting the types of expanded access programs ``to
intermediate-size and large-size treatment INDs with established
inclusion/exclusion enrollment parameters and exclude[ing] emergency
situations and individual patient access to INDs intended for serious
diseases.''
We agree that the codified section of the proposed rule did not
provide specificity with respect to the term ``expanded access
program.'' After considering the issue, in the final rule, we have
revised the phrase ``expanded access program'' to ``expanded access''
for an expanded access record to more accurately characterize the
mechanism through which a responsible party makes its investigational
product available under expanded access. This flexibility will
accommodate both situations in which a responsible party has
established what it considers to be an expanded access program and
those in which a responsible party makes its investigational product
available through expanded access but does not itself characterize that
availability as a ``program.'' Furthermore, because the statutory
requirement for providing information about expanded access did not
explicitly exclude individual patient expanded access, we disagree with
the commenter that ClinicalTrials.gov should only include information
on certain types of expanded access. The final rule broadens the scope
of the proposed rule to include and define all three types of expanded
access under section 561 of the FD&C Act: (1) For individual patients,
including emergency use, as specified in 21 CFR 312.310; (2) for
intermediate-size patient populations as specified in 21 CFR 312.315;
and (3) under a treatment IND or treatment protocol as specified in 21
CFR 312.320. Section 11.10(b)(28) of the final rule, which defines the
Availability of Expanded Access data element, clarifies that if the
investigational product is available for any of these three types of
expanded access, the NCT number of a corresponding expanded access
record must be submitted. As such, the definition of and requirements
for the Availability of Expanded Access data element in the final rule
cover all types of expanded access for investigational drug products
(including biological products) under section 561 of the FD&C Act,
consistent with the statutory requirements. Additionally, Sec.
11.28(c) of the final rule, which indicates the data elements that must
be submitted for an expanded access record, lists the Expanded Access
Type data element, which is defined as ``[t]he type(s) of expanded
access for which the investigational drug product is available, as
specified in Sec. 11.10(b)(28).''
A few commenters expressed concern that requiring responsible
parties who are not industry sponsors and manufacturers of the drug to
create expanded access records could be problematic because only a
manufacturer would know when expanded access to a drug becomes
available and would possess the
[[Page 65052]]
information required to be submitted under Sec. 11.28(c) and updated
under Sec. 11.64. Accordingly, they suggested that the final rule only
require responsible parties who are industry sponsors of relevant
trials and manufacturers of the drug to create expanded access records
for their drugs. Several commenters suggested that the final rule
require drug manufacturers to notify responsible parties for applicable
clinical trials when drugs become available through expanded access
programs and that ClinicalTrials.gov could notify responsible parties
who are not drug manufacturers when an expanded access record has been
submitted for the drug being studied in their applicable clinical
trials. They also requested guidance on whether the Agency would
recommend that ``investigators of investigator-initiated trials'' seek
agreements from manufacturers that require notification that an
expanded access program for a studied drug becomes available. One other
commenter requested clarification on two issues: (1) How independent
investigators who are responsible parties for applicable clinical
trials would know when and what information to submit for an expanded
access record when the manufacturer makes a drug they are studying
available through expanded access and (2) whether the proposed rule
intended for the manufacturer to provide one expanded access record per
drug and an indication for the purposes of the registration
requirements.
We agree with the concerns raised by these commenters and have
modified the final rule to specify that the requirement to submit
information for the Availability of Expanded Access data element only
applies to a responsible party who is both the manufacturer of the
investigational drug product (including a biological product) and the
sponsor of the applicable clinical trial for that investigational
product. We believe that these new requirements will decrease the
burden on responsible parties who are not the manufacturer without
impeding access to information posted on ClinicalTrials.gov about the
availability of investigational drug products (including biological
products) for expanded access. At the same time, these new requirements
will ensure that only one expanded access record is created for each
investigational drug product that is available for expanded access for
any disease or condition. We wish to emphasize, however, that an
expanded access record is required to be submitted regardless of
whether the responsible party registering the applicable clinical
trial, who is both the sponsor of the applicable clinical trial and the
manufacturer of the investigational product, itself oversees the
availability of the investigational product for expanded access (i.e.,
it is required even in situations where the expanded access
availability is managed by a different entity). If certain data
elements required for submitting an expanded access record under Sec.
11.28(c) are unknown to the responsible party because the expanded
access availability is managed by a different entity, the responsible
party will need to consult with NIH concerning these data elements
before submitting the expanded access record. Instructions for
contacting NIH will be available at https://prsinfo.clinicaltrials.gov
(or successor site).
In addition, responsible parties will no longer need to be notified
by the manufacturer when an investigational drug product (including a
biological product) is available through expanded access. We note that
there may be cases in which the sponsor who is the manufacturer of the
unapproved drug product (including a biological product) may designate
the principal investigator to be the responsible party of an applicable
clinical trial of that product. Based on our experience operating
ClinicalTrials.gov, we expect the designation of a principal
investigator to be the responsible party by a manufacturer to be a rare
event. If it does occur, we recommend that the sponsor provide the
necessary information to the responsible party or, on an optional
basis, create an expanded access record to allow information about
expanded access to be shared with individuals who do not qualify for
enrollment in the clinical trial.
One commenter suggested that ClinicalTrials.gov provide links
between applicable drug clinical trial records and expanded access
records for the studied drugs and provide appropriate caveats about the
expanded access programs. ClinicalTrials.gov is able to provide the
appropriate links between matched clinical trial records and expanded
access records after a responsible party has identified in the clinical
trial record(s) that the investigational drug product (including a
biological product) is available through a particular expanded access
program. Once the responsible party submits the NCT number for the
relevant expanded access record, ClinicalTrials.gov creates and
displays a link on the clinical trial record to the related record for
the expanded access program. We can also provide links from expanded
access records to the matched clinical trial records. We note that
ClinicalTrials.gov currently provides links to information about
expanded access on FDA's Web site (e.g., www.fda.gov/NewsEvents/PublicHealthFocus/ExpandedAccessCompassionateUse/default.htm). As
suggested by the commenter, we will consider providing additional
information about expanded access or links on ClinicalTrials.gov.
Taking into consideration the commenters' suggestions and the
statutory requirements for providing information about expanded access
as part of clinical trial registration information, Sec.
11.28(a)(2)(ii)(H) of the final rule modifies the Availability of
Expanded Access data element with respect to which responsible parties
must submit the data element and by expanding the submission
requirement to include applicable clinical trials for which the
investigational drug products (including biological products) that are
being studied are available through individual patient expanded access,
including for emergency use. The Availability of Expanded Access data
element as defined in Sec. 11.10(b)(28) and specified in Sec.
11.28(a)(2)(ii)(H) of the final rule indicates whether the unapproved
drug product (including a biological product) studied in the applicable
clinical trial is available for expanded access under section 561 of
the FD&C Act for those who do not qualify for enrollment in the
applicable clinical trial (i.e., ``yes,'' ``no,'' or ``unknown'').
Under the final rule, the requirement to submit the data element is
limited to a responsible party for an applicable clinical trial of an
unapproved drug product (including a biological product) who is both
the manufacturer of the drug product and the sponsor of the trial.
Therefore, a responsible party for an applicable drug clinical trial
who is not the manufacturer of the drug product (including a biological
product) would not be required to submit information for the
Availability of Expanded Access data element (i.e., response of
``unknown''). This modification will decrease the burden on responsible
parties who are not the manufacturer but will still help ensure the
availability of information about expanded access on
ClinicalTrials.gov.
For an investigational drug product (including a biological
product) that is available through expanded access, including for
individual patients, the responsible party who is both the manufacturer
of the investigational drug product (including biological product) and
the sponsor of an applicable clinical
[[Page 65053]]
trial must provide the NCT number of the expanded access record as part
of the clinical trial information for that applicable clinical trial.
If an expanded access record for the investigational drug product
(including a biological product) has not yet been submitted to
ClinicalTrials.gov, the responsible party is required to create an
expanded access record as specified in Sec. 11.28(c). This new
requirement will provide users of ClinicalTrials.gov with a way to
obtain information about available expanded access to an
investigational drug product (including a biological product) as
required by the statute, including for individual patients.
We note that even though the expanded access record NCT number is a
registration data element, a responsible party is not required to
submit the expanded access data elements under Sec. 11.28(c) and
obtain an NCT number for that expanded access record prior to the date
on which clinical trial registration information under Sec. 11.28(a)
is due for the first applicable clinical trial of that investigational
product that the responsible party registers. Rather, the responsible
party is required at the time it submits clinical trial registration
information for the applicable clinical trial to indicate that expanded
access is available, submit the applicable data elements required by
Sec. 11.28(c), and indicate that the NCT number for the expanded
access record is ``pending.'' As described previously, within 30
calendar days of receipt of the NCT number for the expanded access
record, the responsible party is required to update the applicable
clinical trial record with the NCT number assigned to the expanded
access record. Finally, we note both that expanded access to an
investigational drug product (including a biological product) may not
be available at the time an applicable clinical trial is registered and
that an expanded access program may be discontinued on a date other
than the study completion date of an applicable clinical trial. We
believe that information about changes in the availability of expanded
access must be conveyed to users of ClinicalTrials.gov in a timely
manner and therefore Availability of Expanded Access is a data element
that must be updated more frequently than once every 12 months.
Accordingly, as explained in further detail in Sec. 11.64, the
Availability of Expanded Access data element must be updated within 30
calendar days of expanded access becoming available, consistent with
Sec. 11.64(a).
(iii) Location and Contact Information
(A) Name of the Sponsor. In Sec. 11.10(b)(30) of the NPRM, Name of
the Sponsor is defined as ``the name of the entity or the individual
that is the sponsor of the clinical trial, as defined in Sec.
11.10(a).'' Section 402(j)(2)(A)(ii)(III)(aa) of the PHS Act expressly
requires responsible parties to submit the name of the sponsor as part
of clinical trial information at the time of registration. In the NPRM,
the term ``sponsor'' is defined as ``either a `sponsor' or `sponsor-
investigator,' as each is defined in 21 CFR 50.3, or any successor
regulation.'' As we indicated, if the sponsor is a sponsor-
investigator, we would expect the name of the sponsor to be the name of
an individual; otherwise the name of the sponsor may be an
organizational name (79 FR 69624). We received no comments on this data
element and therefore retain the proposed definition in the final rule,
however, we made minor grammatical corrections (e.g., changing ``that''
to ``who'').
(B) Responsible Party, by Official Title. Section 11.10(b)(31) of
the NPRM defined Responsible Party, by Official Title to mean ``(i)
Indication of whether the responsible party is the sponsor of the
clinical trial, as that term is defined in 21 CFR 50.3, the sponsor-
investigator, as that term is defined in 21 CFR 50.3, or a principal
investigator designated pursuant to this part; and (ii) Either: (A) The
official name of the entity, if the responsible party is an entity; or
(B) The official title and primary organizational affiliation of the
individual, if the responsible party is an individual.'' Section
402(j)(2)(A)(ii)(III)(bb) of the PHS Act expressly requires the
submission of the ``responsible party, by official title'' as part of
clinical trial registration information. When an organizational entity
is the responsible party, we noted our belief that the official name of
the entity (e.g., company name, university name, government agency
name) must be included to satisfy the requirement for the Responsible
Party, by Official Title data element. When the responsible party is an
individual, we noted our belief that the official job title and the
organizational affiliation of the individual are necessary (e.g.,
``Director of Clinical Research, Institution X'' or ``Professor of
Medicine, Institution Y''). In addition, we indicated that we believe
it is necessary to ask whether the responsible party is the sponsor,
sponsor-investigator, or a principal investigator designated by the
sponsor, grantee, contractor, or awardee. Collection of this
information will help determine what information must be provided for
the official title and will allow a principal investigator to provide
an affirmative acknowledgement that he or she has been designated the
responsible party (79 FR 69624). We received no comments on this data
element and therefore retain the proposed definition in the final rule.
We note that an individual who serves as a responsible party and has
multiple affiliations (e.g., a research university and a teaching
hospital, a research institution and a private company) would be
required to submit only one such affiliation, namely, the affiliation
that the individual considers their primary affiliation. A related data
element, Responsible Party Contact Information, is defined in Sec.
11.10(b)(37).
(C) Facility Information. In Sec. 11.10(b)(32) of the NPRM, we
defined Facility Information as (1) ``Facility Name, meaning the full
name of the organization where the clinical trial is being conducted'';
(2) ``Facility Location, including city, state, country and zip code
for U.S. locations (including territories of the United States) and
city and country for locations in other countries,'' and (3) for each
participating facility either ``a Facility Contact, including the name
or title, telephone number, and email address of a person to whom
questions concerning the trial and enrollment at that site can be
addressed'' or a ``Central Contact Person, including the name or title,
toll-free telephone number and email address of a person to whom
questions concerning enrollment at any location of the trial can be
addressed.'' Section 402(j)(2)(A)(ii)(III)(cc) of the PHS Act expressly
requires the submission of ``the facility name and facility contact
information'' as part of clinical trial information at the time of
registration and describes facility contact information as ``including
the city, State, and zip code for each clinical trial location, or a
toll-free number through which such location information may be
accessed.'' Section 402(j)(2)(B)(i) of the PHS Act requires the
Director to ensure that the public may search the entries in
ClinicalTrials.gov by one or more of several enumerated criteria, one
of which is ``location of the clinical trial.'' In the NPRM, we
interpreted ``location of the clinical trial'' to mean each location of
the clinical trial because section 402(j)(2)(A)(ii)(III)(cc) of the PHS
Act describes ``facility contact information'' as meaning contact
information ``for each clinical trial location.'' To enable the public
to search the data bank by the location of the
[[Page 65054]]
clinical trial; in our view, satisfactory searching of the data bank by
location can only be accomplished if responsible parties submit
complete facility location information for each clinical trial
location. Also, in our view, a toll-free telephone number is not a
substitute for the location information for each facility or site but
rather is a source of supplementary information about the clinical
trial overall and an alternative to site-specific contact information
for each location. Therefore, the Agency proposed to exercise its
authority under section 402(j)(2)(A)(iii) of the PHS Act as we noted
our belief that including this information improves and does not reduce
the clinical trial registration information. We noted that our proposal
to permit responsible parties to submit Central Contact instead of
Facility Contact was intended to reduce the burden on responsible
parties who must submit clinical trial registration information.
However, the central contact person should be fully informed of, and
able to respond to, requests for information concerning the clinical
trial at all of its sites (79 FR 69625).
Commenters addressed the proposed Facility Information data
element. One commenter requested that facilities located outside of the
United States be excluded from the submission requirements. We disagree
with this comment. As discussed in the preamble of the NPRM, we
interpret ``location of the clinical trial'' in this context as meaning
each location of the clinical trial because section
402(j)(2)(A)(ii)(III)(cc) of the PHS Act describes ``facility contact
information'' as meaning contact information ``for each clinical trial
location.'' Because the final rule is not limited to applicable
clinical trials that are conducted in the United States, and because it
is important that the database be complete in order to allow users to
search for registered trials by key characteristics (including where
they are being conducted), the Facility Information data element must
include information about all facility locations, including those
outside the United States. A few commenters suggested that the final
rule limit the required Facility Contact Information sub-element to
information about the facility, rather than also requiring information
about an individual, as proposed. One commenter suggested requiring
only a toll-free telephone number for the Central Contact Person and
removing the proposed requirement for a name or title and an email
address to reduce the reporting burden and the submission of personally
identifiable information. Another commenter suggested that providing
contact information for each facility participating in a trial would
increase the burden on academic sites to respond to inquiries and
requested confirmation that a toll-free phone number is only required
for the Central Contact Person, if provided, and not for each study
facility. One commenter suggested that the final rule clarify that the
proposed Central Contact Person sub-element defined in Sec.
11.10(b)(32)(iii)(B) applies to the entire trial. Another commenter
supported the inclusion of contact information for someone who is
knowledgeable about the trial at each facility.
We disagree with these comments and maintain the definition of
``Facility Information.'' As explained in the preamble of the NPRM, the
requirement that the responsible party must submit to the data bank the
location of each facility at which the clinical trial is conducted will
allow users of ClinicalTrials.gov to search the data bank by each
clinical trial location (79 FR 69625). We believe that providing ``the
name or title . . . of a person to whom questions concerning the trial
and enrollment at that site can be addressed . . .'' helps users
identify who they can contact for additional information about a trial.
In addition, we believe that a toll-free telephone number is not a
substitute for the location information for each facility, but rather
is a source of supplementary information about the clinical trial
overall and an alternative to site-specific contact information for
each location. Because a toll-free phone number in one country may not
be applicable when a call originates in another country, and given the
worldwide prevalence of electronic communication, we believe that
submitting email addresses is necessary to provide an alternate method
of contacting someone knowledgeable about the trial. Finally, we note
that proposed Sec. 11.10(b)(32)(iii)(B) already specified ``a person
to whom questions concerning enrollment at any location of the trial
can be addressed'' and we believe that this description sufficiently
indicates that the person must be knowledgeable about all the locations
for a trial.
For these reasons, we believe including the information required in
the final rule improves and does not reduce the clinical trial
registration information. Under our authority in section
402(j)(2)(A)(iii) of the PHS Act, we therefore modify in Sec.
11.28(a)(2)(iii)(C) the requirement in section
402(j)(2)(A)(ii)(III)(cc) of the PHS Act for ``facility name and
facility contact information'' to require Facility Information for each
participating facility in the clinical trial, as defined in Sec.
11.10(b)(31). As noted above, the Agency intends to exercise its
authority under section 402(j)(2)(B)(i) of the PHS Act to enable the
public to search the data bank by the location of a clinical trial; in
our view, satisfactory searching by location can only be accomplished
if responsible parties submit complete facility location information
for each clinical trial location. In addition, the final rule allows,
but does not require, responsible parties to submit the name or title
of a person knowledgeable about the clinical trial at each site, along
with the phone number and email address of that person, which would
help prospective human subjects obtain additional, specific information
about a clinical trial at a particular location. Responsible parties
will also be permitted to submit a Central Contact Person instead of
Facility Contact, which will reduce the burden on responsible parties
who must submit clinical trial registration information. As noted in
the NPRM preamble, the central contact person should be fully informed
of, and able to respond to, requests for information concerning the
clinical trial for all its sites (79 FR 69625).
(iv) Administrative Data
Section 402(j)(2)(A)(ii)(IV) of the PHS Act provides for certain
``administrative data'' to be submitted by responsible parties as part
of clinical trial registration information; however, unlike the other
categories of clinical trial registration information, the statute
specifies that the Secretary may make administrative data ``publicly
available as necessary.'' Accordingly, in the NPRM, we indicated
whether we would make the information publicly available through
ClinicalTrials.gov.
(A) Unique Protocol Identification Number. In Sec. 11.10(b)(33) of
the NPRM, we defined ``unique protocol identification number'' to mean
``any unique identification number assigned to the protocol by the
sponsor.'' Section 402(j)(2)(A)(ii)(IV)(aa) of the PHS Act expressly
requires the submission of ``the unique protocol identification
number'' as part of clinical trial information at the time of
registration, but it does not define the term (79 FR 69625). We did not
receive any comments on this data element, but we are modifying the
proposed data element in the final rule for accuracy. To clarify that
the unique protocol identifier need not be a number, Unique Protocol
Identification Number is defined in the final rule as ``any unique
identifier assigned to the protocol by the
[[Page 65055]]
sponsor.'' We note that once a unique protocol identifier is entered on
ClinicalTrials.gov, the same identifier cannot be assigned to another
protocol for another clinical trial in the sponsor's ClinicalTrials.gov
account. In cases in which multiple identifiers may have been assigned
to a clinical trial (e.g., a funding organization's grant number, a
unique identifier established by another clinical trial registry),
interpreting this term as an identifier ``assigned by the sponsor''
will remove any ambiguity for responsible parties about which
identifier to submit as the unique protocol identifier for purposes of
registration on ClinicalTrials.gov. We also expect that the unique
protocol identifier would be readily available to the responsible
party, whether the sponsor or a designated principal investigator who
would have access to the protocol itself and/or be able to obtain the
unique protocol identifier from the sponsor. Furthermore, these
identifiers are often used in other clinical trial documentation, which
will enable cross-referencing of information submitted to different
data systems. To enable such cross-referencing, this data element will
be publicly available on ClinicalTrials.gov.
(B) Secondary ID. In Sec. 11.10(b)(34) of the NPRM, we defined the
term, in part, as ``[a]ny identification number(s) other than the
organization's unique protocol identification number or NCT number that
is assigned to the clinical trial . . .'' Section
402(j)(2)(A)(ii)(IV)(bb) of the PHS Act expressly requires the
submission of ``other protocol identification numbers, if any,'' at the
time of registration, but it does not define the term. We also proposed
that the Secondary ID include the complete grant or contract number for
any clinical trial that is funded, in whole or in part, by a U.S.
Federal Government agency and ``any unique clinical trial
identification numbers assigned by other publicly available clinical
trial registries'' (e.g., EudraCT in the EU). This requirement would
enable users of ClinicalTrials.gov to identify Government-funded
clinical trials. It also would assist agencies of the Department
(including NIH, FDA, the Centers for Disease Control and Prevention,
and the Agency for Healthcare Research and Quality) to verify that
clinical trial information for each applicable clinical trial for which
a grantee is the responsible party has been submitted consistent with
sections 402(j)(2) and (3) of the PHS Act and this part before the
agency releases any remaining funding for a grant or provides funding
for a future grant to such grantee as required under section
402(j)(5)(A)(ii) of the PHS Act of any agency of the Department that
funds applicable clinical trials. In addition, the inclusion of grant
and contract numbers for awards from other federal agencies (e.g.,
Department of Veterans Affairs, Department of Defense) would facilitate
efforts by the Secretary, as required under section 402(j)(5)(A)(iv) of
the PHS Act, to consult with such other agencies and develop comparable
procedures for the verification of compliance with the requirements of
sections 402(j)(2) and (3) of the PHS Act. Finally, in order for users
to interpret the various types of secondary ID information that might
be provided in response to this requirement, we proposed to require
responsible parties to submit ``[a] description of the type of
Secondary ID'' for each secondary ID submitted. We stated that these
descriptions should be brief but should clearly indicate the source of
the identifier, e.g., ``U.S. NIH Grant Number'' or ``[XYZ] Registry
Identifier.'' To facilitate data entry and improve comparability across
registered clinical trials, we stated that we would include a list of
several common identifier types in ClinicalTrials.gov, as well as
permitting free-text entriesl (79 FR 69626).
Currently, ClinicalTrials.gov allows responsible parties to select
from the following options: ``US NIH Grant/Contract Award Number,''
``Other Grant/Funding Number,'' ``Registry Identifier,'' ``EudraCT
Number,'' and ``Other Identifier.'' Responsible parties who select
``Other Grant/Funding Number,'' ``Registry Identifier,'' or ``Other
Identifier'' are required to enter the name of the funding organization
or a brief description of the identifier. One commenter supported the
proposal to require responsible parties to provide the complete grant
or contract number for any trial that is funded in whole or part by a
U.S. Federal Government agency. We modify the proposed data element in
the final rule for accuracy in a manner similar to the modifications
made to the Unique Protocol Identification Number. To clarify that a
secondary identifier need not be a number, Secondary ID is defined in
the final rule, in part, as ``[a]ny identifier(s) other than the
organization's unique protocol identifier or NCT number that is
assigned to the clinical trial, including any unique clinical trial
identifiers assigned by other publicly available clinical trial
registries.'' We will post the secondary ID publicly, as this
information will enable users to locate additional information in other
clinical trial registries as well as provide grant and contract numbers
for awards from other Federal agencies.
(C) U.S. Food and Drug Administration IND or IDE Number. In Sec.
11.10(b)(35) of the NPRM, we defined the Food and Drug Administration
IND or IDE Number data element to include an indication whether or not
there is an IND or IDE for the clinical trial (a yes/no response) and,
if so, each of the following elements: (1) ``[n]ame or abbreviation of
the FDA center with whom the IND or IDE is filed''; (2) ``IND or IDE
number assigned by the FDA center''; and (3) for an IND, ``the IND
serial number (as defined in 21 CFR 312.23(c), or any successor
regulation), if any, assigned to the clinical trial.'' Section
402(j)(2)(A)(ii)(IV)(cc) of the PHS Act expressly requires the ``Food
and Drug Administration IND/IDE protocol number'' to be submitted to
ClinicalTrials.gov at the time of registration in ClinicalTrials.gov,
but it does not define this term. FDA does not issue an ``IND/IDE
protocol number,'' as referred to in section 402(j)(2)(A)(ii)(IV)(cc)
of the PHS Act; rather it issues an IND or IDE number. We therefore
proposed to use the term ``Food and Drug Administration IND or IDE
number'' to identify this data element on ClinicalTrials.gov. We also
recognized that not all applicable clinical trials will be conducted
under an IND or IDE (e.g., because they are exempt). Because Center for
Drug Evaluation and Research (CDER), Center for Biologics Evaluation
and Research (CBER), and Center for Devices and Radiological Health
(CDRH) each issues IND or IDE numbers using a similar format, we
expressed in the NPRM our belief that, for purposes of registration
with ClinicalTrials.gov, a complete, unambiguous IND or IDE number must
include the name of the FDA center that issued it. In addition, if
several clinical trials are conducted under a single IND, each such
clinical trial may have a different serial number assigned to it. We
noted that any such serial number must also be specified to avoid
confusion. However, the NPRM explained that if multiple serial numbers
are assigned to a single IND (e.g., to reflect different clinical
trials, protocols, or protocol amendments), the responsible party
should submit only the first serial number that corresponds to the
clinical trial being registered (79 FR 69626).
Commenters addressed the Food and Drug Administration IND or IDE
Number data element. One commenter suggested that the final rule remove
the proposed requirement to provide the name or abbreviation of the FDA
center
[[Page 65056]]
with which the IND or IDE is filed. Another commenter requested
clarification on whether submitting an IRB registration number in place
of an IDE number or the FDA center information would be sufficient for
clinical trials of nonsignificant risk devices subject to FDA
abbreviated IDE requirements. We proposed requiring the FDA center name
as a sub-element of the Food and Drug Administration IND or IDE Number
data element because CDER, CBER, and CDRH all issue IND or IDE numbers
using a similar format. We also recognize that not all applicable
clinical trials will be conducted under an IND or IDE (e.g., ``IND-
exempt'' trials) and therefore would permit a responsible party to
indicate that a particular trial is not being conducted under an FDA
IND or IDE (i.e., the responsible party would indicate ``no'' for this
sub-element). We clarify that the FDA IND or IDE Number only refers to
the number that is assigned by one of the FDA centers. Because FDA does
not assign an IDE number for a clinical trial of a non-significant risk
device subject to FDA-abbreviated IDE requirements nor does it issue an
IDE for a clinical trial conducted outside of the United States, a
responsible party for such trials should indicate ``no'' for the U.S.
Food and Drug Administration IND or IDE Number data element. One
commenter suggested that the final rule require information on whether
a trial is being conducted under an IND or BLA for all trials conducted
in the United States. As proposed under the NPRM, all responsible
parties would be required to indicate whether an applicable clinical
trial is being conducted under an IND or IDE, regardless of whether
trial facility locations are within or outside the United States or
both. We do not require the submission of information about BLAs for
this data element because they are submitted to FDA only after trial
completion, when a manufacturer is seeking to obtain a license for
marketing a biological product, and so would not be available during
trial registration. We note, however, that section 402(j)(5)(B) of the
PHS Act requires submissions of BLAs to FDA to be accompanied by a
certification (i.e., Form FDA 3674) that all applicable requirements of
this part have been met and to include a list of appropriate NCT
numbers for applicable clinical trials used to support the BLA. Another
commenter suggested that the final rule require the inclusion of an IND
number or IND-exempt status of a trial to accommodate the determination
of which trials quality for coverage of routine care costs of clinical
trials under the Affordable Care Act in 42 U.S.C. 300gg-8. As noted in
the NPRM, we do not intend to make the Food and Drug Administration IND
or IDE Number available in the posted record. However, we note that
this information would be readily accessible in the PRS to a
responsible party for its own records and could be used by the
responsible party to support this need. After consideration of these
comments, we retain the proposed definition in final rule, but we
clarify that it means ``an indication of whether'' there is an IND or
IDE for the clinical trial. We also change the name of the data element
to ``U.S. Food and Drug Administration IND or IDE Number'' for clarity,
sinces other countries also have governmental agencies named ``Food and
Drug Administration'' (e.g., Korea).
(D) Human Subjects Protection Review Board Status. Section Sec.
11.10(b)(36) of the NPRM defined this data element as ``information to
indicate whether a clinical trial has been approved by a human subjects
protection review board or is exempt from human subjects protection
review board approval. Human Subjects Protection Review Board Status
must be listed as `approved' if at least one human subjects protection
review board has approved the clinical trial.'' While submission of
this information is not required by section 402(j) of the PHS Act, we
proposed to add this requirement pursuant to the authority given by
section 402(j)(2)(A)(iii) of the PHS Act to modify the requirements for
clinical trial registration information if such modification ``improves
and does not reduce such clinical trial information.'' We expressed in
the NPRM our belief that submission of the Human Subjects Protection
Review Board Status to ClinicalTrials.gov would improve, and not
reduce, clinical trial information by indicating to users of the data
bank whether a clinical trial registered on ClinicalTrials.gov is
undergoing or has undergone review by a human subjects protection
review board. Inclusion of this information would inform potential
human subjects of whether the clinical trials they find on
ClinicalTrials.gov have undergone at least one human subjects
protection review board review, have received the necessary approvals
for human subjects research from at least one human subjects protection
review board, or were exempt from such review. We stated in the NPRM
that the responsible party would be required to select from the
following limited set of options intended to cover all possible
statuses: ``Request not yet submitted'' (review board approval is
required but has not yet been requested); ``Submitted, pending''
(review board approval has been requested but not yet granted);
``Submitted, approved'' (review board approval has been requested and
obtained); ``Exempt'' (an exemption in accord with applicable law and
regulation has been granted); ``Submitted, denied'' (review board has
denied the approval request); and ``Submission not required'' (review
board approval is not required because the study is not subject to
laws, regulations, or applicable institutional policies requiring human
subjects review). No ``other'' option was proposed. We requested
comments on whether this menu of options adequately captured all
possible review statuses for clinical trials that would be subject to
this regulation (79 FR 69627).
The NPRM stated that the status would be listed as ``approved'' if
at least one human subjects protection review board has approved the
clinical trial. To clarify for users that the human subjects protection
review board status pertains to only one human subjects protection
review board, we would indicate that fact on ClinicalTrials.gov and
instruct potential human subjects to communicate with the site-specific
point-of-contact or the central contact for the clinical trial
(included as part of the Facility Information data element that is
submitted as part of clinical trial information under Sec.
11.28(a)(2)(iii)(C)) in order to determine the status of human subjects
protection review board review at other sites of interest. We indicated
that we believe this approach will provide users with important
information about human subjects review without burdening responsible
parties with updating information on multiple sites (79 FR 69627). Some
commenters proposed that the final rule require the submission of more
detailed information for the Human Subjects Protection Review Board
Status data element and display that information on the posted record,
with one suggesting that public access to such information would be
helpful for patients as well as for promoting the use of central IRBs
for multicenter trials. As discussed, we believe that the proposed
approach strikes the appropriate balance by providing users with the
important information that at least one human subjects protection
review board has reviewed and approved a trial without burdening
responsible parties with the need to submit and update more detailed
information for each board (up to one per facility). Therefore, we
retain the proposed approach in the final rule.
[[Page 65057]]
We note that an applicable clinical trial could be registered prior to
human subjects protection review board approval by indicating that the
status is Request not yet submitted; Submitted, pending; or Exempt. If
the status subsequently changes, the responsible party would be
required, consistent with Sec. 11.64(a)(1), to update the Human
Subjects Protection Review Board Status data element not later than 30
calendar days after the change. If any IRB is still providing oversight
for at least one site, the status of the trial would not be suspended
even if such action is taken in relation to another site. We will
continue to make available, as optional data elements, more detailed
information about IRB approval, such as the name of the IRB, to support
a responsible party's and/or an organization's tracking needs.
(E) Record Verification Date. Section Sec. 11.10(b)(37) of the
NPRM defined Record Verification Date as ``the date upon which the
responsible party last verified the clinical trial information in the
entire ClinicalTrials.gov record for the clinical trial, even if no
additional or updated information was submitted at that time.'' This
data element is required by section 402(j)(2)(A)(ii)(IV)(cc) of the PHS
Act to be submitted as part of clinical trial information at the time
of registration, but it does not define the term. In the NPRM, we
expressed our belief that the record verification date is intended to
be submitted as a separate data element that indicates to users of the
data bank how recently the information for a particular clinical trial
was verified and, hence, whether it may be out of date. We stated our
intent to collect and post publicly the Record Verification Date data
element on ClinicalTrials.gov (79 FR 69628).
We proposed requiring responsible parties to include the Record
Verification Date data element as part of the initial submission of
clinical trial registration information to ClinicalTrials.gov and to
update it any time the responsible party reviews the complete clinical
trial record for accuracy, such as when making a periodic review of an
entire clinical trial record. However, if the responsible party submits
updates to one or more data elements without reviewing the accuracy of
the rest of the record, the Record Verification Date data element would
not be updated. We noted that the proposed approach would not require a
responsible party to review records more frequently or regularly than
would be needed in order to update submitted information as specified
in Sec. 11.64 (should the responsible party use this method to help
ensure that updates are submitted on time), but it would require that
the Record Verification Date be updated if the complete record was
reviewed for accuracy during such an update (79 FR 69628).
One commenter requested that we delete the word ``entire'' from the
definition so that the responsible party is not required to review all
data in the record any time the responsible party reviews some of the
information. We agree with the commenter's point that a responsible
party is not required to review all data each time a record is
accessed. We believe, however, that the proposed definition makes it
clear that the record verification date needs to be updated only when
the responsible party does review the entire record, not just part of
the record. This data element allows users to determine when all of the
data submitted in the record was last reviewed and verified by the
responsible party. Therefore, we maintain the NPRM definition in the
final rule, but we note that Sec. 11.64 of the final rule specifies
that ``Record Verification Date must be updated any time the
responsible party reviews the complete set of submitted clinical trial
information for accuracy and not less than every 12 months, even if no
other updated information is submitted at that time.''
(F) Responsible Party Contact Information. In Sec. 11.10(b)(38) of
the NPRM, we described Responsible Party Contact Information as
``[a]dministrative information to identify and allow communication with
the responsible party by telephone, email, and regular mail or delivery
service. Responsible Party Contact Information includes the name,
official title, organizational affiliation, physical address, mailing
address, phone number, and email address of the individual who is the
responsible party or of a designated employee of the organization that
is the responsible party.'' Section 402(j)(1)(B) of the PHS Act
requires the Secretary to develop a mechanism ``by which the
responsible party for each applicable clinical trial shall submit the
identity and contact information of such responsible party to the
Secretary at the time of submission of clinical trial information. . .
.'' Using the authority in section 402(j)(2)(A)(iii) of the PHS Act, we
proposed to modify the requirements for clinical trial information
submitted at the time of registration to require responsible parties to
submit Responsible Party Contact Information. As noted in the NPRM, we
believe that the addition of this information will improve and not
reduce clinical trial information by providing a mechanism for the
Agency to communicate with the responsible party about submitted
information, which can improve its quality, accuracy, and completeness.
We noted that we do not intend to post the physical address, mailing
address, phone number or email address of the responsible party (79 FR
69628). We received no comments on this data element and therefore
maintain it in the final rule. In general, we intend to post the name
of the responsible party if the responsible party is an individual
(e.g., a sponsor-investigator who holds the IND or IDE for a clinical
trial or a designated principal investigator). We would post the name
of the responsible party, along with the Responsible Party, by Official
Title data element as specified in Sec. 11.28(a)(2)(iii)(B) of the
final rule, which section 402(j)(2)(A)(ii)(III)(bb) of the PHS Act
requires to be made publicly available. We believe that the posting of
the individual's name is necessary to avoid ambiguity; for example, if
the responsible party is a university professor, there may be a number
of individuals with the same title and affiliation (professor of
medicine at ABC University). Posting the name of the individual when an
individual is the responsible party would also be consistent with
posting the name of the entity when an entity is the responsible party
of an applicable clinical trial. The Responsible Party Contact
Information data element would be required to be updated as specified
in Sec. 11.64.
Data elements that were suggested in public comments but not
incorporated into the final rule are discussed below.
Bioequivalence and Bioavailability. One commenter requested the
addition of data elements to identify bioequivalence and
bioavailability studies and to indicate specific biomarkers relevant to
the population studied. We note that ClinicalTrials.gov currently
offers an optional registration data element, Study Classification,
that includes both ``Bio-equivalence'' and ``Bio-availability'' as
options. Biomarkers that are the focus of a study may be listed in the
Primary Disease or Condition Being Studied in the Trial, or the Focus
of the Study data element specified in proposed Sec. 11.48(a)(1)(ix)
and defined in proposed Sec. 11.10(b)(9). We also note that biomarkers
may be described in the context of outcome measures that are evaluated
in the clinical trial. Otherwise, responsible parties could provide
such information voluntarily as part of an optional data element (e.g.,
Detailed Description). Because responsible parties can submit
[[Page 65058]]
this information using optional data elements, and consistent with our
goal to minimize the number of required data elements, we do not
require the submission of this information in the final rule. We
understand the growing interest in and research on biomarkers and will
continue to evaluate this topic and ways to further optimize the
collection, retrieval, and display of such information.
Individual Participant Data (IPD) Availability. One commenter
requested that the final rule include an optional data element for
indicating whether IPD or CSRs are being made available to others and,
if so, the location of the data and contact information. In December
2015, ClinicalTrials.gov added the following optional data elements
that allow responsible parties to provide information about their plans
for sharing IPD and to describe where data sets and/or study documents
are available: Plan to Share Data? and Available Study Data/Documents.
Because responsible parties can choose to submit this information using
the optional data elements, and consistent with our goal to minimize
the number of required data elements, we do not include these data
elements in the final rule.
Other Trial Characteristics. Several commenters suggested that
whether a registered trial is ``for profit'' should be clearly labeled
on the posted record on ClinicalTrials.gov. We are not aware of any
standard approaches for defining a trial's profit status (e.g., ``for
profit'' or ``non-profit'') and the commenters did not suggest any
operational definitions. In addition, there are many features of a
trial's sponsor that may be of interest to potential participants, as
well as those interested in the study's results; ClinicalTrials.gov can
help identify the trial and its sponsor but cannot provide all
potentially relevant information. One other commenter recommended
adding a data element that could be used for searching for trials of
genetic therapies. We note that the Intervention Type data element
defined in Sec. 11.10(b)(13) includes a ``genetic'' (including gene
transfer, stem cell and recombinant DNA) option that a responsible
party could choose to identify a genetic therapy intervention. For
these reasons, we are not adding additional data elements to include
other trial characteristics, but we will consider providing an Advanced
Search feature in the future that would allow users to search
ClinicalTrials.gov for registered studies by Intervention Type.
Schedule of Events. One commenter suggested that the Agency
consider adding a ``schedule of events'' data element that would
provide information for participants about the medical care that will
be covered in a study. While we understand that this information could
be important for a potential participant, we believe it is more
appropriate for this information be provided by the study contact at
the time that potential participants and/or their health care providers
are seeking further information about the study. Accordingly, we are
not including this data element in the final rule.
Sec. 11.28(b)--Pediatric Postmarket Surveillance of a Device Product
That Is Not a Clinical Trial
Overview of Proposal
(b) Data elements required to register a pediatric postmarket
surveillance of a device product that is not a clinical trial. Proposed
Sec. 11.28(b) specified the clinical trial information that must be
submitted to ClinicalTrials.gov to register a pediatric postmarket
surveillance of a device that is not a clinical trial, as defined in
this part, but is required to be registered under proposed Sec. 11.22.
Section 801(c) of FDAAA recognizes that not all of the clinical trial
information specified in section 402(j) of the PHS Act or proposed in
this rule will apply to all pediatric postmarket surveillances of a
device and directs the Secretary to issue guidance explaining how the
registration and results information submission provisions of section
402(j) of the PHS Act apply to a pediatric postmarket surveillance of a
device that is not a clinical trial. As stated in the NPRM, the Agency
intended for the discussion of the proposed sections related to
pediatric postmarket surveillances of a device to provide draft
guidance. In 21 CFR 822.3, ``postmarket surveillance'' is defined as
the ``active, systematic, scientifically valid collection, analysis,
and interpretation of data or other information about a marketed
device.'' The Agency interpreted a pediatric postmarket surveillance of
a device as a postmarket surveillance of a device used in a pediatric
population (i.e., patients who are 21 years of age or younger at the
time of diagnosis or treatment) (see 21 U.S.C. 360j(m)(6)(c)). The
clinical trial information specified in proposed Sec. 11.28(a) and
defined in proposed Sec. 11.10(b) would apply to any pediatric
postmarket surveillance of a device that is a clinical trial (i.e.,
Study Type would be ``interventional''). However, because not all
pediatric postmarket surveillances under section 522 of the FD&C Act
are clinical trials, as defined in this part, many of the data elements
listed in proposed Sec. 11.28(a) or the definitions proposed in Sec.
11.10(b) may not apply. Therefore, proposed Sec. 11.28(b) specified a
more limited set of data elements required to register a pediatric
postmarket surveillance of a device that is not a clinical trial;
moreover, it also modified the definitions of certain data elements
that were defined in proposed Sec. 11.10(b) (79 FR 69629).
In general, the proposed definitions of these data elements were
consistent with the definitions of the named data elements in proposed
Sec. 11.10(b); however, we had modified them, where appropriate, to
better match the characteristics of pediatric postmarket surveillances
of a device that are not clinical trials. For example, Study Start
Date, which was defined in proposed Sec. 11.10(b)(16) for a clinical
trial as ``the estimated date on which a clinical trial will be open to
enrollment of human subjects, or the actual date on which the first
human subject was enrolled,'' was defined in proposed Sec.
11.28(b)(1)(xi) as the ``date on which FDA approves the postmarket
surveillance plan, as specified in 21 CFR 822.19(a) (or any successor
regulation).'' Similarly, the definition of Completion Date in section
402(j)(1)(A) of the PHS Act and proposed Sec. 11.10(b)(17) generally
would not apply to a pediatric postmarket surveillance of a device that
is not a clinical trial; therefore, in proposed Sec. 11.28(b)(1)(xii)
we proposed to require submission of the Completion Date data element,
which was defined as ``[t]he estimated date on which the final report
summarizing the results of the pediatric postmarket surveillance of a
device is expected to be submitted to FDA. Once the final report has
been submitted, the actual date on which the final report is submitted
to FDA.'' The Agency considered the proposed list of required data
elements for a pediatric postmarket surveillance of a device that is
not a clinical trial to be the most inclusive set of data elements that
could be expected to apply to all pediatric postmarket surveillances of
a device that are not clinical trials, regardless of the design of the
surveillance. The proposed required information would allow users to
access records of pediatric postmarket surveillances of a device that
are not clinical trials by conducting searches using a number of
relevant criteria, retrieve basic descriptive information about the
surveillances, and find a point-of-contact for additional information.
We did not propose the submission of those data elements listed under
section 402(j)(2)(A)(ii) of the PHS Act that are not expected to apply
to all
[[Page 65059]]
pediatric postmarket surveillances of a device that are not clinical
trials. For example, Study Phase is relevant only to clinical trials
involving drugs. The specific elements of Study Design (e.g.,
Interventional Study Model, Allocation, Masking, Single Arm
Controlled?) would not apply to most studies that are not
interventional clinical studies (i.e., clinical trials). Eligibility
Criteria, Age, and Gender may not be defined specifically for the study
population in a pediatric postmarket surveillance of a device that is
not a clinical trial. Enrollment would not be relevant to a pediatric
postmarket surveillance of a device that takes the form of a literature
review. We noted that we expect that some information about the study
design and relevant study population would be included in the brief
summary of the pediatric postmarket surveillance of a device. We
invited comments on alternative approaches for specifying the
registration requirements for a pediatric postmarket surveillance of a
device that is not a clinical trial (79 FR 69629).
Comments and Response
One commenter suggested that the registration data elements
required to be submitted for a pediatric postmarket surveillance of a
device that is not a clinical trial in proposed Sec. 11.28(b) be
replaced in the final rule with the same set of data elements required
for clinical trials as specified in proposed Sec. 11.28(a). The Agency
disagrees with this suggestion. As described in the preamble, not all
pediatric postmarket surveillances of a device product under section
522 of the FD&C Act are clinical trials. For such pediatric postmarket
surveillances of a device product, many of the data elements for
clinical trials listed in proposed Sec. 11.28(a) and defined in
proposed Sec. 11.10(b) would not apply. Therefore, we specified in
proposed Sec. 11.28(b), and retain in the final rule, a limited set of
registration data elements that would more likely apply across all
pediatric postmarket surveillances of a device product, and we modified
the definitions in proposed Sec. 11.10(b) accordingly.
Final Rule
Taking into consideration the commenter's suggestions and the
statutory requirements for what constitutes clinical trial registration
information, Sec. 11.28(b) of the final rule retains the data elements
proposed in the NPRM but modifies some of the names and definitions to
improve clarity and for consistency with the data elements named in
Sec. 11.28(a) and defined in Sec. 11.10(b) of the final rule. Section
11.28(b) of the final rule identifies the structured information, or
data elements, that constitute clinical trial information that a
responsible party must submit in order to register a clinical trial.
While the full set of data elements from the NPRM is maintained in the
final rule, we have modified some of the names and definitions. For
example, we have clarified that ``device'' means ``device product'' and
the proposed name of Whether the Study is a Pediatric Postmarket
Surveillance of a Device data element in Sec. 11.28(b)(1)(v) of the
NPRM has been renamed ``Pediatric Postmarket Surveillance of a Device
Product'' throughout the final rule (i.e., in Sec. Sec. 11.10(b)(8),
11.28(a), 11.28(b), 11.60(b)(2)(i)(B)) for clarity and convenience, but
the proposed definition is maintained in the final rule. Conversely,
while the name of the Unique Protocol Identification Number data
element has been retained, the definition has been modified from ``the
unique identification number'' to ``the unique identifier'' for
accuracy (i.e., is not limited to numbers).
As set forth in Sec. 11.28(b) of the final rule, to register a
pediatric postmarket surveillance of a device product that is not a
clinical trial, the responsible party must provide the following data
elements: (1) Brief Title; (2) Official Title; (3) Brief Summary; (4)
Study Type; (5) Pediatric Postmarket Surveillance of a Device Product;
(6) Primary Disease or Condition Being Studied, or the Focus of the
Study; (7) Intervention Name(s); (8) Other Intervention Name(s); (9)
Intervention Description; (10) Intervention Type; (11) Study Start
Date; (12) Primary Completion Date; (13) Name of the Sponsor; (14)
Responsible Party, by Official Title; (15) Contact Information; (16)
Unique Protocol Identification Number, if any; (17) Secondary ID; (18)
Human Subjects Protection Review Board Status; (19) Record Verification
Date; and (20) Responsible Party Contact Information. Consistent with
the elaboration of these data elements in Section IV.B.4 of the
preamble, for a pediatric postmarket surveillance of a device product
that is not a clinical trial the Study Type must be designated as
``observational'' and Pediatric Postmarket Surveillance of a Device
Product must indicate ``yes.''
In addition, for a pediatric postmarket surveillance of a device
product that is not a clinical trial, we recommend that the responsible
party submit any other registration information data elements that are
consistent with the surveillance design and are capable of being
accepted by ClinicalTrials.gov. For example, for a pediatric postmarket
surveillance of a device product that takes the form of a prospective
observational study, information such as the location(s) of the
surveillance, its eligibility criteria, the recruitment status, and its
outcome measures would also be relevant and should be submitted. We
believe the public would be best served if additional descriptive
information about these pediatric postmarket surveillances of a device
product were included in the data bank, but, given the lack of
experience to date, we cannot at this time specify what additional
information would be relevant to a particular type of pediatric
postmarket surveillance of a device product that is not a clinical
trial.
Sec. 11.28(c)--Expanded Access Records
Overview of Proposal
(c) Data elements required to create expanded access records.
Proposed Sec. 11.28(c) described the clinical trial information that
must be submitted to ClinicalTrials.gov to create an expanded access
record when a responsible party registers an applicable drug clinical
trial that studies an unapproved drug or unlicensed biological product
that is available via an expanded access program under section 561 of
the FD&C Act to those who do not qualify for enrollment in the clinical
trial. However, because expanded access programs do not share all of
the characteristics of clinical trials, as defined in this part, many
of the data elements listed in proposed Sec. 11.28(a) or their
definitions in proposed Sec. 11.10(b) do not apply. Therefore,
proposed Sec. 11.28(c) specified a limited set of data elements
required to create an expanded access record; moreover, it also
modified the definitions of certain data elements in proposed Sec.
11.10(b). Overall, in the NPRM we considered the proposed set of data
elements required to create an expanded access record to be the most
inclusive that would be relevant to all expanded access programs (other
than individual-patient access), regardless of design, and helpful to
users of ClinicalTrials.gov who wish to determine whether they may be
eligible to receive an investigational drug through an expanded access
program and to obtain additional information about such access. The
descriptions of the data elements in the NPRM generally paralleled the
definitions of the data elements in proposed Sec. 11.10(b) that are
required to be submitted when registering a clinical trial under
proposed Sec. 11.28(a), but were modified in proposed Sec. 11.28(c)
to refer to expanded access programs rather than
[[Page 65060]]
clinical trials and to be limited to expanded access programs for drugs
and biologics. One data element that was not defined in proposed Sec.
11.10(b) but is required to be submitted for expanded access records
only is the Expanded Access Status data element. We invited comments on
whether the proposed list of options for this data element was
sufficient to describe the status of an expanded access program (79 FR
69630).
We proposed requiring the submission of information to create an
expanded access record using the statutory authority in section
402(j)(2)(A)(iii) of the PHS Act, which allows the Secretary by
regulation to modify the requirements for clinical trial registration
information if the Secretary provides a rationale why such a
modification ``improves and does not reduce such clinical trial
information.'' Information about the availability of expanded access is
a data element that a responsible party is required to submit under
section 402(j)(2)(A)(ii)(II) of the PHS Act and thus meets the
definition of ``clinical trial information'' as that term is used in
section 402(j)(1)(A)(iv) of the PHS Act. We noted in the NPRM that we
think these additional data elements describing expanded access would
improve and not reduce clinical trial information by providing users
with more complete and consistent information about expanded access
programs for drugs studied in applicable clinical trials than would be
available pursuant to section 402(j)(A)(ii)(II)(gg) of the PHS Act
alone. We further concluded that the clinical trial information
required under proposed Sec. 11.28(c), to be submitted by creating a
separate expanded access record in ClinicalTrials.gov, under section
402(j)(2)(B)(iv) of the PHS Act would help ensure that the public can
more easily use the data bank to determine whether there is expanded
access to a drug and to compare different expanded access programs. In
addition, this approach was consistent with the practice followed prior
to the enactment of FDAAA, when those registering trials in compliance
with FDAMA submitted expanded access information in the form of
expanded access records on ClinicalTrials.gov. We proposed that in the
rare instance in which an expanded access program for a drug met all of
the elements of an applicable drug clinical trial, the expanded access
program would have to be registered as an applicable drug clinical
trial (79 FR 69630). In developing the NPRM, we considered alternative
approaches, such as requiring the responsible party to submit the name,
phone number, and email address of a point-of-contact or Web site for
information about the expanded access program for each clinical trial
of a drug that has such a program. However, we concluded that this
approach would not ensure that complete information is available and,
by including such information as part of clinical trial registration
information, we can better ensure that the information is kept up-to-
date as required in proposed Sec. 11.64. Another alternative we
considered was to require responsible parties to enter the additional
data elements describing expanded access with every applicable clinical
trial of a drug or biological product for which expanded access is
available. Under our proposal, however, in situations in which multiple
applicable clinical trials study the same drug that is available via
the expanded access program, the expanded access record would be
submitted only once. Thereafter, any responsible party could link the
expanded access record to the clinical trial record(s) using the NCT
number assigned to the expanded access record, thereby reducing the
burden a responsible party faces when providing information about
expanded access for multiple records (79 FR 69631).
As explained in Section IV.B.4 of the NPRM, in the discussion of
the Availability of Expanded Access data element, the expanded access
record generated on ClinicalTrials.gov pursuant to the submission of
the data elements at proposed Sec. 11.28(c) would be assigned its own
NCT number and would be searchable and retrievable independent of the
record(s) for the clinical trial(s) that study(ies) the drug or
biological product for which expanded access is offered. To allow
ClinicalTrials.gov to establish a link between the expanded access
record and the clinical trial record(s), the responsible party(ies) for
any applicable clinical trials of the drug available via expanded
access would be required to include the NCT number that is assigned to
the expanded access record as part of the registration information
submitted for that clinical trial. In this way, the expanded access
record could be linked in this fashion to multiple applicable clinical
trials that study the drug or biological product that is available via
the expanded access program. We sought comments on this proposed
approach.
We also proposed that expanded access information for a medical
device that was studied in an applicable device clinical trial could be
submitted voluntarily under section 402(j)(4)(A) of the PHS Act to
create an expanded access record for the device. (79 FR 69630) We
further proposed that if a responsible party chose to submit this
information, the responsible party would be required to submit all of
the data elements that are required for expanded access to a drug in
Sec. 11.28(c), and that such expanded access records for
investigational devices would be required to be updated in accordance
with Sec. 11.64(b)(1)(v).
Comments and Response
We received comments addressing the proposed content of an expanded
access record. A commenter suggested that NIH and FDA should streamline
and standardize expanded access information for patients and that NIH
should collect and post the results obtained through expanded access
programs on ClinicalTrials.gov. A commenter proposed linking expanded
access records to the FDA application forms for expanded access
programs. Section 11.28(c) of the NPRM represented our efforts to
develop a streamlined and standardized approach to presenting
information on ClinicalTrials.gov about expanded access programs. The
proposed set of data elements represents, for the most part, a subset
of the registration data elements required for an applicable clinical
trial of a drug under proposed Sec. 11.28(a). These proposed data
elements were selected to represent key information that would
generally apply across all expanded access programs. We stated in the
NPRM that these data elements would allow ClinicalTrials.gov to display
a structured summary about each expanded access program in a consistent
format that would allow users to review important information quickly
and easily (e.g., eligibility criteria, disease or condition,
intervention name and description). Regarding the suggestion to require
the submission of results from expanded access use, as discussed in
Section IV.A.5, we have concluded that use of an investigational drug
product (including a biological product) under expanded access will not
be considered an applicable clinical trial. Therefore, no expanded
access use of an investigational drug product (including a biological
product) will be subject to the results information submission
requirements of this rule. We will consider providing links to
additional resources about expanded access such as FDA application
forms on the ClinicalTrials.gov public Web site, as suggested.
[[Page 65061]]
Final Rule
Taking into consideration the commenters' suggestions and the
statutory requirements for what constitutes clinical trial registration
information, Sec. 11.28(c) of the final rule modifies the set of data
elements from the NPRM that a responsible party must submit in order to
create an expanded access record as required in Sec.
11.28(a)(2)(ii)(H) of the final rule. Some of the data elements in
Sec. 11.28(c) that have been modified from what was proposed address
the modification described in section IV.B.4 of this preamble in the
discussion of the Availability of Expanded Access data element, which
requires submission of an expanded access record for all expanded
access types, including when expanded access is available for
individual patients, including emergency use. Other modifications
include some of the names and definitions of the proposed data elements
to improve clarity and consistency with the data elements named in
Sec. 11.28(a) and defined in Sec. 11.10(b) of the final rule,
including the clarification that ``drug'' means ``drug product'' and
that ``device'' means ``device product''. In addition, we provide
further elaboration on the purpose of some data elements and how a
responsible party can meet the data element requirements. Section
11.28(c) of the final rule also clarifies that expanded access records
are only required to be created and updated by a responsible party who
is both the manufacturer of the investigational drug product (including
biological product) that is available through expanded access and the
sponsor of an applicable clinical trial of that investigational drug
product (including biological product), as specified in Sec. Sec.
11.10(b)(28) and 11.28(a)(2)(ii)(H) of the final rule. Finally, we
exclude from the final rule the proposed provision regarding the
voluntary submission of expanded access information for a medical
device under section 402(j)(4)(A) of the PHS Act, and we provide a
further explanation below.
The Expanded Access Type data element, which was not proposed in
the NPRM, is defined in Sec. 11.28(c)(1)(x) of the final rule as
``[t]he type(s) of expanded access for which the investigational drug
product (including a biological product) is available as specified in
Sec. 11.10(b)(28).'' For this data element, responsible parties would
be required to select one or more options from the following limited
set: ``individual patient'' (i.e., expanded access for individual
patients, including for emergency use, as specified in 21 CFR 312.310),
``intermediate'' (i.e., expanded access for intermediate-size patient
populations, as specified in 21 CFR 312.315), or ``treatment use''
(i.e., expanded access for widespread treatment use under a treatment
IND or treatment protocol, as specified in 21 CFR 312.320). As
described in section IV.B.4 of this preamble, in the discussion of the
Availability of Expanded Access data element, the final rule expands
the proposed requirement to provide expanded access records for all
types of expanded access available for an unapproved drug product
(including a biological product). In light of this expansion, the
Expanded Access Type data element is required to indicate the
particular type(s) of expanded access under which an investigational
drug product (including a biological product) is available.
Additionally, the submission of certain expanded access record data
elements specified in Sec. 11.28(c)(2) are not required if the
Expanded Access Type indicates that expanded access is available only
for individual patients, including for emergency use. Thus, the
Expanded Access Type data element facilitates identifying which
information must be provided, specific to the type of availability of
expanded access. For these reasons, this new registration data element
is authorized by section 402(j)(2)(A)(ii) of the PHS Act because
requiring it improves and does not reduce the clinical trial
information.
While the other required data elements from the NPRM are maintained
in the final rule, we have modified some of the names and definitions
to be consistent with other modifications throughout this final rule.
For example, the proposed Gender data element in Sec. 11.28(c)(2)(ii)
of the NPRM is renamed ``Sex/Gender'' here and throughout the final
rule to be consistent with the same modification described in section
IV.B.4 of this preamble and Sec. 11.28(a)(2)(ii) of the final rule.
Conversely, while the name of the Unique Protocol Identification Number
data element is maintained, the definition has been modified from ``the
unique identification number'' to ``the unique identifier'' for
accuracy (i.e., is not limited to numbers) and the explanation modified
to explain it can also be an identifier of the expanded access record.
Specifically, if the sponsor did not assign a unique identifier to the
availability of its investigational drug product (including a
biological product) for expanded access use, an identifier for the
expanded access record must be provided. This identifier is composed of
numbers and/or letters and is needed to uniquely identify an expanded
access record in the PRS prior to submission and assignment of an NCT
number. The Agency will provide additional instructions at https://prsinfo.clinicaltrials.gov (or successor site) to assist sponsors in
creating a unique identifier for the expanded access record if the
sponsor did not assign an identifier to the expanded access. Similarly,
instructions will also be available at https://prsinfo.clinicaltrials.gov (or successor site) for sponsors needing to
create a Brief Title as specified in Sec. 11.28(c)(1)(i), which is
used for identification of the expanded access record in the PRS and on
the publicly posted study record.
As set forth in Sec. 11.28(c) of the final rule, if expanded
access is available for an intermediate-size patient population as
specified in 21 CFR 312.315) or through a treatment IND or treatment
protocol (as specified in 21 CFR 312.320), a responsible party who is
both the manufacturer of an investigational drug product (including a
biological product) that is available through expanded access and the
sponsor of an applicable clinical trial of that investigational product
must provide the following data elements to create an expanded access
record: (1) Brief Title; (2) Official Title; (3) Brief Summary; (4)
Study Type (which is ``expanded access'' for this type of record); (5)
Primary Disease or Condition; (6) Intervention Name(s); (7) Other
Intervention Name(s); (8) Intervention Description; (9) Intervention
Type (which is typically ``drug''), (10) Expanded Access Type; (11)
Eligibility Criteria; (12) Sex/Gender; (13) Age Limits; (14) Expanded
Access Status; (15) Name of the Sponsor; (16) Responsible Party, by
Official Title; (17) Contact Information; (18) Unique Protocol
Identification Number; (19) Secondary ID; (20) U.S. Food and Drug
Administration IND Number; (21) Record Verification Date; and (22)
Responsible Party Contact Information.
If expanded access is only available for individual patients,
including for emergency use as specified in 21 CFR 312.310, then only
the following data elements are required: (1) Brief Title; (2) Brief
Summary; (3) Study Type; (4) Intervention Name; (5) Intervention Type;
(6) Expanded Access Type; (7) Expanded Access Status; (8) Name of
Sponsor; (9) Responsible Party, by Official Title; (10) Contact
Information; (11) Unique Protocol Identification Number; (12) U.S. Food
and Drug Administration IND number, if
[[Page 65062]]
applicable; (13) Record Verification Date; and (14) Responsible Party
Contact Information. This more limited set of expanded access
information is sufficiently detailed to address the availability of an
investigational drug product (including biological product) under
individual patient expanded access.
If information necessary to complete certain data elements required
for submitting an expanded access record under Sec. 11.28(c)(1)-(4)
are unknown to the responsible party because the expanded access
availability is managed by a different entity, the responsible party
will need to consult with NIH concerning those data elements before
submitting the expanded access record, Instructions for contacting NIH
will be available at https://prsinfo.clinicaltrials.gov (or successor
site). We also note that the definition of Official Title specified in
Sec. 11.28(c)(1)(ii) has been clarified to indicate it only needs to
be provided if one exists (i.e., if there is an official title then it
must be provided; if there is not an official title, the data element
does not need to be provided). Similarly, the U.S. Food and Drug
Administration IND Number data element has been modified to allow a
responsible party to specify whether the expanded access is being
conducted under an IND, but to allow for certain elements related to
the IND to be provided ``if applicable''.
Expanded Access Status is another data element that is required to
be submitted only for expanded access records and is not defined in
Sec. 11.10(b). It is defined in Sec. 11.28(c)(2)(iv) of the final
rule to mean ``[t]he status of availability of the investigational drug
product (including a biological product) through expanded access.''
When submitting this data element, responsible parties are required to
select from the following limited set of options for describing the
current status of availability of the investigational drug product
through the expanded access program: ``Available'' (expanded access is
currently available), ``No longer available'' (expanded access was
available previously but is not currently available and is not expected
to be available in the future), ``Temporarily not available'' (expanded
access was previously available, is not currently available, but is
expected to be available in the future), and ``Approved for marketing''
(expanded access was available previously but is not currently
available because the drug or device has been approved, licensed, or
cleared by FDA).
We have further considered the proposal regarding the voluntary
submission of expanded access information under section 402(j)(4)(A) of
the PHS Act for unapproved or uncleared device products that are
studied in an applicable device clinical trial and have decided not to
include this provision in the final rule under Sec. 11.60. The
Availability of Expanded Access data element defined in Sec.
11.10(b)(28) and specified in Sec. 11.28(a)(2)(ii)(H) of the final
rule is a data element that is specific to the availability of expanded
access for an applicable drug clinical trial of an investigational drug
product (including a biological product). Similarly, the obligations in
Sec. 11.28(c) to create an expanded access record are, consistent with
section 402(j)(2)(A)(ii)(II)(gg) of the PHS Act, are specific to the
provision of information when expanded access to an investigational
drug product (including a biological product) is available under
section 561 of the FD&C Act and 21 CFR 312.310 (for individual
patients, including for emergency use), 21 CFR 312.315 (for an
intermediate-size patient population), or 21 CFR 312.320 (under a
treatment IND or treatment protocol). Therefore, for the purposes of
the voluntary submission of expanded access information under section
402(j)(4)(A) of the PHS Act and Sec. 11.60 for unapproved or uncleared
device products that are studied in an applicable device clinical
trial, ``complete clinical trial information'' does not include
information about the availability of expanded access for the
investigational device product.
We note that a responsible party for an applicable device clinical
trial could choose to create an expanded access record for the
investigational device product being studied in that trial if the
investigational product is being made available under section 561 of
the FD&C Act and 21 CFR 812.36. We intend to provide additional
information at https://prsinfo.clinicaltrials.gov (or successor site)
to clarify which data elements would apply in such a situation.
5. 11.35--By when will the NIH Director post clinical trial
registration information submitted under Sec. 11.28?
Overview of Proposal
According to section 402(j)(2)(D)(i) of the PHS Act, for applicable
clinical trials, NIH is to post registration information not later than
30 days after the information is submitted. In the NPRM, we proposed in
Sec. 11.35(a) that NIH will post publicly the clinical trial
registration information, except for certain administrative data, ``not
later than 30 calendar days after the responsible party has submitted
such information in accordance with Sec. 11.24 of this part'' (79 FR
69631).
For an applicable device clinical trial of a device that was
previously cleared or approved by FDA, section 402(j)(2)(D)(ii)(II) of
the PHS Act requires registration information to be posted ``not later
than 30 days after'' results information is required to be posted. The
Agency interpreted section 402(j)(2)(D)(ii)(II) of the PHS Act as
providing a deadline by which such registration information must be
posted. The Agency considered the requirement to post registration
information ``not later than 30 days after [results information] is
required to be posted'' to be the last possible date on which it may
post registration information and that it is permissible to post
registration information prior to the deadline. The NPRM at Sec.
11.35(b)(1) proposed that for an applicable device clinical trial of a
device that was previously approved or cleared, NIH will publicly post
the clinical trial registration information, except for certain
administrative data, not later than 30 calendar days after clinical
trial results information is required to be posted in accordance with
proposed Sec. 11.52 (79 FR 69631).
Section 402(j)(2)(D)(ii)(I) of the PHS Act stipulates that for an
applicable device clinical trial of a device that has not previously
been cleared or approved, registration information must be posted
publicly not earlier than the date of clearance or approval of the
device and not later than 30 days after such date. Proposed Sec.
11.35(b)(2) reflected this statutory provision by stating that for an
applicable device clinical trial of a device that has not been
previously approved or cleared, ``NIH will post publicly at
ClinicalTrials.gov the clinical trial registration information, except
for certain administrative data, not earlier than the date of FDA
approval or clearance of the device, and not later than 30 calendar
days after the date of such approval or clearance.'' In the NPRM, we
acknowledged that while postponing the posting of clinical trial
registration information for applicable device clinical trials for a
device that previously has not been approved or cleared may protect the
commercial interests of device manufacturers, there are a number of
situations in which those who conduct such clinical trials may prefer
to make such information publicly available in the data bank prior to
the time frames specified by section 402(j) of the PHS Act. Therefore,
we invited comments from the public on how, given the statutory
language of Section 402(j)(2)(D)(ii)(I) of the PHS Act,
[[Page 65063]]
the Agency may address the concerns of sponsors and responsible parties
who wish to have clinical trial registration information for applicable
device clinical trials of devices that previously have not been
approved or cleared made publicly accessible in ClinicalTrials.gov when
the responsible party so chooses (79 FR 69576).
In order to help NIH meet the posting deadline and identify the set
of applicable device clinical trials for which registration information
must be posted after approval or clearance of a device, the NPRM
included a requirement in proposed Sec. 11.64(b)(2) for the
responsible party to update the U.S. FDA Approval, Licensure, or
Clearance Status data element not later than 15 calendar days after a
change in status has occurred. The responsible party would be required
to update that data element for all applicable device clinical trials
that study a device that was approved or cleared (79 FR 69631).
Comments and Response
We received comments on the specific question of when NIH should
post clinical trial registration information. Some commenters supported
and some opposed the proposed approach to determining which devices
would be able to take advantage of the delayed posting available to
devices that have not been previously approved or cleared. This topic
is addressed in more detail in Section IV.B.4 of this preamble.
Some commenters indicated they did not support the delayed posting
of registration information for devices that have not been previously
cleared or approved. Delayed posting is outlined in Section
402(j)(2)(D)(ii)(I) of the PHS Act, which says that the Agency may not
post publicly clinical trial registration information before the date
of clearance or approval for an applicable device clinical trial of a
device that was not previously cleared or approved. Section 11.35(b)(2)
of the NPRM, and the final rule at Sec. 11.35(b)(2)(i), reflect this
limit. Other commenters argued that the delayed posting of clinical
trial registration information provision in the statute should not be
understood as a bar to consensual disclosure of such information if a
device sponsor wishes to waive the right to delayed posting. The
commenters noted that under circumstances where a party wishes to waive
a statutory right, and that waiver would not frustrate the public
purpose of that statute, courts have acknowledged that statutory rights
intended to protect individual rights may be waived by the persons for
whom the statute provides protection.
We agree with views expressed by commenters that because the
delayed posting of registration information benefits the responsible
party, the responsible party should be able to choose to authorize the
Agency to make registration information available earlier. There may be
any number of reasons a responsible party would wish to opt out of the
delayed posting of registration information, such as to enhance patient
enrollment or to meet the requirements for consideration by a journal
abiding by ICMJE policy [Ref. 2]. Although Section 402(j)(2)(D)(ii)(I)
of the PHS Act provides that the Director of NIH ``shall'' ensure that
clinical trial information for an applicable device clinical trial of
an unapproved or uncleared device is not posted on ClinicalTrials.gov
earlier than the date of clearance or approval of the device, section
402(j)(2)(A)(iii) of the PHS Act gives the Secretary authority to
modify by regulation the requirements for clinical trial information
under paragraph (2), which includes the delayed posting provision in
402(j)(2)(D)(ii), so long as a rationale is provided for why the
modification improves and does not reduce such clinical trial
information. The Agency believes that allowing the responsible party to
authorize that clinical trial registration information that would
otherwise fall under the delayed posting provision be publicly posted
prior to approval or clearance of the product would improve and not
reduce such clinical trial information by making it accessible to the
public earlier. This approach would strike the proper balance between
affording the statutory protections of delayed disclosure to those
responsible parties that would like to take advantage of it while
promoting transparency of clinical trial registration information by
allowing responsible parties to authorize earlier posting.
Pursuant to section 402(j)(2)(A)(iii) of the PHS Act, we are adding
a new provision at Sec. 11.35(b)(2)(ii) to incorporate this option for
a responsible party to authorize early posting as well as a specific
data element in Sec. 11.28(a)(2)(i)(Q) that will be the mechanism
through which a responsible party can indicate to the Director that it
is authorizing the Director to publicly post its clinical trial
registration information prior to U.S. FDA approval or clearance of the
device product. See further discussion in this Section describing the
final rule as well as in Section IV.B.4 of this preamble.
Final Rule
We have taken into consideration the commenters' suggestions and
the statutory requirements for posting registration information in
developing Sec. 11.35 of the final rule. Section 11.35(a) states that
the Director will post publicly at ClinicalTrials.gov the clinical
trial registration information for an applicable drug clinical trial
not later than 30 calendar days after the responsible party has
submitted such information, as specified in Sec. 11.24.
Section 11.35(b)(1), which covers posting of registration
information for an applicable device trial of a device product that has
been previously approved or cleared, has been modified from the NPRM
for clarity. We have added the phrase ``as soon as practicable'' to
indicate that NIH will post registration information for an applicable
device clinical trial of a device product that previously was approved
or cleared ``as soon as practicable, but not later than'' the statutory
deadline outlined in section 402 (j)(2)(D)(ii)(II) or successor
statute. Section 402(j)(2)(D)(ii)(II) stipulates that clinical trial
registration information for an applicable device clinical trial of a
device that was previously cleared or approved will be posted ``not
later than 30 days after the clinical trial information under paragraph
(3)(C) is required to be posted by the Secretary.'' The information
referred to by ``in paragraph (3)(C)'' is basic results information.
The additional phrase of ``as soon as practicable'' clarifies in the
regulatory language the NIH's intent, described in the NPRM, to post
registration information for such applicable device clinical trials as
soon as practicable after submission, but not later than 30 calendar
days after clinical trial results information is required to be posted.
Posting this information prior to the deadline is consistent with the
objectives of expanding the registry and results data bank by
rulemaking, facilitating enrollment in clinical trials, and providing a
mechanism to track subsequent progress of clinical trials. Conversely,
waiting to post registration information for applicable device clinical
trials of device products that were previously approved or cleared
until after results information is required to be posted would delay
access to information about such clinical trials and would eliminate
the possibility for the data bank to be used to facilitate enrollment
in such trials and to allow the public to track such trials while they
are ongoing. We have also clarified that ``device'' means ``device
product.''
Section 11.35(b)(2) covers posting of registration information for
an applicable device trial of a device product that has not been
previously
[[Page 65064]]
approved or cleared. Proposed Sec. 11.35(b)(2) has been separated in
the final rule into Sec. 11.35(b)(2)(i) and Sec. 11.35(b)(2)(ii). In
these sections, we have clarified that ``device'' means ``device
product.'' Additionally, Sec. 11.35(b)(2)(i) adds a reference to the
exception in Sec. 11.35(b)(2)(ii) for earlier posting of registration
information by the Director if authorized by the responsible party.
New Sec. 11.35(b)(2)(ii) allows a responsible party for an
applicable clinical trial that is initiated on or after the effective
date of the rule to indicate to the Director, prior to the date of
approval or clearance of the device product, that it is authorizing the
Director to publicly post its clinical trial registration information
that would otherwise be subject to delayed posting as specified in
paragraph (b)(2)(i) prior to the date of FDA approval or clearance of
the device product. Upon notification, in the form of the responsible
party's submission of the Post Prior to U.S. FDA Approval or Clearance
data element under Sec. 11.28(a)(2)(i)(Q), the Director will post the
clinical trial registration information, except for certain
administrative data, as soon as practicable. Additionally, the Director
intends to follow the timelines established by section 402(j)(2)(D)(i)
of the PHS Act of posting the clinical trial registration information
not later than 30 days after such submission. While this section of the
statute refers to applicable drug clinical trials, it establishes a
clear timeline between the submission of clinical trial registration
information and its posting.
Two additional issues directly related to posting of registration
information are briefly described further: (1) The administrative data
elements that the Agency does not intend to post publicly and (2) the
relationship of posting and quality control described in Section IV.D.3
of this preamble. First, section 402(j)(2)(A)(ii)(IV) of the PHS Act
specifies that the Secretary ``may make publicly available as
necessary'' administrative data that are submitted as part of clinical
trial registration information. We interpret this provision to permit
the Secretary to not post certain administrative data in the data bank
if the data are not considered necessary for understanding the clinical
trial or for recruitment. As noted for each data element discussed in
Section IV.B.4 of this preamble, we do not believe it is necessary to
make public the following administrative data and currently do not
intend to post them publicly in ClinicalTrials.gov for any applicable
clinical trials: (1) Food and Drug Administration IND or IDE Number and
(2) Responsible Party Contact Information other than the name of the
responsible party if the responsible party is an individual (as opposed
to an entity). Second, as described in further detail in Section IV.D.3
of this preamble, we intend to continue a form of quality control
review at the time of clinical trial information submission that is
similar to the procedures we have been using for the past several
years. We note here, however, that, because the quality control review
process does not affect the statutory deadlines for submitting or
publicly posting submitted clinical trial information, there will be
cases in which submitted clinical trial information is posted even
though the quality control review process has not concluded. Although
we will post clinical trial registration information not later than 30
calendar days after submission, we will not assign an NCT number until
the quality control review process has concluded. Thus, the clinical
trial registration information will be posted to the ClinicalTrials.gov
Web site without an NCT number. In addition, the clinical trial record
will contain information that will be visible to those viewing the
record on ClinicalTrials.gov to make it clear that the quality control
review process has not concluded for the posted registration
information.
Reflecting section 402(j)(2)(C) of the PHS Act, as codified in
Sec. 11.22, the timelines in Sec. 11.35 apply only to clinical trials
that are required to register with ClinicalTrials.gov. If a clinical
trial is registered with ClinicalTrials.gov as a voluntary submission
as specified in Sec. 11.60, the registration information will be
posted as soon as practicable after it has been submitted and reviewed
as part of quality control review procedures.
C. Subpart C--Results Information Submission
Subpart C sets forth requirements and procedures related to the
submission of results information. In addressing what constitutes
results information, subpart C does not specify what results
information must be collected while the applicable clinical trial or
other clinical trial is being conducted, but rather spells out which
elements of the collected data must be submitted and in what required
format. Subpart C also specifies when NIH will post results information
in ClinicalTrials.gov and what procedures may be used to request a
waiver of any applicable requirements for results information
submission. Below, we summarize each section of subpart C, summarizing
its statutory basis, what we proposed in the NPRM, any public comments
received on the proposal, and the approach we take in the final rule.
1. Sec. 11.40--Who must submit clinical trial results information?
Overview of Proposal
Proposed Sec. 11.40 required that the responsible party for an
applicable clinical trial specified in proposed Sec. 11.42 submit
clinical trial results information for that clinical trial. This
approach is consistent with section 402(j)(3)(E)(i) of the PHS Act (79
FR 69632).
Comments and Response
No comments were received on this section.
Final Rule
The final rule maintains Sec. 11.40 as proposed.
2. Sec. 11.42--For which applicable clinical trials must clinical
trial results information be submitted?
Overview of Proposal
In the NPRM, Sec. 11.42 detailed the applicable clinical trials
for which results information would be required to be submitted in
accordance with subpart C to ClinicalTrials.gov, unless the requirement
is waived under proposed Sec. 11.54 (79 FR 69632). Pursuant to section
402(j)(3)(D)(ii)(I) of the PHS Act, Sec. 11.42 proposed to require the
submission of results information for specified: (1) Applicable
clinical trials of drugs that are approved under section 505 of the
FD&C Act or licensed under section 351 of the PHS Act; and (2)
applicable clinical trials of devices that are cleared under section
510(k) of the FD&C Act or approved under section 515 or 520(m) of the
FD&C Act. Proposed Sec. 11.42 also would have required the submission
of results information for specified applicable clinical trials of
drugs or devices that are not approved, licensed, or cleared for any
indication (regardless of whether the sponsor seeks approval,
licensure, or clearance). We noted that proposed Sec. 11.42 pertains
to section 402(j)(3)(D)(ii)(II) of the PHS Act, which directs that the
Secretary establish through regulation whether or not results
information must be submitted for applicable clinical trials of drugs
and devices that have not been approved, licensed, or cleared by FDA,
whether or not approval, licensure, or clearance is sought (79 FR
69632).
In the NPRM, Sec. 11.42 proposed to require responsible parties to
submit
[[Page 65065]]
results information for applicable clinical trials that are required to
be registered with ClinicalTrials.gov under Sec. 11.22 and that met
one of the following criteria: (a) The completion date is on or after
the rule's effective date (Sec. 11.42(a)); or (b) the completion date
is prior to the effective date of this rule, the applicable deadline
established by Sec. 11.44 is on or after the effective date of the
rule, and clinical trial results information is submitted on or after
the effective date of the rule, consistent with the applicable deadline
established by Sec. 11.44 (Sec. 11.42(b)) (79 FR 69632). The NPRM
also stated in the discussion of the effective date/compliance date
(Section III.D) that for results information due prior to the rule's
effective date under section 402(j)(3)(C) of the PHS Act, if the
responsible party did not in fact submit these results by the effective
date, then the responsible party would be required to submit the
clinical trial results information specified by Sec. 11.48 (79 FR
69593).
In addition, the NPRM proposed how the rule would handle an
applicable clinical trial of a drug or device under study that was not
approved, licensed, or cleared by FDA and reached its completion date
prior to the effective date of the rule, but the product is
subsequently approved, licensed, or cleared by FDA after the effective
date. We proposed that responsible parties for such applicable clinical
trials be required to submit clinical trial results information
specified in Sec. 11.48 by the earlier of 1 year after the completion
date or 30 calendar days after the date of initial FDA approval,
licensure, or clearance (79 FR 69594).
Comments and Response
We received a few comments on the issues specifically covered by
proposed Sec. 11.42. Those commenters suggested that results
information submission should not be required for trials with results
published in a peer-reviewed journal and that a hyperlink from
ClinicalTrials.gov to the published study and lay summary of results
would suffice. While results information submission to
ClinicalTrials.gov is required by section 402(j) of the PHS Act
independently of publication, ClinicalTrials.gov currently provides a
number of optional data elements such as Citations and Links, which can
be used to link a record to relevant trial results cited in
publications or available at another Web site, respectively [Ref. 97].
We anticipate that these optional data elements will continue to be
available on ClinicalTrials.gov.
We also received comments on issues relevant to proposed Sec.
11.42. Several commenters suggested that the rule should require
results information for applicable clinical trials completed at any
time, in order to ensure public access to such results information for
completed trials of drugs that are currently on the market. Applicable
clinical trials initiated on or before September 27, 2007, or completed
before December 26, 2007, are not required to register or submit
results information under section 402(j) of the PHS Act. As discussed
here and furthermore in Section III.B Submission of Results Information
for Applicable Clinical Trials of Unapproved, Unlicensed, or Uncleared
Products for Any Use and Section IV.F Effective Date, Compliance Date,
and Applicability of Requirements in this Part in the preamble, in the
final rule, the NIH requires results information submission from
applicable clinical trials of products that were unapproved,
unlicensed, or uncleared before the primary completion date but
subsequently approved, licensed, or cleared after the primary
completion date when the primary completion date is on or after the
effective date of the final rule. That is, with this rule, we require
results information from trials completed after the effective date,
regardless of whether approval, licensure, or clearance of the studied
product is sought. A related suggestion in comments was to require
submission of results information from applicable clinical trials
completed since the year 2000. The submission of results information
pursuant to these regulations, from trials with a primary completion
date before the effective date of the regulations, is not required.
Submission of basic results information (as defined in 402(j)(3)(C) of
the PHS Act) from applicable clinical trials has been a statutory
requirement since September 27, 2008, however, and is required for
applicable clinical trials with a primary completion date before the
effective date of the final rule.
Finally, some commenters opposed the NPRM requirement that
responsible parties who previously submitted results information for
outcome measures would be required to comply with the final rule,
anissue discussed in more depth in Section IV.F. of the preamble,
Effective Date, Compliance Date, and Applicability of Requirements in
this Part. As discussed in Section IV.F., the results information
submission requirements that apply to an applicable clinical trial are
determined by the date on which the trial reaches its actual primary
completion date rather than when a responsible party submits results
information.
Final Rule
Taking into consideration these submitted comments as well as the
statutory requirements, we have modified Sec. 11.42 in the final rule.
We clarify which applicable clinical trials must submit results
information according to the final rule and, consistent with the
discussion in Section IV.F. of the preamble, we have made revisions and
have restructured Sec. 11.42 to address the differing requirements
that apply to applicable clinical trials (and, if voluntarily
submitted, other clinical trials). Section 11.42(a) applies to
applicable clinical trials for which the studied product is approved,
licensed, or cleared by FDA. If the primary completion date for such
trial is before the effective date of the final rule, Sec. 11.42(a)(1)
requires clinical trial results information submission as specified in
sections 402(j)(3)(C) and 402(j)(3)(I) of the PHS Act. If the primary
completion date for such trial is on or after the effective date of the
final rule, Sec. 11.42(a)(2) requires clinical trial results
information submission as specified in Sec. 11.48. As discussed
further in Section IV.F. on Effective Date, Compliance Date, and
Applicability of Requirements in this Part, results information
submission requirements are determined by the date on which the trial
reaches its actual primary completion date. Thus, for trials that reach
their primary completion date before the effective date of the final
rule, results information submission is required as specified in
sections 402(j)(3)(C) and 402(j)(3)(I) of the PHS Act, and for trials
that reach their primary completion date on or after the effective date
of the final rule, results information submission is required as
specified in this final rule.
Section 11.42(b) applies to applicable clinical trials for which
the studied product is not approved, licensed, or cleared by FDA. As
discussed in Section III.B Submission of Results Information for
Applicable Clinical Trials of Unapproved, Unlicensed, or Uncleared
Products for Any Use and Section IV.E. Effective Date, Compliance Date,
and Applicability of Requirements in this Part, such applicable
clinical trials are not subject to results information submission
requirements until the effective date of the final rule. Thus, Sec.
11.42(b) only applies to applicable clinical trials for which the
studied product is not approved, licensed, or cleared if those trials
have a primary completion date on or after the effective date of the
final rule. For such trials,
[[Page 65066]]
clinical trial results information is required to be submitted as
specified in Sec. 11.48.
We note that proposed Sec. 11.42(b) had outlined scenarios in
which the completion date of the trial is prior to the effective date
of the rule and results information was required to be submitted
according to the proposed rule. Under the simplified approach taken in
the final rule, as discussed in Section IV.F., because determination of
results information submission requirements relies on the primary
completion date in relation to the effective date, proposed Sec.
11.42(b) is no longer necessary. That is, there will be no scenarios in
which the primary completion date is prior to the effective date of the
rule and results information is required to be submitted according to
the rule. We also note that the requirement to submit results
information for applicable clinical trials with a primary completion
date that is on or after the effective date, as specified in Sec.
11.48, applies regardless of whether any results information, including
for primary outcome measure(s), has been submitted before the effective
date.
3. Sec. 11.44--When must results information be submitted for
applicable clinical trials subject to Sec. 11.42?
Overview of Proposal
Proposed Sec. 11.44 specified the deadlines for submitting results
information for applicable clinical trials, implementing section
402(j)(3)(E) of the PHS Act. Proposed Sec. 11.44(a) specified the
standard submission deadlines for applicable clinical trials that are
clinical trials subject to proposed Sec. 11.42. Proposed Sec.
11.44(b) and (c) described procedures for delaying the standard
submission deadlines with certification when seeking approval,
licensure, or clearance of a new use or initial approval, licensure, or
clearance, respectively, of a drug (including a biological product) or
device studied in an applicable clinical trial. Proposed Sec. 11.44(d)
specified the procedures for submitting partial results information,
while Sec. 11.44(e) described the process for requesting an extension
of the results information submission deadline for good cause. Finally,
proposed Sec. 11.44(f) established the timeline for submitting results
of a pediatric postmarket surveillance of a device that is not a
clinical trial (79 FR 69632). Below we discuss each part of Sec. 11.44
separately.
Sec. 11.44(a) Standard Submission Deadline
Overview of Proposal
Proposed Sec. 11.44(a)(1) specified that, in general, the deadline
for submitting results information for an applicable clinical trial
would be 1 year after the completion date of the clinical trial. As
explained in the NPRM, sections 402(j)(3)(E)(i)(I) and (II) of the PHS
Act specify that results information is to be submitted not later than
1 year after the ``earlier of'' the estimated completion date or the
actual completion date (79 FR 69632). Under proposed Sec. 11.64(b)(1),
however, responsible parties would be required to update the estimated
completion date not later than 30 calendar days after a change to the
estimated completion date has occurred or after the applicable clinical
trial has reached its actual completion date. Therefore, submission 1
year after the actual completion date would then always reflect the
``earlier of'' 1 year after the estimated completion date or the actual
completion date. Thus, under proposed Sec. 11.44(a)(1), results
information would be due not later than 1 year after the actual
completion date of the applicable clinical trial. This proposed 1 year
standard submission deadline would apply to applicable clinical trials
of drugs and devices in order to simplify results information
submission procedures and provide consistency between the deadlines for
applicable clinical trials, regardless of the approval status of the
products under study. Section 402(j)(3)(D)(iv)(III) of the PHS Act
requires the Secretary to determine by regulation ``the date by which .
. . clinical trial [results] information [for applicable clinical
trials of unapproved, unlicensed, or uncleared products] shall be
required to be submitted . . .'' Applicable clinical trials of
unapproved, unlicensed, or uncleared drugs and devices, and of
approved, licensed, or cleared drugs and devices that are studied for a
new use may, however, qualify for delayed submission of results
information, as described below. As we noted in the NPRM, although
section 402(j)(3)(D)(iv)(I) of the PHS Act requires the Secretary to
determine whether to increase the standard submission deadline for
results information submission from 1 year to ``a period not to exceed
18 months'' after the earlier of the estimated or actual primary
completion date, the Agency chose not to propose extending the general
results information submission deadline to as long as 18 months (79 FR
69633).
Proposed Sec. 11.44(a)(2) specified that the deadline for
submitting results information for any applicable clinical trial of an
FDA-regulated drug (including a biological product) or device that is
unapproved, unlicensed, or uncleared as of its completion date would be
by the earlier of 1 year after the completion date, or 30 calendar days
after FDA approves, licenses, or clears the drug or device for any
indication studied in the applicable clinical trial (79 FR 69633).
Comments and Response
Comments on proposed Sec. 11.44 expressed different opinions.
While one commenter expressed overall support for the proposal, others
suggested modifications to various parts. Others raised concerns that
the overall proposed submission and public posting timelines for trial
results information could lead to premature dissemination of
confidential commercial information, especially if posted prior to
peer-reviewed publication or review by the FDA.
As we explained in the NPRM, we did not propose to require the
submission of detailed information about clinical trial results (such
as required for inclusion in an NDA submitted to FDA), but only summary
results data typically found as tables or figures in journal articles,
scientific abstracts, and press releases. As mandated by section
402(j)(3) of the PHS Act and established in the final rule Sec. 11.48,
responsible parties are required to submit at minimum a standard set of
data elements needed to understand the findings from an applicable
clinical trial for all prespecified primary and secondary outcome
measures and serious adverse events in a structured manner. Further,
results information submissions are required for all applicable
clinical trials subject to the final rule according to deadlines
established by the final rule, regardless of product approval status,
to ensure consistent and timely public access to comprehensive summary
results for all relevant clinical trials, thereby mitigating the
prevalent problems of selective results reporting and negative results
publication bias [Ref. 21, 22].
One commenter suggested that the results information submission
time frames prescribed in the final rule should conform to those
outlined in the 2015 IOM report on sharing clinical trial data [Ref.
47] to minimize the administrative burden on sponsors and responsible
parties. Another commenter suggested that results information should be
made available as it is created (i.e., real time submission). The
[[Page 65067]]
requirements in the final rule are consistent with the Agency's
authority in section 402(j) of the PHS Act and represent the Agency's
determination, consistent with that authority, as to the appropriate
results information submission deadlines for applicable clinical trials
of unapproved products.
Regarding the standard results information submission deadline
following initial approval, licensure, or clearance, described in
proposed Sec. 11.44(a)(2), one commenter recommended that, for
applicable clinical trials of unapproved, unlicensed, or uncleared
products for which the collection of pre-specified secondary outcome
measures continues past the completion date, the standard results
information submission deadline should be extended to the date of final
data collection for all pre-specified secondary outcome measures (i.e.,
at LPLV). The commenter also suggested that such a change would be
consistent with results information submission deadlines established
under the EU's Clinical Trials Regulation [Ref. 70]. Section
402(j)(D)(iv)(I) of the PHS Act authorizes the Agency to increase by
regulation the standard results information submission deadline from 1
year following the completion date described in 402(j)(3)(E)(i) of the
PHS Act ``to a period not to exceed 18 months.'' The statutorily-
mandated definition of completion date (here referred to as primary
completion date; see preamble Section IV.A.5 and Sec. 11.10(a)) is
determined by the status of data collection for solely the primary
outcome measure(s), as is the basis for determining the standard
results information submission deadline from the statutorily-mandated
primary completion date. The final rule permits the responsible party
to delay submission of results information for applicable clinical
trials for up to 2 additional years by submitting a certification under
Sec. 11.44(b) if the manufacturer is the sponsor and is seeking
approval, licensure, or clearance for a new use or under Sec. 11.44(c)
if the sponsor is seeking initial approval, licensure, or clearance.
Such delays provide up to 2 additional years to complete data
collection for pre-specified outcome measures and/or additional adverse
event information.
Further, the final rule specifies timelines in Sec. 11.44(d) for
submitting partial results information by the date on which results
information is due even if data collection for secondary outcome
measure(s), or the pre-specified time frame for collecting additional
adverse events information, has not been completed. These timelines
provide submission deadlines for additional partial results information
of not later than 1 year after the date on which final data collection
for secondary outcome measure(s) or the pre-specified time frame for
collecting additional adverse event information is completed, or on the
date on which results information for primary outcome measure(s) is due
following delayed certification, as specified in Sec. 11.44(b) and
(c). In addition, this approach ensures timely submission of results
information for the primary outcome measure(s), but permits delays for
the submission of other results information to allow time for the final
collection and analysis of secondary outcome measure(s) and/or
additional adverse event information. We note that, in situations in
which the submission of results information for the primary outcome(s)
of an applicable clinical trial would impair or otherwise bias the
ongoing collection, analysis, and/or interpretation of data for
secondary outcome(s) (e.g., need to maintain masking in a trial),
responsible parties may request an extension of the results information
submission deadline for good cause by following the procedures
specified in Sec. 11.44(e).
A few other commenters suggested modifying proposed Sec.
11.44(a)(2), which addressed results information submission for
applicable clinical trials of products not approved, licensed, or
cleared as of the completion date, but that receive FDA approval,
licensure, or clearance thereafter. These commenters asserted that the
proposal is inconsistent with the statutory language. In particular,
they asserted the proposed regulatory language stating that results
information submission is required ``by the earlier of'' (i) 1 year
after the completion date or (ii) 30 calendar days after FDA approval,
licensure, or clearance of the product contradicts section
402(j)(3)(E)(i) of the PHS Act, which states ``not later than 1 year,
or such other period as may be provided by regulation.'' The commenters
suggested that to be consistent with the statute, the standard results
information submission deadline should be changed to ``by the later
of'' in the final rule. As discussed in Section IV.F below, we have
reconsidered the approach described in the NPRM (79 FR 69593) with
respect to determining whether an applicable trial involves an
approved, licensed, or cleared product, or whether it involves an
unapproved, unlicensed, or uncleared product. For purposes of this
final rule, the marketing status of a product will be determined based
on its marketing status on the primary completion date. Thus, if a drug
product (including a biological product) or a device product is
approved, licensed, or cleared for any use as of the primary completion
date, we will consider that applicable clinical trial to be a trial of
an approved, licensed, or cleared product. Similarly, if a drug product
(including a biological product) or a device product is unapproved,
unlicensed, or uncleared for any use as of the primary completion date,
regardless of whether it is later approved, licensed, or cleared, we
will consider that applicable clinical trial to be a trial of an
unapproved, unlicensed, or uncleared product. Furthermore, as noted in
the preamble section discussing Sec. 11.42(b) and in Section III.B
Submission of Results Information for Applicable Clinical Trials of
Unapproved, Unlicensed, or Uncleared Products for Any Use and Section
IV.F. Effective Date, Compliance Date, and Applicability of
Requirements in this Part, applicable clinical trials of an unapproved,
unlicensed, or uncleared product are not subject to results information
submission requirements until the effective date of the final rule.
Thus, whether results information submission is required for an
applicable clinical trial of an unapproved, unlicensed, or uncleared
product depends on whether the primary completion date for that trial
falls before, on, or after the effective date of the rule. Results
information submission, therefore, is not required for applicable
clinical trials of products not approved, licensed, or cleared for any
use as of the primary completion date but receive FDA approval,
licensure, or clearance thereafter when the primary completion date is
before the effective date of the rule.
Other commenters suggested that results information submission
should be required earlier than the proposed standard submission
deadline (i.e., earlier than 1 year after the completion date) whenever
a responsible party publicly discloses results information for a
clinical trial elsewhere, such as in a publication. Some commenters
also suggested that the deadline for submission of results information
in this circumstance should be 30 days after the date of public
disclosure.
The Agency disagrees with the suggestion that we should make the
date of any public disclosure of trial results a ``trigger'' for
mandatory early results information submission. Sponsors and
researchers publicly disclose trial results for many reasons, including
compliance with other federal laws or policies (e.g., disclosure
requirements to the U.S. Securities and Exchange
[[Page 65068]]
Commission that may contain information about trial results). The final
rule is consistent with section 402(j)(3)(E)(i) of the PHS Act, which
provides up to 1 year from the completion date for results information
submission. For the purpose of describing mandatory results information
submission deadlines under this section, a triggering event refers to
any of the events specified in paragraphs (b)(1)(i), (ii), and (iii)
and paragraphs (c)(1)(i) and (ii) of this section that prompt results
information submission for a clinical trial with a certification for
delayed results information submission. The responsible party has 30
calendar days from the date of a triggering event to submit results
information. We note that the definition of ``primary completion date''
in Sec. 11.10(a) refers to the definition of ``completion date'' in
Sec. 11.10(a), which is ``for a clinical trial, including an
applicable clinical trial, the date that the final subject was examined
or received an intervention for the purposes of final collection of
data for the primary outcome, whether the clinical trial concluded
according to the pre-specified protocol or was terminated. In the case
of clinical trials with more than one primary outcome measure with
different primary completion dates, this term refers to the date on
which data collection is completed for all of the primary outcomes. For
a pediatric postmarket surveillance of a device product that is not a
clinical trial, completion date means the date on which the final
report of the pediatric postmarket surveillance of the device product
is submitted to FDA. For purposes of this part, completion date will be
referred to as `primary completion date.' '' In the case that data
collection is completed for at least one primary outcome measure (but
not yet for all primary outcome measures), clinical trial results
information as specified in Sec. 11.48(a) may be submitted before the
primary completion date of the clinical trial.
Final Rule
Taking into consideration the commenters' suggestions and the
statutory requirements for results information submission deadlines,
the final rule modifies the approach proposed in Sec. 11.44(a) by
deleting proposed Sec. 11.44(a)(2), which would have required results
information submission for a clinical trial of a product that is
unapproved, unlicensed, or uncleared for any use as of its completion
date by the earlier of 1 year after the completion date or 30 calendar
days after the date FDA approves, licenses, or clears the drug or
device for any indication studied in the applicable clinical trial.
As noted above and discussed in Section IV.F on Effective Date,
Compliance Date, and Applicability of Requirements in this Part, the
Agency has reconsidered its approach with respect to determining
whether an applicable clinical trial involves an approved, licensed, or
cleared product, or whether it involves an unapproved, unlicensed, or
uncleared product. For purposes of this final rule, the marketing
status of a product will be determined based on its marketing status as
of the primary completion date. With this approach, under section
402(j)(3)(C) of the PHS Act, results information submission is not
required for clinical trials of a product that is unapproved,
unlicensed, or uncleared for any indication as of its primary
completion date where the primary completion is before the effective
date. Further, as discussed in Section III.B Submission of Results
Information for Applicable Clinical Trials of Unapproved, Unlicensed,
or Uncleared Products for Any Use and Section IV.F Effective Date,
Compliance Date, and Applicability of Requirements in this Part of the
preamble, when the primary completion date is on or after the effective
date of the final rule, the rule requires results information
submission from applicable clinical trials of all products that were
unapproved, unlicensed, or uncleared for any indication before the
primary completion date. For trials of unapproved, unlicensed, or
uncleared products completed after the effective date, results
submission is generally required in accordance with the standard
submission deadline. Thus, it is not necessary for final Sec. 11.44(a)
to contain separate subparagraphs to account for the approval,
clearance, or licensure status of the product studied by the applicable
clinical trial.
Final Sec. 11.44(a) retains the proposed standard submission
deadline of 1 year after the primary completion date regardless of
product approval, clearance, or licensure status. We clarify that Sec.
11.44(a) applies to applicable clinical trials subject to Sec. 11.42
and that the results information required is specified in either
sections 402(j)(3)(C) and 402(j)(3)(I) of the PHS Act or in Sec.
11.48, as appropriate. As discussed in Section IV.F Effective Date,
Compliance Date, and Applicability of Requirements in this Part, below,
whether a responsible party is required to submit either results
information specified in sections 402(j)(3)(C) and 402(j)(3)(I) of the
PHS Act or the results information specified in Sec. 11.48 will depend
on whether the primary completion date of the applicable clinical trial
is before, on, or after the effective date of the final rule.
Sec. 11.44(b) and (c)--Delayed Submission of Results Information With
Certification
Overview of Proposal
Proposed Sec. 11.44(b) and (c) established procedures whereby
responsible parties may delay submission of results information for a
particular applicable clinical trial beyond the standard submission
deadline specified in proposed Sec. 11.44(a)(1) (i.e., 1 year after
the completion date) (79 FR 69633).
Delayed Submission of Results Information With Certification If Seeking
Approval, Licensure, or Clearance of a New Use
Consistent with sections 402(j)(3)(E)(iii) and (v) of the PHS Act,
we proposed in Sec. 11.44(b) to allow a delay in the submission of
results information if the responsible party certifies that an
applicable clinical trial meets the following criteria: (1) The drug
(including biological product) or device studied in the applicable
clinical trial previously has been approved, licensed, or cleared by
FDA; (2) the sponsor of the applicable clinical trial is the
manufacturer of the product; and, (3) the manufacturer has filed, or
will file within 1 year, an application or premarket notification
seeking approval, licensure, or clearance of the use being studied in
the applicable clinical trial (and is not included in the labeling of
the approved, licensed, or cleared drug or device). As proposed, the
responsible party would need to submit this certification to
ClinicalTrials.gov before the standard submission deadline specified in
proposed Sec. 11.44(a)(1) (i.e., 1 year or less after the completion
date). We also proposed to indicate on the posted record for the
clinical trial that results submission has been delayed, but would not
specify the particular reason for the delay (79 FR 69633).
As we explained in the NPRM, in accordance with section
402(j)(3)(E)(v) of the PHS Act, once a certification has been submitted
to ClinicalTrials.gov, proposed Sec. 11.44(b)(2) would permit a delay
in the submission of results information of up to 2 years after the
date on which the certification is submitted, unless one of the
following events occurs: (1) FDA approves, licenses, or clears the drug
or device for the use studied in the applicable clinical trial; (2) FDA
issues a letter that
[[Page 65069]]
ends the regulatory review cycle for the application or submission
(e.g., a complete response letter, a not substantially equivalent
letter, or a not approvable letter) but does not approve, license, or
clear the drug or device for the use studied in the applicable clinical
trial; or, (3) the manufacturer, which is also the sponsor of the
applicable clinical trial, withdraws the application or premarket
notification seeking approval, licensure, or clearance of the new use
and does not resubmit it within 210 calendar days. In the event that
any one of these triggering events occurs, the proposed rule said that
the responsible party would be required to submit results information
for the applicable clinical trial for which a certification had been
submitted under proposed Sec. 11.44(b)(1) not later than 30 calendar
days after the earliest of the triggering events occurred, consistent
with section 402(j)(3)(E)(v)(I) of the PHS Act (79 FR 69633).
As we noted, proposed Sec. 11.44(b)(3) implemented section
402(j)(3)(E)(v)(II) of the PHS Act, which specifies that if a
responsible party who is both the manufacturer of the drug or device
studied in the applicable clinical trial and the sponsor of the
applicable clinical trial submits a certification to delay submission
of results information because the manufacturer is seeking or will seek
within 1 year approval, licensure, or clearance of a new use for a drug
or device, that responsible party must submit such a certification for
each applicable clinical trial that meets the following criteria: (i)
The applicable clinical trial is required to be submitted in an
application or premarket notification for seeking approval, licensure,
or clearance of a new use; and, (ii) the applicable clinical trial
studies the same drug or device for the same use as studied in the
applicable clinical trial for which the initial certification was
submitted (79 FR 69633).
Delayed Submission of Results With Certification If Seeking Initial
Approval, Licensure, or Clearance
Proposed Sec. 11.44(c) described requirements for delayed
submission of results information with certification when seeking
initial approval, licensure, or clearance of a drug or device. As we
explained in the NPRM, section 402(j)(3)(D)(iv)(III) of the PHS Act
required that, when proposing to require the submission of results
information for trials of unapproved, unlicensed, or uncleared
products, we take into account the certification process in section
402(j)(3)(E)(iii) of the PHS Act ``when approval, licensure, or
clearance is sought,'' and that we determine ``whether there should be
a delay of submission when approval, licensure or clearance will not be
sought'' (79 FR 69634).
We proposed in Sec. 11.44(c) to allow a delay in the submission of
results information if the responsible party certifies that an
applicable clinical trial meets the following criteria: (1) The drug
(including biological product) or device studied in the applicable
clinical trial was not approved, licensed, or cleared by FDA for any
use before the completion date of the clinical trial; and, (2) the
sponsor of the applicable clinical trial intends to continue with
product development and is seeking, or may at a future date seek, FDA
approval, licensure, or clearance of the drug or device under study. As
proposed, this certification would be required to be submitted to
ClinicalTrials.gov before the standard submission deadline specified in
proposed Sec. 11.44(a)(1) (i.e., 1 year or less after the completion
date). The record for the clinical trial would indicate that results
submission has been delayed, but would not specify the particular
reason for the delay (79 FR 69634).
As proposed in Sec. 11.44(c), submission of a certification would
permit a delay in the submission of results information of up to 2
years after the date on which the certification is submitted to
ClinicalTrials.gov, unless either of the following events occurs: (1)
FDA approves, licenses, or clears the drug or device studied in the
applicable clinical trial for any indication that is studied in the
clinical trial; or, (2) the application or premarket notification is
withdrawn without resubmission for not less than 210 calendar days. The
responsible party would be required to submit results information not
later than 30 calendar days after the one of these triggering events
occurs. We explained that the Agency included the second event (i.e.,
withdrawn without resubmission for not less than 210 calendar days)
because we believe that this situation represents a significant enough
interruption to product development to trigger the submission of
results information. Unlike delayed results information submission with
certification under proposed Sec. 11.44(b), which applies when the
sponsor (which is the manufacturer) of the applicable clinical trial is
seeking approval, licensure, or clearance of a new use, we did not
propose to require the submission of results information 30 calendar
days after FDA issues a letter not approving, not licensing, or not
clearing the product under study for delayed results information
submission with certification seeking initial approval, licensure, or
clearance because the issuance of such a letter does not necessarily
indicate abandonment of product development (79 FR 69634).
Two-Year Limitation of Delay
As we discussed in the NPRM, with regard to the maximum 2-year
delay pursuant to a certification submitted under section
402(j)(3)(E)(iii) of the PHS Act, we had considered establishing the
maximum available delay with certification when seeking initial
approval, licensure, or clearance to be 3 years from the completion
date of the applicable clinical trial, regardless of when during the 1-
year period following the completion date the certification is
submitted. Such a provision would have accomplished the same objective
as the statutory provision for delayed submission when seeking
approval, licensure, or clearance of a new use by allowing responsible
parties to delay results submission by as long as 3 years beyond the
completion date of a clinical trial, but without creating a
disincentive to submit the certification early. As we explained in the
NPRM, measuring the 2-year period from the date on which the
certification is submitted may result in responsible parties submitting
certifications as close as possible to the standard results submission
deadline under proposed Sec. 11.44(a)(1) to obtain the full 3-year
delay after the completion date. Section 402(j)(3)(D)(iv)(III) of the
PHS Act expressly authorizes the Secretary to establish the date by
which clinical trial information for applicable clinical trials of
unapproved products must be submitted to ClinicalTrials.gov. Thus, in
order to maintain the same maximum delay for results information
submission whether seeking initial approval, licensure, or clearance or
seeking approval, licensure, or clearance of a new use, we did not
propose that the maximum 3-year delay apply regardless of when during
the 1-year period following the completion date the certification is
submitted. We invited public comments on establishing different maximum
timelines for results information submission under the two delayed-
results-with-certification provisions and on alternative approaches to
encourage early submission of certifications that would be consistent
with the statute, without causing a responsible party to have to submit
results information earlier than the latest deadline they could have
under the statute (79 FR 69635).
[[Page 65070]]
Explanation of ``initial approval,'' ``initial clearance,'' and
``approval of a new use,'' or clearance of a new use''
For purposes of proposed Sec. 11.44(b) and (c), we interpreted the
term ``drug'' in sections 402(j)(3)(E)(iv) and 402(j)(3)(E)(v) of the
PHS Act to mean ``drug product'' or ``biological product,'' referring
to a finished product that is approved or licensed for marketing, and
not to the active ingredient or active moiety in such a product. We
concluded that this is the most appropriate interpretation of the
statutory term and that this interpretation is consistent with the
statutory intent to draw a distinction between applicable drug clinical
trials that are ``completed before the drug is initially approved''
(see section 402(j)(3)(E)(iv) of the PHS Act) and those pertaining to
uses ``not included in the labeling of the approved drug'' (see section
402(j)(3)(E)(v) of the PHS Act). Accordingly, we interpreted ``initial
approval'' to pertain to the approval or licensure of an original NDA,
ANDA or BLA, and ``new use'' to pertain to the approval or licensure of
a supplemental NDA, ANDA, or BLA for an additional use for that
particular drug product or biological product. Similarly, we
interpreted ``initial approval'' of a device under sections 515 or
520(m) of the FD&C Act to pertain to the approval of an original PMA or
HDE and ``new use'' to pertain to the approval of a supplemental PMA
for an additional use for that particular device. In addition, for
purposes of proposed Sec. 11.44(c), we considered the first 510(k)
cleared for a particular device type as the ``initial clearance'' of
the device. Consequently, for purposes of proposed Sec. 11.44(b), all
other 510(k)s cleared for a device type, other than the first one,
would have been considered ``clearance of a new use.'' We solicited
comments on whether these are appropriate interpretations and
distinctions for purposes of proposed Sec. 11.44(b) and (c) (79 FR
69635).
Comments and Response
Commenters addressed delayed submission of results with
certification in proposed Sec. 11.44(b) and (c). While one commenter
supported the proposed delay of results submission for up to 2 years
following the date of submission of a certification in proposed Sec.
11.44(c), another commenter proposed simplifying the approach for
calculating the deadline for this maximum delay by uniformly allowing
up to 3 years after the primary completion date, regardless of when a
certification is submitted. This commenter, however, did not explain
how the statute allows for this proposed approach. As noted previously
here and in the proposed rule, the statute does not permit changing by
rulemaking when the 2-year maximum available delay for results
submission would begin for submitted certifications seeking approval,
licensure, or clearance of a new use for the studied drug or device.
Section 402(j)(3)(E)(v)(III) of the PHS Act states that the time period
begins on the date that the certification is submitted. While the
statute provides greater flexibility for establishing the timelines for
certifications seeking initial approval, licensure, or clearance for a
studied drug or device, we have decided to keep the same approach for
determining the maximum delay under both types of certifications, for
reasons discussed in the NPRM. As such, the final rule retains the
proposed approach (i.e., ``not later than 2 years after the date on
which the certification was submitted'').
One commenter proposed allowing an additional year to delay the
submission of results for purposes of journal publication. Another
commenter suggested that the Agency provide a new certification-like
mechanism for delaying the submission of results of applicable clinical
trials of approved, licensed, or cleared products for up to 2 years (as
permitted for unapproved, unlicensed, or uncleared products) to allow
academic researchers to prepare for journal publication. Several
commenters proposed that the final rule routinely provide delayed
submission of results for other reasons, such as publication prior to
public posting on ClinicalTrials.gov. The statutory provision that
pertains to delayed submission of results with certification is in
section 402(j)(3)(D)(iv)(III) of the PHS Act, which explicitly directs
the Agency to take into account during rulemaking the delayed
submission of results with certification provisions when proposing to
require the submission of results for applicable clinical trials of
unapproved, unlicensed, or uncleared products, whether or not approval,
licensure, or clearance is sought. In response to this mandate, the
Agency proposed permitting delayed submission of results in proposed
Sec. 11.44(c) for applicable clinical trials of unapproved,
unlicensed, or uncleared products undergoing product development.
However, the NPRM proposed at Sec. 11.44(a) to require the standard
submission deadline for trials of unapproved, unlicensed, or uncleared
products for which product development has been abandoned (see Section
III.B of this preamble).
The Agency does not agree that submission of results information
should be delayed for purposes of journal publication. Moreover, we
note that the ICMJE clinical trial registration policy recognizes the
results reporting obligations under section 402(j) of the PHS Act and
states that ``the ICMJE will not consider results data posted in the
tabular format required by ClinicalTrials.gov to be prior publication''
[Ref. 98]. Therefore, we do not expect that the requirements of the
final rule for submission of results information will interfere with
journal publication of articles about applicable clinical trials.
One commenter proposed requiring submission of results information
for applicable device clinical trials only after the manufacturer has
declared product development to be abandoned. This commenter noted
further that receipt of an initial non-approval or not substantially
equivalent finding from the FDA does not necessarily indicate that
product development has stopped and suggested that the final rule
provide for additional delays for results submission until the
manufacturer has declared product development to be abandoned. As
discussed in more detail in Section III.B of this preamble, the Agency
has decided to maintain the requirement of results information
submission for applicable clinical trials of drug and device products
that are not approved, licensed, or cleared by the FDA for any use,
regardless of whether approval, licensure, or clearance is sought. We
continue to believe that this approach is consistent with the express
statutory purpose of the expanded data bank ``[t]o provide more
complete results information and to enhance patient access to and
understanding of the results of clinical trials'' (see section
402(j)(3)(D)(i) of the PHS Act). As discussed previously, Sec.
11.44(c) mitigates concerns about potential competitive harm resulting
from disclosure of results information from applicable clinical trials
of products that are not approved, licensed, or cleared by delaying the
results submission deadline for applicable clinical trials of products
that are still under development. Thus, we do not agree with commenters
who suggested that results submission for applicable device clinical
trials (or for applicable drug clinical trials) should be limited to
trials of abandoned products. Consistent with section
402(j)(3)(E)(v)(I)(bb) of the PHS Act, Sec. 11.44(b)(1)(ii) of the
final rule provides that the issuance of a letter by the FDA including
``a complete response letter, not approving the
[[Page 65071]]
submission or not clearing the submission, a not approvable letter, or
a not substantially equivalent letter for a new use of the drug or
device'' that ends the regulatory review cycle for the application or
submission but does not approve, license, or clear the product for the
use studied in the applicable clinical trial, requires the responsible
party to submit within 30 calendar days clinical trial results
information for an applicable clinical trial, which had previously been
subject to delayed submission of results information.
One commenter suggested that confidential commercial or proprietary
information should not need to be submitted as part of the
certification process. We clarify that to obtain a certification for
delayed results information submission, a responsible party will need
to indicate that a particular applicable clinical trial meets the
requirement for delayed submission with certification in accordance
with Sec. 11.44(b) or (c) and provide the name(s) of the drug
product(s), biological product(s), or device product(s), to which the
certification applies. This information is necessary to demonstrate
that the certification requirement has been met. No additional
information will be required as part of this process.
One commenter suggested that we should post the reason a
responsible party has been granted a certification for delayed results
submission or extension. As noted above in the discussions of Sec.
11.44(b) and (c), for applicable clinical trials that have been granted
a certification for delayed results information submission or
extension, the posted record will indicate only that the results
information submission has been delayed but it will not specify the
particular reason for the delay.
Finally, a few commenters disagreed with the Agency's
interpretation that only the first 510(k) cleared for a particular
device type be considered ``initial clearance.'' They asserted that
every 510(k) clearance should be considered ``initial clearance,''
which would result in a potentially longer delay in submitting results
information, rather than considered clearance of a ``new use'' because
the trigger for submitting results information in proposed Sec.
11.44(b)(1)(ii) is not found in proposed Sec. 11.44(c). The
commenters' arguments appear to be rooted in a concern that premature
disclosure of clinical trial results information would enable
competitors to shorten the time and expense to develop and market a
similar device. The commenters' proposal would result in treating all
510(k) clearances as ``initial clearance'' under section
402(j)(3)(E)(iv) regardless of whether or not the 510(k) submission is
an original submission by a manufacturer to obtain initial clearance of
a device product as compared with a subsequent application by the same
manufacturer to obtain clearance of the same device product for a
different use. The Agency disagrees with the commenters' proposal
because, by considering every 510(k) clearance to be an ``initial
clearance'' under section 402(j)(3)(E)(iv) of the PHS Act, and
considering no 510(k) clearances to be clearance of a ``new use'' under
section 402(j)(3)(E)(v) of the PHS Act, such an interpretation would
deprive section 402(j)(3)(E)(v) of the PHS Act of any meaning with
respect to 510(k)s. Accordingly, the commenters' approach would
contravene the principle of statutory construction that courts should
give effect, if possible, to every clause and word of a statute, so as
to avoid rendering any statutory language superfluous.
For NDA, ANDA, BLA, and PMA approvals, the NPRM focused on a
manufacturer's particular ``product'' rather than on the ``type'' when
determining whether a trial would be considered seeking ``initial
approval,'' as specified in section 402(j)(3)(E)(iv), or ``approval of
a new use,'' as specified in section 402(j)(3)(E)(v). In contrast, for
510(k)s, the NPRM focused on the device ``type'' rather than the device
``product'' for making such a determination. Under the NPRM, only the
first 510(k) cleared for a device type was considered ``initial
clearance'' and all other 510(k)s cleared for a device type were
considered ``clearance of a new use.'' As a result, the NPRM approach
resulted in disparate treatment of 510(k)s compared with the treatment
of all other types of applications, including device PMAs.
To avoid disparate treatment of 510(k) submissions as compared with
the treatment of all other types of applications, including PMA
applications, in the final rule, the Agency is focusing on the device
``product'' rather than the device ``type'' when determining which
510(k) clearances are considered ``initial clearance'' versus
``clearance of a new use.'' That is, in the final rule, we interpret
``initial clearance'' to pertain to the clearance of a manufacturer's
original 510(k) submission for a particular device product whereas
``clearance of a new use'' of a device pertains to the clearance of the
same manufacturer's subsequent 510(k) submission for an additional use
for the same device product. ``Manufacturer'' means a manufacturer who
is the sponsor for the applicable clinical trial. The final rule, thus,
treats 510(k)s in the same way it treats NDAs, ANDAs, BLAs, and PMAs by
consistently basing its determination on the ``product'' rather than
the ``type'' when determining whether a trial is seeking ``initial''
approval, licensure, or clearance, or approval, licensure, or clearance
of a ``new use.'' This represents a middle-ground approach between the
NPRM approach and the approach advocated by the commenters.
For the purposes of this final rule only, we interpret ``use'' to
include ``indication.'' For the purposes of this final rule,
``indication'' means ``the disease or condition the product is intended
to diagnose, treat, prevent, cure, or mitigate.''
Thus, for purposes of the final rule, the Agency interprets the
first 510(k) clearance of a device ``product'' rather than the first
510(k) clearance of a device ``type'' as ``initial clearance'' under
section 402(j)(3)(E)(iv) of the PHS Act. Any subsequent clearance of an
``initially cleared'' 510(k) device product for a different use will be
considered a ``clearance of a new use'' under section 402(j)(3)(E)(v)
of the PHS Act.
This interpretation in the final rule allows a responsible party
for an applicable clinical trial of a 510(k) device product that is
uncleared on the primary completion date to seek delayed submission of
results information by submitting a certification that it is seeking
``initial clearance'' of its device product under Sec. 11.44(c),
rather than ``clearance of a new use'' under final Sec. 11.44(b). With
regard to FDA's issuance of a letter that ends the regulatory review
cycle but does not approve, license, or clear the product for the use
studied in the applicable clinical trial, as described in Sec.
11.44(b)(1)(ii), we note, first, that it does not trigger results
information submission within 30 calendar days of the event under Sec.
11.44(c)(1) and, second, that there are no ``additional requirements''
in Sec. 11.44(c) for responsible parties who are both the manufacturer
of the product and the sponsor of the applicable clinical trial to
submit certifications for each additional applicable clinical trial
that studies the same product for the same use and is required to be
submitted in a premarket notification for that use (as required in
Sec. 11.44(b)(3)).
We also note that this interpretation has implications for the
registration requirements in the final rule because the concepts of
``initial clearance'' and ``clearance of a new use'' also appear in the
registration provisions of the statute. This interpretation subjects
clinical trial
[[Page 65072]]
registration information for more applicable clinical trials of
unapproved or uncleared devices to delayed posting under section
402(j)(2)(D)(ii)(I) as compared with the NPRM approach because each
individual device manufacturer seeking initial clearance of its device
product would be subject to delayed posting of its clinical trial
registration information, as specified in final Sec. 11.35(b)(2)(i),
rather than only the first manufacturer to obtain clearance for the
device type. We note, however, that under final Sec. 11.35(b)(2)(ii),
a responsible party for an applicable device clinical trial that is
initiated on or after the effective date of the rule may choose to
indicate to the Director that it is authorizing the Director to
publicly post its clinical trial registration information, that would
otherwise be subject to delayed posting, as specified in Sec.
11.35(b)(2)(i), prior to the date of FDA approval or clearance of the
device product.
Final Rule
Final Sec. 11.44(b)(1) retains the proposed procedure to allow a
responsible party to delay results information submission with a
certification indicating that the manufacturer, who is also the sponsor
of the applicable clinical trial, is or will be seeking approval,
licensure, or clearance of a new use for the studied drug product
(including biological product) or device product, but clarifies that
``drug'' means ``drug product'' and ``device'' means ``device
product.'' To obtain such a delay, the responsible party would need to
submit a certification to ClinicalTrials.gov before the standard
submission deadline specified in Sec. 11.44(a) (i.e., 1 year or less
after the primary completion date). The responsible party would need to
certify that (1) an applicable clinical trial involves an FDA-regulated
drug product (including biological product) or device product that
previously has been approved, licensed, or cleared by the FDA; (2) for
which the manufacturer is the sponsor of the applicable clinical trial;
and, (3) for which an application or premarket notification seeking FDA
approval, licensure, or clearance of the use being studied in the
applicable clinical trial, which is not included in the labeling of the
approved, licensed, or cleared drug product (including a biological
product) or device product, has been filed or will be filed within 1
year with FDA. The posted record for the applicable clinical trial
would indicate that results information submission has been delayed,
but would not specify the particular reason for the delay. For purposes
of this part, we interpret ``manufacturer'' to mean a manufacturer who
is the sponsor of the applicable clinical trial. Note that if the
manufacturer designates a principal investigator as the responsible
party as provided for at Sec. 11.4(c)(2), the designated principal
investigator would be required to submit the certification for delayed
submission of clinical trial results information.
The deadline for the delayed submission of results information
under Sec. 11.44(b) would be 30 calendar days after the earliest of:
(1) FDA approval, licensure, or clearance of the drug product
(including a biological product) or device product for the use studied
in the applicable clinical trial; (2) FDA issuance of a letter ending
the regulatory review cycle for the application or submission without
product approval, licensure, or clearance for the use studied in the
applicable clinical trial (e.g., a complete response letter, a not
substantially equivalent letter, or a not approvable letter); or, (3)
withdrawal of the application or premarket notification without
resubmission within 210 calendar days (i.e., 240 calendar days after
submission of the withdrawal request). Final Sec. 11.44(b)(2) provides
a maximum deadline for delayed results information submission of 2
years after the date of submission of the certification, except to the
extent that Sec. 11.44(d) applies. Final Sec. 11.44(b)(3) provides an
additional requirement that any responsible party who is both the
manufacturer of the drug product (including a biological product) or
device product studied and the sponsor of an applicable clinical trial,
and who submits a certification for the delayed submission of results
under Sec. 11.44(b)(1) for that applicable clinical trial, must also
submit such a certification for each applicable clinical trial for
which the manufacturer of the drug product (including a biological
product) or device product studied is the sponsor and which is required
to be submitted in an application or premarket notification seeking
approval, licensure, or clearance of a new use studied in the clinical
trial.
We note that if the sponsor of an applicable clinical trial for
which a ``new use certification'' has been submitted is also the
manufacturer the drug product (including a biological product) or
device product studied in the applicable clinical trial, but has
designated the principal investigator as the responsible party, then
the manufacturer may need to notify the responsible party of the
occurrence of a triggering event in order to help ensure that the
responsible party is aware of the results information submission
deadline. As discussed in Sec. 11.4(c)(2)(i) (see Section IV.A.2 of
this preamble), the sponsor may designate a principal investigator as
the responsible party only if, among other things, the principal
investigator ``[h]as the ability to meet all of the requirements for
submitting and updating clinical trial information as specified in this
part.'' Accordingly, a responsible party who is not the manufacturer of
the drug product (including a biological product) or device product
studied will only be able to comply with the results information
submission requirements subsequent to a certification under sections
402(j)(3)(E)(iii) and (v) if notified by the manufacturer when one of
these triggering events occurs. If a manufacturer is not willing or
able to provide the principal investigator with this information, the
conditions for designation under Sec. 11.4(c)(2) cannot be met and the
manufacturer would become the responsible party until the manufacturer
assigns a new responsible party (see Sec. 11.4(c)(3)).
We also note that the maximum delay of 2 years specified in Sec.
11.44(b)(2) would apply to clinical trial results information specified
in sections 402(j)(3)(C) and 402(j)(3)(I) of the PHS Act or Sec.
11.48, as applicable. With respect to applicable clinical trials for
which data collection for any secondary outcome measures and/or
additional adverse event information extends beyond the primary
completion date, the deadlines for submission of these clinical trial
results information are discussed under final Sec. 11.44(d).
We recognize that in some cases a responsible party may not know
whether a particular applicable clinical trial will be used to support
an original NDA, ANDA, BLA, PMA, or HDE for initial approval or
licensure of a product as opposed to a supplemental NDA, ANDA, BLA, or
PMA for approval or licensure of a new use. Similarly, a responsible
party may not know whether a clinical trial will be used to support a
510(k) seeking ``initial clearance'' of a device product as opposed to
a 510(k) seeking ``clearance of a new use.'' Responsible parties should
use their best judgment based on information available at the time of
certification in order to determine whether certification under Sec.
11.44(c) (initial approval, licensure, or clearance) or Sec. 11.44(b)
(approval, licensure, or clearance of a new use) is appropriate.
As discussed above, the Agency interprets ``initial clearance'' in
the final rule to apply to the clearance of a manufacturer's original
510(k) submission for a device product for purposes of this part and
any
[[Page 65073]]
subsequent clearance of that device product by that manufacturer for a
different use would be considered ``clearance of a new use.'' By making
this change, the final rule focuses on the device product, rather than
the device type, to determine whether an applicable clinical trial of a
510(k) device will be considered as seeking ``initial clearance''
versus ``clearance of a new use.'' This means that under the final
rule, 510(k) device product trials will be considered not by whether
the type of device has ever been cleared before, but by whether the
particular manufacturer's device product has ever been cleared.
Final Sec. 11.44(c)(1) retains the proposed procedure to allow a
responsible party to delay results information submission with a
certification indicating that the sponsor is seeking initial approval,
licensure, or clearance for the drug product (including a biological
product) or device product, but clarifies that ``drug'' means ``drug
product'' and ``device'' means ``device product.'' To obtain such a
delay, the responsible party will need to submit a certification to
ClinicalTrials.gov before the standard deadline specified in proposed
Sec. 11.44(a) (i.e., 1 year or less after the primary completion
date). The responsible party would need to certify that an applicable
clinical trial (1) studies a drug product (including a biological
product) or device product that was not approved, licensed, or cleared
by FDA for any use before the primary completion date of the clinical
trial; and, (2) the sponsor of the applicable clinical trial intends to
continue product development and is seeking or intends to seek FDA
approval, licensure, or clearance of the drug product (including a
biological product) or device product under study. Certifications
cannot be submitted for applicable clinical trials of products that the
sponsor has no intention of marketing or for which product development
has been abandoned.
When a certification for delay is submitted, the posted record for
the clinical trial will indicate that results information submission
has been delayed, but will not specify the particular reason for the
delay. The deadline for delayed submission of results information under
Sec. 11.44(c) will be 30 calendar days after the earlier of: (1) FDA
approval, licensure, or clearance of the drug product (including a
biological product) or device product for the use studied in the
applicable clinical trial; or, (2) withdrawal of the application or
premarket notification by the sponsor of the applicable clinical trial
without resubmission within 210 calendar days (i.e., 240 calendar days
after submission of the withdrawal request). We believe that this
latter situation represents a significant enough interruption to
product development to trigger the submission of results information.
Final Sec. 11.44(c)(2) retains a maximum deadline for delayed results
information submission of 2 years after the date of certification
submission. The Agency expects that a delay of an additional 2 years
beyond the date the certification is submitted (i.e., up to 3 years
after the primary completion date of the clinical trial, assuming that
the certification is submitted 1 year after the primary completion
date) is sufficient to address any confidentiality concerns that may be
expressed by responsible parties. This time frame allows a sponsor or
manufacturer to decide whether to initiate another clinical trial or
submit a marketing application or premarket notification to the FDA. A
subsequent pre-market clinical trial of a drug product (including a
biological product) would likely be an applicable clinical trial that
would be registered at ClinicalTrials.gov, making public information
about the sponsor's intention to pursue product development. Thus, the
total delay in disclosure of results information of up to 3 years after
the completion date of the trial would provide sponsors with
significant lead time in product development over potential
competitors. As discussed further in Section III.B of this preamble, we
conclude that any competitive disadvantage that may be caused by the
disclosure of summary results information for clinical trials of
products that have not been approved, licensed, or cleared for any use
3 years or more after the primary completion date of the trial is
limited and, in any case, outweighed by the public health benefits of
making such information publicly available. Furthermore, as discussed
above, even if such summary results information were to contain trade
secret and/or confidential commercial information, the requirement that
such information be posted on ClinicalTrials.gov is authorized by law
for the purposes of the U.S. TSA.
Section 11.44(c) permits delayed submission of results information
only if the responsible party certifies that the sponsor of the
applicable clinical trial is continuing to study the product with an
expectation of seeking future initial approval, licensure, or
clearance. While we recognize it may be difficult for the sponsor of
the applicable clinical trial to know early on in the product
development process whether it will seek future initial approval,
licensure, or clearance for a product studied in an applicable clinical
trial, we would, in general, view further development of a product
through subsequent clinical trials as an indication that the product
development process is continuing and may lead to seeking initial
approval, licensure, or clearance. A responsible party who is not the
sponsor of the applicable clinical trial cannot submit a certification
to delay results information submission unless the responsible party
can obtain such information from the sponsor. If a principal
investigator who has been designated as the responsible party by the
sponsor cannot obtain such information, then the conditions for
designation under Sec. 11.4(c)(2) cannot be met and the responsible
party will not be able to submit a certification for delayed results
information submission. If a triggering event occurs, the responsible
party who is not the sponsor (i.e., a responsible party who is a
principal investigator) will only be able to comply with the results
information submission requirements under Sec. 11.44(c)(2) if notified
by the sponsor. In a situation in which the sponsor is not willing or
able to provide the principal investigator with this information, the
conditions for designation under Sec. 11.4(c)(2) cannot be met and the
responsible party will not be able to submit a certification for
delayed results information submission.
As discussed with respect to Sec. 11.44(b)(2), the maximum delay
of 2 years specified in Sec. 11.44(c)(2) would apply to clinical trial
results information specified in Sec. 11.48. In the event that data
collection for any secondary outcome measure(s) will not be completed
as of the primary completion date of the trial or the time frame for
additional adverse event collection extends beyond the primary
completion date, clinical trial results information for such secondary
outcome measure(s) and additional adverse events information shall be
due by the later of (1) the deadline for delayed submission of results
with certification established by either final Sec. 11.44(b) or (c) or
(2) the submitting partial results deadlines established in final Sec.
11.44(d)(1).
We also note that after a certification for delayed results
information submission has been submitted under either Sec. 11.44(b)
or (c) for an applicable clinical trial, the final rule does not permit
submission of an additional certification under Sec. 11.44(b) to
extend the results information submission deadline established by the
existing certification for the same trial (see
[[Page 65074]]
Sec. 11.44(c)(2)). For example, a responsible party who has submitted
a certification seeking ``initial approval'' under Sec. 11.44(c) must
submit results information by the earlier of 30 calendar days of the
first triggering regulatory event (Sec. 11.44(c)(1)) or 2 years after
the date of certification (Sec. 11.44(c)(2)), and cannot submit a
certification seeking ``approval of a new use'' for that same trial,
even if it studied both uses. Similarly, a responsible party who has
submitted a certification seeking approval of a ``new use'' under Sec.
11.44(b) must submit results information by the earlier of 30 calendar
days of the first event described (Sec. 11.44(b)(1)) or 2 years after
the date of certification (Sec. 11.44(b)(2)), and cannot submit
another certification seeking approval of a ``new use'' for the same
trial. We note that in certain situations, as discussed below in this
section of the preamble, a responsible party may be able to request an
extension for good cause under Sec. 11.44(e).
Sec. 11.44(d)--Submitting Partial Results Information
Overview of Proposal
Proposed Sec. 11.44(d) specified procedures for submitting results
information when required results information, as specified in proposed
Sec. 11.48, has not been collected for all secondary outcome measures
by the date on which results information is due. Since the definition
of completion date in proposed Sec. 11.10(a) is determined by the
status of data collection solely for the primary outcome measure(s), an
applicable clinical trial may therefore still be collecting data for
the secondary outcome measure(s) after it has reached its completion
date. In this situation, the responsible party would be required to
submit results information for the primary outcome measure(s) by the
required due date specified in proposed Sec. 11.44(a), (b), or (c), as
applicable. Under proposed Sec. 11.44(d)(1)(i), if a certification to
delay results information submission had not been submitted under
proposed Sec. 11.44(b) or (c), results information for each remaining
secondary outcome measure would be due not later than 1 year after the
date on which the final subject is examined or receives an intervention
for the purposes of final collection of data for that secondary outcome
measure, whether the clinical trial was concluded according to the pre-
specified protocol or was terminated. If the responsible party had
submitted a certification to delay results information submission,
results information for the secondary outcome measures could be
submitted by the later of the date specified in proposed Sec.
11.44(d)(1)(i) or the date on which the primary outcome measure(s)
would be required to be submitted under proposed Sec. 11.44(b) or (c)
as specified in proposed Sec. 11.44(d)(1)(ii). We noted that in either
situation, if data collection for a secondary outcome measure is
completed as of the completion date, results information for that
secondary outcome measure would be required to be submitted on the same
date as results information for the primary outcome measure(s) (79 FR
69635).
We also clarified in proposed Sec. 11.44(d)(2) the process to
handle results information submission if results information related to
the primary outcome(s) was submitted prior to the effective date of the
final rule, but results information for the secondary outcome(s) is
required to be submitted after the effective date. In such cases, the
responsible party would be required to provide results information for
all primary and secondary outcome(s) as specified in Sec. 11.48 of the
proposed rule. We indicated that, because we believe consistent data
must be provided for all outcome measures in a single clinical trial,
the requirements of proposed Sec. 11.48 would apply to all clinical
trial results information submitted for a trial (79 FR 69636).
With respect to adverse event information, considered to be part of
clinical trial results information described under proposed Sec.
11.48, a responsible party would be required to submit information
summarizing serious and frequent adverse events recorded to-date each
time results information for a secondary outcome is submitted until all
the adverse event information required by this part has been submitted.
We indicated that we believe such an approach would provide a better
mechanism for handling submission of adverse event information than
extending the general results submission deadline for all applicable
clinical trials up to 18 months after the completion date. It would
ensure that key results information for primary outcome measures is
submitted to ClinicalTrials.gov within 1 year of the completion date,
while allowing subsequent data collection to continue as planned (79 FR
69636).
Comments and Response
Commenters addressed Sec. 11.44(d). One commenter suggested that
the final rule require the submission of data for additional adverse
event information on an annual basis, rather than during each deadline
for the submission of partial results information involving secondary
outcomes for which data collection was incomplete by the completion
date. The Agency believes that requiring additional adverse event
information data to be submitted annually rather than by the proposed
partial results deadlines would potentially be more burdensome for
responsible parties with few benefits for the public. For example, if a
study protocol pre-specified time frames for both a secondary outcome
measure and adverse events collection 5 years after the completion
date, under the approach proposed in Sec. 11.44(d), the responsible
party would only need to submit results information once for the
secondary outcome measure as well as data for additional adverse event
information not later than 1 year after the date of final data
collection (i.e., up to 6 years after the completion date). Under the
approach proposed by the commenter, however, that responsible party
would also need to submit four datasets of additional adverse event
information for this trial, once per year after the completion date
until submission of results for the secondary outcome measure. In
addition, protocols might not pre-specify that data for adverse event
information will be analyzed annually, placing additional burden on the
responsible party to prepare adverse event information for submission
to the data bank. Thus, the Agency retains the proposed approach with
respect to submission of adverse event information each time results
information for a secondary outcome is submitted and extends the
requirement until all additional adverse event information collected in
accordance with the time frame for collecting adverse events pre-
specified in the protocol are submitted, even after submission of data
for all secondary outcomes.
Reporting of adverse event information is required as part of Sec.
11.48(a)(4), yet the time frame for reporting of partial adverse event
information was not specified in proposed Sec. 11.44(d). After
reviewing proposed Sec. 11.44(d) in response to this comment, we
identified the need to specify explicitly the deadline for submitting
partial results information when the pre-specified time frame for
collecting data for additional adverse event information is not
completed by the primary completion date. We clarify that the final
rule addresses this situation by specifying that a responsible party
submitting partial results information under Sec. 11.44(d) must submit
additional adverse event
[[Page 65075]]
information by the later of either 1 year after the date of data
collection for additional adverse event information or the date on
which results information for the primary outcome measures is due if a
certification to delay results information submission has been
submitted under Sec. 11.44(b) or (c). Further, we have added the Study
Completion Date data element, defined in final Sec. 11.10 and
discussed in Section IV.A.5 of this preamble, to clinical trial
registration information specified in Sec. 11.28.
The Study Completion Date is needed to assist responsible parties
and viewers of the posted record to help identify when the final rule
requirements for results information submission and obligations for
updates and corrections in Sec. 11.64 are fulfilled. Note that even
though a responsible party for a trial may need to submit partial
results information several times in order to meet different deadlines
(i.e., because of different dates for final data collection for primary
and/or secondary outcome measures or for the pre-specified time frame
for collecting adverse events), that responsible party's obligation
under subpart C continues until all required results information is
submitted not later than 1 year following the Study Completion Date.
Several additional commenters opposed proposed Sec. 11.44(d)(2),
which required that results for primary and secondary outcomes
submitted prior to the effective date of the final rule be resubmitted
in accordance with final Sec. 11.48 by the deadline for reporting
partial results information for secondary outcome measures specified in
proposed Sec. 11.44(d)(1). The Agency agrees with these comments. The
final rule specifies that if any results information is submitted for a
clinical trial under sections 402(j)(3)(C) and 402(j)(3)(I) of the PHS
Act prior to the effective date, those results do not need to be
resubmitted in accordance with final Sec. 11.48. In addition, partial
results submitted for that trial after the effective date are also not
subject to Sec. 11.48 of the final rule, but are subject to the
results data elements established by sections 402(j)(3)(C) and
402(j)(3)(I) of the PHS Act, in order to ensure that results data are
displayed in a consistent format on the posted record.
Final Rule
The final rule substantively revises the proposed approach to Sec.
11.44(d) in three ways. First, final Sec. 11.44(d)(1)(ii) adds a
partial results information submission deadline when adverse event
information required in Sec. 11.48(a)(4) has not been collected by the
primary completion date. Under the final rule, data collected for
additional adverse event information after the primary completion date
through the pre-specified adverse event collection time frame must be
submitted by the later of 1 year after the date of data collection for
additional adverse event information or the date on which results
information is due if a certification to delay results information
submission has been submitted under Sec. 11.44(b) or (c). Second, the
final rule modifies Sec. 11.44(d)(2) to specify that, if any partial
results information for a clinical trial is submitted prior to the
effective date of the final rule, any remaining results information
required to be submitted for that trial after the effective date will
be subject to the results requirements established by sections
402(j)(3)(C) and 402(j)(3)(I) of the PHS Act [42 U.S.C. 282(j)(3)(C)
and 282(j)(3)(I)], not by the final rule (Sec. 11.48). Third, the
final rule adds Sec. 11.44(d)(3) to require (i) the submission of a
copy of any revised protocol and/or statistical analysis plan, as
described in Sec. 11.48(a)(5), if any amendments were made to the
protocol and/or statistical analysis plan since the previous submission
of partial results information and (ii) the submission of results
information about certain agreements between the principal investigator
and the sponsor as described in Sec. 11.48(a)(6)(ii) if that
information has changed since the previous submission of partial
results information.
Final Sec. 11.44(d)(1) describes the partial results information
submission deadlines when all clinical trial results information
required in Sec. 11.48 has not been collected by the primary
completion date. In such cases, results information for secondary
outcome measures must be submitted by the later of 1 year after the
date on which the final subject is examined or receives an intervention
for the purposes of final collection of data for that secondary outcome
measure or the date on which results information is due if a
certification to delay results information submission has been
submitted under Sec. 11.44(b) or (c). Furthermore, as discussed above,
data collected for additional adverse event information after the
primary completion date through the pre-specified adverse event
collection time frame must be submitted by the later of 1 year after
the date of data collection for additional adverse event information or
the date on which results information is due if a certification to
delay results information submission has been submitted under Sec.
11.44(b) or (c).
We clarify that when submitting partial results information
(pending completion of data collection for secondary outcomes and/or
the pre-specified time frame for collecting additional adverse event
information), the responsible party is required to submit the clinical
trial results information as specified in Sec. 11.48 that is otherwise
available when submitting partial results information. This means that,
with respect to adverse event information (considered to be part of
clinical trial results information described under Sec. 11.48), each
time results information for a secondary outcome is submitted, a
responsible party would be required to submit results information
summarizing serious and frequent adverse events and all-cause mortality
recorded to that date until all the adverse event information required
by this part has been submitted. If adverse event information was not
planned to be collected and reported in the same time frame(s) as
secondary outcome measures, then it does not need to be reported each
time information for a secondary outcome measure(s) is submitted.
However, as specified in Sec. 11.48(a)(4)(i)(A), the Time Frame must
clearly indicate the time period over which adverse information is
reported and describe any additional time periods over which adverse
event information will be submitted, as pre-specified. It is important
to reiterate that this provision would not impose requirements on the
design or conduct of the clinical trial or on the data that must be
collected during the clinical trial.
Final Sec. 11.44(d)(2) specifies that if any results information
is submitted for a clinical trial under sections 402(j)(3)(C) and
402(j)(3)(I) of the PHS Act prior to the effective date, the
responsible party is not required to resubmit those results in
accordance with Sec. 11.48. In addition, subsequent partial results
information as specified in Sec. 11.44(d)(1) submitted for the same
trial after the effective date is also not required to be submitted in
accordance with final Sec. 11.48, but in accordance with the results
data elements established by sections 402(j)(3)(C) and 402(j)(3)(I) of
the PHS Act. Final Sec. 11.44(d)(3)(i) specifies that the responsible
party is required to also submit a copy of the revised protocol and/or
statistical analysis plan when submitting partial results information
if the protocol and/or statistical analysis plan was amended since the
previous submission of partial results information for that clinical
trial. Final Sec. 11.44(d)(3)(ii) specifies that the
[[Page 65076]]
responsible party is required to submit information to reflect any
changes in the status of certain agreements between the principal
investigator and the sponsor if that information has changed since the
previous submission of partial clinical trial results information.
Sec. 11.44(e)--Extensions for Good Cause
Overview of Proposal
Proposed Sec. 11.44(e) outlined procedures for requesting
extensions of the deadline for submitting results information for good
cause. Section 402(j)(3)(E)(vi) of the PHS Act authorizes the Director
to ``provide an extension of the deadline for submission of clinical
trial [results] information . . . if the responsible party for the
trial submits to the Director a written request that demonstrates good
cause for the extension and provides an estimate of the date on which
the information will be submitted.'' We interpreted this authority as
allowing the Director to grant an extension of any results information
submission deadline that may be in effect for a given applicable
clinical trial specified in proposed subpart C (e.g., the general 12
month results information submission deadline); a delayed submission
deadline established by the submission of an appropriate certification
under section 402(j)(3)(E)(iii) of the PHS Act; or an extended deadline
established by a previously granted extension. As for the latter,
section 402(j)(3)(E)(vi) of the PHS Act explicitly allows the Director
to ``grant more than one extension for a clinical trial.'' (79 FR
69636)
Section 402(j)(3)(E)(vi) of the PHS Act does not define ``good
cause.'' Similarly, the proposed rule did not contain specific
proposals for determining which situations would and would not be
considered good cause for an extension. Instead, we indicated our
intention to develop guidance (which would be subject to public
comment) as the Agency gained more experience with extension requests
and to communicate with the regulated community via other channels,
including the ClinicalTrials.gov Web site. We intend to issue guidance
on what might be considered ``good cause'' under particular
circumstances as soon as practicable. In order to assist responsible
parties who are considering submitting an extension request, we stated
our intention to prepare, update periodically, and post on
ClinicalTrials.gov a non-exhaustive list of reasons that the Agency
generally will consider to be ``good cause'' and not ``good cause'' for
granting an extension under section 402(j)(3)(E)(vi) of the PHS Act and
proposed Sec. 11.44(e). Such a list would contain those reasons that
we consider would serve as useful examples for responsible parties of
other applicable clinical trials. We also indicated that all extension
requests would be considered on a case-by-case basis, and any
generalizable conclusions that can be drawn from the granting or denial
of a request may be added to the list of good causes and not-good
causes for granting extensions (79 FR 69636).
In general, we indicated that there are likely to be only a few
situations that would constitute good cause under section
402(j)(3)(E)(vi) of the PHS Act and proposed Sec. 11.44(e) and listed
the two situations that we have identified to date that we proposed
would constitute good cause:
(1) The need to preserve the scientific integrity of an applicable
clinical trial for which data collection is ongoing, including
situations in which the submission of results information for the
primary outcome(s) of an applicable clinical trial would impair or
otherwise bias the ongoing collection, analysis, and/or interpretation
of data for secondary outcome(s). We indicated our belief that an
extension should be granted only in those situations in which the
following could be demonstrated: Data collection for the secondary
outcome(s) of interest extends more than 1 year beyond the completion
date, the secondary outcome(s) is pre-specified in the protocol or SAP,
and the planned analysis of the outcome measure is also described in
the protocol or SAP. We noted that the responsible party could provide
this information either by voluntarily submitting copies of the
protocol or statistical analysis plan with the extension request or
describing them in the extension request itself.
(2) Emergencies that would prevent timely submission of clinical
trial results information, including situations in which one or more
data collection sites were affected by natural disasters or other
catastrophes outside the responsible party's or sponsor's control. In
such cases, we indicated that we would generally expect to grant the
responsible party an initial extension of up to 6 months, after which
time additional extensions could be granted, as necessary. We generally
would not consider events that might reasonably have been avoided or
anticipated through standard contingency planning (e.g., transition
planning for key staff members who leave an organization) to constitute
good cause for an extension under section 402(j)(3)(E)(vi) of the PHS
Act or proposed Sec. 11.44(e) (79 FR 69637).
To clarify what we believed would not ordinarily constitute good
cause, we discussed two scenarios in the proposed rule's preamble.
First we pointed out that a request containing only a general statement
without any specific reason for a delay in data analysis (e.g., ``data
could not be analyzed fully within 12 months'') would not be a good
cause. Second, we indicated that ``awaiting journal publication'' would
not constitute a good cause. We noted that the ICMJE has stated that
results information submission to ClinicalTrials.gov in compliance with
section 402(j) of the PHS Act will not be considered ``prior
publication'' and will not preclude future publication [Ref. 2, 98]. We
invited public comment on these specific situations and on more general
criteria that could be used to determine what constitutes good cause
for an extension (79 FR 69637).
Proposed Sec. 11.44(e)(1) specified that a responsible party may
submit a request for an extension to ClinicalTrials.gov at any time
before any results information submission deadline established in
proposed Sec. 11.44(a), (b), or (c), if the relevant certification has
been submitted; or Sec. 11.44(f), for a pediatric postmarket
surveillance of a device that is not a clinical trial. Consistent with
section 402(j)(3)(E)(vi) of the PHS Act, our proposal would require an
extension request to include a complete description of the reason(s)
why results information cannot be provided according to the applicable
deadline and an estimated date on which results information will be
submitted. The submitted extension request would be reviewed by an
Agency official designated by the Director (79 FR 69637).
Proposed Sec. 11.44(e)(2) indicated that the Agency would notify
the responsible party electronically whether the request has been
granted and, if granted, the Agency-specified extended deadline by
which results information must be submitted. If the extension request
is denied, the responsible party may either submit an appeal to the
Director or would submit results information by the later of the
original deadline or 15 calendar days after the date the Agency sends
the electronic notice of the denial to the responsible party (79 FR
69637).
Proposed Sec. 11.44(e)(3) specified that a responsible party may
appeal a denied extension request or the Agency-specified extended
deadline by which results information must be submitted not later than
15 calendar days after the date the Agency sends the electronic notice
of the denial. Responsible parties are required to submit a description
of the reasons for the appeal with
[[Page 65077]]
sufficient detail to allow for evaluation. If the appeal is granted,
the responsible party must submit results information by the revised
deadline set by the Director in the electronic notification. If the
appeal is denied, the responsible party must submit results information
by the later of the following: The original deadline, the Agency-
specified extended deadline provided in the electronic notification, or
15 calendar days after the date the Agency sends the electronic notice
of denial of the appeal to the responsible party (79 FR 69637).
We also noted that extensions would apply only in the context of
applicable clinical trials subject to the results information
submission requirements of section 402(j)(3) of the PHS Act because the
extension provision specifically refers to results information
submission under 402(j)(3)(E)(i) of the PHS Act. Accordingly,
extensions do not apply to clinical trial results information that is
submitted under section 402(j)(4)(A) of the PHS Act (i.e., voluntarily
submitted trials (see final rule Sec. 11.60(a)(1)) and triggered
trials (see final rule Sec. 11.60(a)(2)(ii))) (79 FR 69636).
Posting of Information About Certifications for Delayed Submission and
About Extensions for Good Cause
In the proposed rule, we suggested that there would be value in
posting information on the ClinicalTrials.gov Web site about the
specific mechanism that had been used to delay the submission of
clinical trial results information for a particular applicable clinical
trial (i.e., an extension request had been granted under proposed Sec.
11.44(e) or the responsible party had submitted a certification for
delayed submission, specifying either proposed Sec. 11.44(b) or (c)).
Doing so would provide a way to track the progress of clinical trials
by informing users why clinical trial results information is not yet
publicly available. Without such an indication, users who view a posted
clinical trial record that contains no results information more than 1
year after the primary completion date might be led to believe,
incorrectly, that the responsible party has not complied with the
results information submission requirements of this proposed rule or
that the Agency has failed to post such information. However, we
recognized that information about the specific mechanism used to delay
results information submission might in some circumstances be
considered confidential (e.g., the fact that the manufacturer had
submitted or was planning to submit within 1 year a marketing
application or premarket notification to FDA for a new use of a drug or
device that was studied in the applicable clinical trial prior to any
public statement by the or manufacturer about its plans).
In order to balance the competing interests, we proposed posting
only minimal information about delayed results information submissions
in these circumstances. That is, whether a responsible party delayed
results information submission via certification or is granted an
extension of the deadline, we would indicate in the posted record only
that results information submission has been delayed, but not which
mechanism had been used. As described previously, we proposed posting
and updating periodically on the ClinicalTrials.gov Web site a
generalized list of reasons for which extensions have and have not been
granted (without information that might allow a user to identify a
specific applicable clinical trial) to provide responsible parties with
insight into the types of reasons that have and have not been
considered to constitute good cause for an extension (79 FR 69638).
We invited public comments on our overall proposed approach and on
the advantages and disadvantages of providing more specific information
about extension requests (e.g., whether submission was delayed via
extension or certification), including alternative approaches that we
could take that would provide more information to the public about the
reasons for delayed submissions of clinical trial results information.
We also invited public comment on whether extension requests could be
submitted without containing any information that would be considered
confidential (79 FR 69638).
Comments and Response
Commenters addressed the proposed approach for implementing
extensions of the results information submission deadline in Sec.
11.44(e). One commenter suggested that 15 calendar days do not provide
sufficient time for a responsible party either to submit a written
letter to appeal a denial for an extension request or to submit results
information following notification that an appeal has been denied as
proposed in Sec. 11.44(e)(3)(i) and (vi), respectively. We note that
several other commenters requested more broadly that the 15 calendar
day deadlines proposed in the proposed rule be changed to 30 calendar
day deadlines in the final rule (see discussion of Sec. 11.64 in
Section IV.D.3 of this preamble). The Agency generally agrees with the
commenters and has changed, where possible, the 15 calendar day
deadlines in the proposed rule to 30 calendar day deadlines in the
final rule (see Section IV.D.3 of this preamble).
One commenter requested clarification that extension requests are
not subject to any limitations in time, in contrast to the 2-year
limitation for delayed submission of results with certification as
specified in proposed Sec. 11.44(b)(2) and (c)(2). We clarify that
requests for extensions of the results information submission deadline
are not subject to a time limit and may include estimated submission
dates over 2 years after the date of the request. However, all
submitted requests must provide a sufficient description of the
reason(s) for proposing the particular estimated submission date. We
also note that, because the statute and final rule permit the Director
to grant more than one extension, a final extended results information
submission deadline may exceed more than 2 years, even if the initial
extension did not.
Several commenters suggested additional good cause reasons, such as
for trials of device products that have received either a non-
substantially equivalent or non-approval letter from the FDA, for
preparation and analysis of data from large and complex trials, and for
pending publication of trial results. One commenter requested
clarification regarding the circumstances under which a sponsor of an
applicable clinical trial of an unapproved, unlicensed, or uncleared
product could request an extension. Another commenter proposed limiting
the situations that would be considered ``good cause'' to national
emergencies or catastrophic events. As stated in the proposed rule and
this preamble, the Agency plans to prepare and periodically update a
public, non-exhaustive list of reasons that it considers to be ``good
cause'' and ``not good cause.'' At present, we have identified only two
general situations that we believe would constitute good cause: (1) The
need to preserve the scientific integrity of a trial; and, (2)
emergencies outside the control of a responsible party that would
prevent timely submission, such as natural disasters or other
catastrophes. In addition, we reiterate that we generally believe that
pending publication and delays in data analysis for unspecified causes
would not be considered good cause. We also note that requests for good
cause may be submitted to extend any type of results information
submission deadline, including the standard submission deadlines in
Sec. 11.44(a) (i.e., 1 year after the primary completion date).
One commenter proposed that responsible parties submitting requests
[[Page 65078]]
for extensions not be required to include confidential commercial or
proprietary information. This commenter also requested that
ClinicalTrials.gov provide a way for the public to distinguish between
applicable clinical trials with missing results submissions because of
missed regulatory deadlines (i.e., late submissions) and those for
which an extension has been granted, as required in Sec. 11.44(e).
Although we do not believe that confidential commercial or proprietary
information will generally need to be submitted, the responsible party
must provide in a submitted request for an extension ``sufficient
detail to allow for the evaluation of the request'' as stated in final
Sec. 11.44(e)(1)(ii)(A). The Agency will not post detailed information
about the request publicly and retains its plan to post minimal
information on posted records to notify users when results information
submission has been delayed without specifying whether a certification
or extension mechanism was used. The Agency believes this approach will
provide sufficient and appropriate information to the public to explain
the reason for delay (see discussion above on Sec. 11.44(b), (c), and
(e)).
One commenter suggested that the final rule provide members of the
public, including third-party researchers, the ability to appeal any
reasons given for delaying the submission of results and that any such
appeals be made publicly available with contact information. The Agency
does not agree with this approach. We do plan, as proposed, to post
publicly a list of general reasons provided in requests for extensions
which the Agency considers to be ``good cause'' and ``not good cause.''
Regarding the proposal to post on ClinicalTrials.gov a list of
general reasons the Agency will consider to be ``good cause'' and ``not
good cause'' for granting extensions, one commenter requested that the
actual reasons cited in extension requests submitted by responsible
parties not be posted while two other commenters suggested that all
submitted justifications and estimated submission dates be posted
publicly for greater transparency. Another commenter proposed requiring
the posting of submitted information for extension requests no later
than 30 calendar days after receipt. As stated in the proposed rule and
in this preamble above, the generalized list of reasons for which
extensions have and have not been granted that is to be posted and
updated periodically on ClinicalTrials.gov will not include any
information that might allow a user to identify a specific applicable
clinical trial. The intent is to provide responsible parties and
members of the public with insight into the types of reasons that have
and have not been considered to constitute good cause for an extension.
We believe that this approach provides sufficient information about the
process for requesting extensions for good cause.
Final Rule
Final Sec. 11.44(e) largely retains the proposal outlined in the
NPRM with the following exceptions. First, the final rule replaces the
15 calendar day deadlines (e.g., for submission of results information
or an appeal after a request is denied) as proposed in the proposed
rule with 30 calendar days in the final rule in response to public
comments. Second, the final rule clarifies that some applicable
clinical trials may be subject to section 402(j)(3)(E)(vi) of the
Public Health Service Act. Third, the final rule adds Sec. 11.44(e) to
the list of provisions in Sec. 11.44(e)(1)(i) and Sec.
11.44(e)(2)(ii) regarding the submission deadlines that would otherwise
apply. Fourth, formatting changes are made for consistency and clarity.
Final Sec. 11.44(e)(1) stipulates that extension requests must be
submitted to the Agency via direct electronic submission to
ClinicalTrials.gov prior to the date on which results information would
otherwise be due in accordance with the results information submission
deadlines, including one for a previously-granted extension request.
Responsible parties are required to submit a description of the reasons
that they believe constitute good cause to justify an extension and an
estimated extended results information submission date with sufficient
detail to allow for evaluation of both requested components.
Under Sec. 11.44(e)(2), a response to the extension request will
be communicated electronically via ClinicalTrials.gov to the
responsible party, providing notice as to whether or not the requested
extension has been granted. If a request is granted because it
demonstrates good cause, a revised deadline for results information
submission will be communicated in the notice. If a request is denied,
the deadline for submitting results is the later of the deadline (e.g.,
1 year after the primary completion date or the delayed submission
deadline if a certification has been filed under subparts (b) or (c))
or 30 calendar days after the date the electronic notice of the denial
of the request is sent to the responsible party.
Section 11.44(e)(3) specifies that a responsible party who appeals
a denied extension request must submit the appeal to the Director in
the format specified at https://prsinfo.clinicaltrials.gov/ (or
successor site) not later than 30 calendar days after the date on which
electronic notification of the granting or denial of the request was
sent to the responsible party. The appeal must explain why, in the view
of the responsible party, the initial decision to deny an extension
request or to grant an extension request with a shorter deadline than
requested by the responsible party should be overturned or revised
(e.g., by providing further elaboration of the grounds for the request
or by highlighting factors that justify an extension). Generally, new
information should not be submitted upon appeal. The submitted appeal
will be considered by the Director or his delegate. If an appeal is
granted, a revised deadline for results information submission will be
set by the Director and provided to the responsible party in an
electronic notification. If the appeal is denied, the deadline for
submitting results information will be the later of the original
submission deadline or 30 calendar days after the electronic
notification of the denial of the appeal is sent to the responsible
party. If the appeal of an extension request that was granted with a
shorter deadline than was originally requested is denied, the deadline
for submitting results information is the later of the deadline
specified in the notification granting the extension request or 30
calendar days after the electronic notification of the denial of the
appeal is sent to the responsible party.
We note that if the estimated primary completion date is earlier
than the actual (or current estimated) primary completion date, a
responsible party must update the estimated primary completion date in
the clinical trial record to reflect the actual (or revised estimated)
primary completion date within 30 calendar days, as required by Sec.
11.64(a)(1)(ii)(I), but should not request an extension based on the
outdated primary completion date. The fact that the responsible party
has updated the primary completion date will be reflected in
ClinicalTrials.gov, consistent with the handling of all updates under
Sec. 11.64.
Posted records of trials that have been granted certification for
delayed submission or extension will indicate that results information
submission has been delayed by displaying minimal information. This
will provide significant information for users to know whether a trial
has met the requirements for results information
[[Page 65079]]
submission under the final rule. As soon as practicable, we will post
on the ClinicalTrials.gov Web site, and periodically update, a list of
reasons for which extensions have and have not been granted to provide
responsible parties and the public with insight into the types of
reasons that have and have not been considered to constitute good cause
for an extension. We note that entries on this list will not contain
any information that might allow a user to identify a specific
applicable clinical trial.
Sec. 11.44(f)--Pediatric Postmarket Surveillance of a Device That Is
Not a Clinical Trial
Overview of Proposal
We proposed in Sec. 11.44(f) that results information for a
pediatric postmarket surveillance of a device that is not a clinical
trial be submitted not later than 30 calendar days after the date that
the final report is submitted to FDA. We believe that 30 calendar days
provide sufficient time to allow the responsible party to format and
submit the information as required by this part.
We noted in the NPRM that we recognize that the proposed deadlines
for submitting clinical trial results information under proposed Sec.
11.44(a)-(d) are not well adapted to a pediatric postmarket
surveillance of a device that is not a clinical trial. Such
surveillances generally do not have a completion date that can be
easily measured by the date that the final subject was examined or
received an intervention for the purposes of final collection of data
for the primary outcome. However, these surveillances will have a date
on which a final report must be sent to the FDA, as specified in the
approved postmarket surveillance plan (79 FR 69638).
Comments and Response
One commenter addressed proposed Sec. 11.44(f) and suggested that
the timeline submission requirement should apply as to Sec. 11.44(a)-
(d). We note that any pediatric postmarket surveillance of a device
that is also a clinical trial would be subject to the results
information submission deadlines that apply to clinical trials (e.g.,
standard submission deadline in proposed Sec. 11.44(a)). For a
pediatric postmarket surveillance of a device that is not a clinical
trial the proposed deadlines Sec. 11.44(a)-(d) are not well adapted.
Therefore, the final rule retains the deadline specified in proposed
Sec. 11.44(f).
Final Rule
Aside from clarifying that ``device'' means ``device product'' and
that some surveillances that are not clinical trials may be subject to
section 402(j)(C)(3) of the PHS Act, no changes were made in Sec.
11.44(f) of the final rule, which requires the submission of results
information not later than 30 calendar days after the date on which the
final report of the approved pediatric postmarket surveillance of a
device product as specified in 21 CFR 822.38 is submitted to FDA (i.e.,
the primary completion date as defined in Sec. 11.10(a)).
4. Sec. 11.48--What constitutes clinical trial results information?
Overview of Proposal
Section 11.48(a) of the NPRM proposed the general requirements for
clinical trial results information that would apply to an applicable
clinical trial other than a pediatric postmarket surveillance of a
device that is not a clinical trial. Proposed Sec. 11.48(b) described
the requirements for a pediatric postmarket surveillance of a device
that is not a clinical trial. In specifying the results information
that must be submitted for a clinical trial, proposed Sec. 11.48(a)
separated the data elements into the following general categories of
information: (1) Participant flow, (2) demographic and baseline
characteristics, (3) outcomes and statistical analyses, (4) adverse
event information, (5) administrative information, and (6) additional
results information for applicable device clinical trials of unapproved
or uncleared devices. The proposal also indicated that whenever
possible ClinicalTrials.gov will use information submitted during
registration to pre-populate the column and row names of the tables of
information that are required as part of results submission. We noted
that doing so reduces the data entry burden on responsible parties and
minimizes the possibility of clerical errors. However, in all cases,
the responsible party is required to revise the information, as needed,
so that the results information appropriately and accurately reflects
the way that data were collected and analyzed in the clinical trial.
Each of the categories of results information that are required to be
submitted are addressed, in order, below (79 FR 69638).
Comments and Response
Numerous commenters addressed the requirements for clinical trial
results information that would apply to an applicable clinical trial.
The specific comments are described in the sections of Sec. 11.48 to
which they apply. We received one general comment in support of the
proposed requirements for results information. We also received one
general comment requesting that the Agency minimize the number of
fields and amount of data required for clinical trial results
information in order to provide responsible parties with more
flexibility in reporting the results of different types of trials.
Based on more than 7 years of experience operating the results
database, we recognize the need for flexibility and generally agree
with the commenter. The final rule represents our attempt to balance
the statutory requirements with the minimum information needed to
understand study results in a way that is consistent across clinical
trials and with existing reporting standards, such as the CONSORT
statement [Ref. 93] which are used to guide the publication of trial
results in peer-reviewed literature.
Sec. 11.48(a)(1)--Participant Flow
Overview of Proposal
Proposed Sec. 11.48(a)(1) addressed the statutory requirement for
the submission of specified participant flow information as part of
clinical trial results information. Section 402(j)(3)(C)(i) of the PHS
Act specifies that a responsible party must submit ``[a] table of . . .
data collected overall and for each arm of the clinical trial to
describe the patients who participated in the clinical trial, including
the number of patients who dropped out of the clinical trial and the
number of patients excluded from the analysis, if any.'' Consistent
with this section of the PHS Act and pursuant to our authority under
section 402(j)(3)(D)(iii)(IV) of the PHS Act, we proposed in Sec.
11.48(a)(1) to require the submission of the following participant flow
information: (1) Participant Flow Arm Information, (2) Pre-assignment
Information, and (3) Participant Data. This information permits the
construction of a table that shows the number of participants starting
the clinical trial and the flow through completion of the trial. In our
proposed approach, information about the number of participants
excluded from the analysis would not be contained in the participant
flow but would be submitted as part of the information about outcome
measures specified and described in proposed Sec. 11.48(a)(3). We also
described how we intend to continue to provide responsible parties with
a means of providing, on an optional basis, additional details about
the participant flow in a manner consistent with CONSORT guidelines
[Ref. 93] (79 FR 69639). We invited public comments on
[[Page 65080]]
the value of providing additional information describing study periods
(e.g., wash-out, consecutive cycles of the intervention), particular
milestones, and reasons for non-completion on ClinicalTrials.gov as
well as comments on approaches for collecting this information.
Comments and Response
Commenters addressed specific aspects of the proposed requirements
for participant flow information in Sec. 11.48(a)(1). One commenter
suggested requiring the submission of information on the number of
participants that are enrolled and who complete the trial at the time
that the trial ends (instead of at the time of clinical trial results
submission). We agree with the commenter that the actual number of
participants enrolled in the trial must be provided in a timely manner
as specified in Sec. Sec. 11.28 and 11.64. However, the number of
participants completing the trial is considered clinical trial results
information that must be submitted in accordance with section
402(j)(3)(C)(i) of the PHS Act and Sec. 11.24. Another commenter
suggested requiring the submission of information on the number of
participants not completing the trial by sex and gender and in a
standardized format, citing associated scientific principles. While we
agree with the commenter on the potential value of such information,
requirements regarding which data must be collected during a clinical
trial are outside the scope of this rule. We therefore are not
proposing to make submitting the requested participant flow information
a requirement, but we do intend to evaluate ways to accommodate the
submission of any such available information. We did not receive any
comments on the value of providing additional information for
describing study periods, milestones, and reasons for non-completion on
ClinicalTrials.gov or on approaches for collecting this information.
However, one commenter provided general support for providing Pre-
assignment Information.
Final Rule
Taking into consideration the comments, as well as the statutory
requirements for clinical trial results information, we are generally
maintaining the approach for participant flow information described in
the NPRM. However, we are providing clarification on certain aspects of
the requirements, based on our operational experience and routine
queries received from users. First, we provide additional elaboration
to clarify the information that is required to be provided as part of
the brief description of each arm. Second, we clarify the definition of
Pre-assignment Information in Sec. 11.48(a)(1)(ii). The proposed
definition indicated that Pre-assignment Information consists of ``[a]
description of significant events affecting the number of human
subjects enrolled in the clinical trial but not assigned to an arm, if
any.'' The phrase ``affecting the number of'' may incorrectly imply
that the actual number of human subjects enrolled changes based on a
pre-assignment event. Instead, the intent is to describe events that
occur between enrollment and assignment to an arm that are planned as
part of the study design and other events that lead to differences in
the number of human subjects enrolled and the number of human subjects
assigned to an arm. Third, we explain the terms ``started'' and
``completed,'' which are used to describe Participant Data in Sec.
11.48(a)(1)(iii). Fourth, we address requirements for clinical trials
that assign participants to arms based on units other than participants
(e.g., lesions, eyes, implants). While the NPRM included a proposal for
how such information is specified when reporting an outcome measure in
Sec. 11.48(a)(3)(ii), Analysis Population Information, it did not
address similar information in Sec. 11.48(a)(1), Participant flow and
Sec. 11.48(a)(2) Demographic and baseline characteristics.
Final Sec. 11.48(a)(1) requires the submission of the following
participant flow information: (1) Participant Flow Arm Information,
consisting of ``[a] brief description of each arm used for describing
the flow of human subjects through the clinical trial, including a
descriptive title used to identify each arm''; (2) Pre-assignment
Information, consisting of ``[a] description of significant events in
the clinical trial that occur after enrollment and prior to assignment
of human subjects to an arm, if any''; and (3) Participant Data, which
is ``[t]he number of human subjects that started and completed the
clinical trial, by arm. If assignment is based on a unit other than
participants, also include a description of the unit of assignment and
the number of units that started and completed the clinical trial, by
arm.'' This information permits the construction of a table that shows
the flow of participants through the clinical trial, with each
participant represented in only one arm. Information about the number
of participants excluded from the analysis is not contained in the
participant flow; it is submitted as part of the information about
outcome measures (Sec. 11.48(a)(3), Outcomes and statistical
analyses). ClinicalTrials.gov will use the Arm Information,
Intervention Name, and Intervention Description data elements
(submitted as part of clinical trial registration information) to
provide the responsible party with an option for pre-populating table
column names and descriptions for Participant Flow Arm Information. The
responsible party will review and edit the information as needed to
ensure that it appropriately and accurately reflects the participant
flow for the clinical trial, or the responsible party may instead
define new arms to reflect how participants were assigned to arms. In
general, the Participant Flow Arm Information must include all arms to
which participants were assignedand must contain sufficient details to
understand the arms to which participants were assigned and the
intervention strategy used in each arm. The amount and level of detail
are similar to what is described in Sec. 11.10(b) for the arm and
intervention data elements that are used to pre-populate Participant
Flow Arm Information.
Pre-assignment Information is collected in a free text field to
allow the responsible party to explain significant events that occur
between the enrollment of human subjects and their assignment to an
arm. These events may be planned as part of the study design or
unplanned. An example of a significant event that is planned as part of
the study design is a run-in period during which all participants
receive an intervention, which may result in identifying participants
who are not eligible to continue in the study or may otherwise
influence assignment to an arm. An example of an unplanned event is the
voluntary withdrawal of a participant prior to assignment to an arm.
Either event may result in the number of human subjects starting the
trial (e.g., assigned to an arm) being fewer than the total number of
human subjects enrolled. Pre-assignment Information is where the
responsible party describes any such differences. As part of
Participant Data, the responsible party provides the number of human
subjects that started and completed each arm. The number of
participants that ``started'' the clinical trial means the number of
participants assigned to the arm (regardless of whether these
participants received the assigned intervention). The meaning of the
number of participants that ``completed'' the arm may vary, based on
the specific context of the clinical trial. However, if there is more
than one
[[Page 65081]]
period (e.g., a discrete stage) in the clinical trial, the meaning of
the number of participants starting and completing is in the context of
initial assignment and the specific period. Specifically, ``started''
in the first period (and the overall clinical trial) means the number
of participants assigned to each arm, and ``started'' in subsequent
periods (if any) means the number of participants initiating each
period of the clinical trial in each arm. In order to retain the
flexibility desired by responsible parties in reporting results, we do
not intend to define this further. However, we will implement an
optional data element to allow responsible parties to explain the
meaning of ``started'' and/or ``completed'' in the context of their
specific clinical trial. If the assignment of participants to an arm is
based on a unit other than human subjects (e.g., lesions, eyes,
implants), the responsible party must also provide, in addition to
participants, the type and number of units that started and completed
the clinical trial, by arm. Based on our experience with submitted
results information and routine queries from users of
ClinicalTrials.gov, this information is necessary for accurately
representing the assignment strategy and for interpreting similar
information on the units analyzed in Analysis Population Information
for Demographic and baseline characteristics in Sec. 11.48(a)(2)(ii)
and Outcomes and statistical analyses in Sec. 11.48(a)(3)(ii).
Therefore, consistent with section 402(j)(3)(C)(i) of the PHS Act and
pursuant to our authority under section 402(j)(3)(D)(iii)(IV) of the
PHS Act, final Sec. 11.48(a)(1) requires the submission of the
following participant flow information: (1) Participant Flow Arm
Information, (2) Pre-assignment Information, and (3) Participant Data.
Although we did not receive any comments in response to our request
for comment on the topic of describing study periods, milestones, and
reasons for non-completion on ClinicalTrials.gov, we intend to continue
to provide responsible parties with a means of submitting, on an
optional basis, additional details about the participant flow in a
manner consistent with CONSORT guidelines [Ref. 93]. This information
consists of details about the flow of participants through different
periods or milestones defined for the clinical trial and the reason(s)
why participants did not complete the clinical trial or reach a
particular milestone. Clinical trials often proceed through multiple
periods (e.g., wash-out, consecutive cycles of the intervention), and
having information about the participant flow in each period and the
reasons why participants did not complete the clinical trial or reach a
particular milestone, if applicable, improves users' understanding of
the clinical trial results data. Clinical trials vary considerably in
their design, and some may not include specific periods or milestones.
However, when a study does include such aspects, we will continue to
encourage responsible parties to provide clinical trial results
information in a manner that most clearly describes the study design
and what happened to participants as they progressed through the study.
We intend to provide additional guidance, including case examples, to
help responsible parties understand how to optimally present various
study designs.
Sec. 11.48(a)(2)--Demographic and Baseline Characteristics
Overview of Proposal
Proposed Sec. 11.48(a)(2) addressed the statutory requirement for
the submission of demographic and baseline characteristics as part of
clinical trial results information. Section 402(j)(3)(C)(i) of the PHS
Act specifies that a responsible party must submit ``[a] table of the
demographic and baseline data collected overall and for each arm of the
clinical trial to describe the patients who participated in the
clinical trial . . .'' (79 FR 69639). Consistent with this section of
the PHS Act, the Agency proposed in Sec. 11.48(a)(2) to require
``[i]nformation for completing a table of demographic and baseline
measures and data collected by arm or comparison group and for the
entire population of human subjects who participated in the clinical
trial.'' The information must include the following: (i) Baseline
Characteristics Arm/Group Information; (ii) Overall Number of Baseline
Participants; (iii) Baseline Measure Information, to include the Name
and Description of the measure, Measure Type, Measure of Dispersion,
and Unit of measure; and (iv) Baseline Measure Data. We further
proposed that Baseline Measure Information must include ``[a]
description of each baseline or demographic characteristic measured in
the clinical trial, including age, gender, and any other measure(s)
that were assessed at baseline and used in the analysis of outcome
measures in accordance with Sec. 11.48(a)(3).'' We invited public
comment on the sufficiency of this proposed approach for submitting
baseline characteristics as well as whether we should require the
submission of additional demographic or baseline characteristics
collected during the clinical trial that are common across many trials,
such as country-of-origin or country-of-residence. We also invited
comment on whether the list of proposed choices for measures of central
tendency and of dispersion was adequate to provide an accurate
description of the measures used in any clinical trial (79 FR 69640).
Comments and Response
Commenters addressed specific aspects of the proposed requirements
for demographic and baseline characteristics in Sec. 11.48(a)(2). One
commenter provided general support for the proposed baseline
characteristics requirements. Some commenters supported adding a
requirement for reporting race and ethnicity information, with several
commenters citing similar FDA and NIH requirements. One commenter
stated that having race and ethnicity information was important for
different groups ``seeking to understand how representative minority
populations are in [applicable clinical trials] . . .'' Some of these
commenters also recommended including an option to specify that race
and ethnicity information was not collected. While we did not propose
to require race and ethnicity information because of a concerns that
this information may not be routinely collected during all clinical
trials, we agree that providing the responsible party with a mechanism
to indicate that race and/or ethnicity information was not collected
would address this concern. Therefore, the final rule adds a
requirement for the reporting of race and ethnicity information, or an
indication that such information was not collected during the trial, as
a component of Baseline Measure Information. The final rule follows the
same approach to indicating that information was not collected during
the trial as for other baseline measures required by ClinicalTrials.gov
(e.g., age, sex/gender). One commenter indicated that country of origin
information ``could be an important data point'' to require but did not
provide further elaboration on why it is important. Although it may be
important for some clinical trials, in considering other commenters
concerns about additional requirements (noted below) as well as the
addition of a requirement to submit race and ethnicity informatoin, we
are not persuaded that the benefits of requiring country-of-origin
information would outweigh the burdens. However, we will, continue to
make available ``region of enrollment'' as part of the limited list of
options for Baseline
[[Page 65082]]
Measure Information to facilitate the optional reporting of such
information if it was assessed at baseline. One commenter recommended
that the term ``gender'' be replaced by ``sex.'' We partially addressed
this issue in Sec. 11.10, and to address the same issue in the context
of clinical trial results information, we are revising the term
``gender'' to ``sex/gender'' to indicate that the submission of
Baseline Measure Information on sex and/or gender would meet the
requirement. Other commenters opposed any additional requirements for
demographic information, citing concerns that expanded reporting
requirements would lead to future requirements to collect such data
during a trial. As explained in proposed Sec. 11.48(a)(2)(iii), only
summary data for measures assessed at baseline are required to be
reported, and the final rule does not impose requirements on the design
or conduct of clinical trials or on the data that must be collected
during clinical trials.
After consideration of the comments, we believe it is appropriate
in the final rule to limit the requirement to report any measure(s)
assessed at baseline and used in the analysis of outcome measure(s) in
Sec. 11.48(a)(2)(iii) to those baseline measure(s) used in the
analysis of primary outcome measure(s). One commenter suggested that
baseline measures related to outcome measures be reported as part of
outcome measure information in proposed Sec. 11.48(a)(3). We
acknowledge that, in limited circumstances, the arms or groups used for
demographics and baseline characteristics may differ from those used in
the primary outcome measure and agree with the commenter that providing
such Baseline Measure Information as part of Outcome Measure
Information would be appropriate in such circumstances. When relevant,
the final rule also permits the reporting of baseline measure
information as a component of both demographic and baseline
characteristics in Sec. 11.48(a)(2) as well as outcomes and
statistical analyses in Sec. 11.48(a)(3). In addition, we will
continue to evaluate methods for displaying results information on
ClinicalTrials.gov to improve linking these two relevant sections when
the baseline and outcome measures are related.
Based on our experience with submitted results information and
routine queries from users, we note that some clinical trials include
baseline measures and outcome measures that are based on units of
analysis other than participants. While the NPRM did not address how
such information could be specified in proposed Sec. 11.48(a)(2),
Demographic and baseline characteristics, it did include a proposal for
reporting such information as an outcome measure in Sec.
11.48(a)(3)(ii) Analysis Population Information. To address this
inadvertent omission and facilitate the accurate submission of Baseline
Measure Information and Baseline Measure Data in a manner that is
consistent with the design, conduct and analysis of the clinical trial,
the final rule adds similar data elements to Sec. 11.48(a)(2) for the
limited cases in which units of analysis are other than participants
(e.g., lesions, eyes, implants). We also note that if such a
requirement were not added, it would not be possible for a responsible
party to submit baseline measure(s) that were assessed at baseline and
used in the analysis of the primary outcome measures(s), when the unit
of analysis for the primary outcome measure(s) is other than
participants. We also add an element to describe the analysis
population when the Overall Number of Baseline Participants (or units)
differs from the number of human subjects (or units) assigned to an arm
or comparison group, similar to Analysis Population Description in
Sec. 11.48(a)(3)(ii)(C). Analysis Population Description was added to
Demographic and baseline characteristics as an optional data element in
January 2013 in response to queries routinely received from responsible
parties as well as our experience with submitted results information.
Based on a review of clinical trials with results posted on
ClinicalTrials.gov, the number of participants analyzed in Demographic
and baseline characteristics differed from the number assigned to an
arm in 15 percent of clinical trials. The addition of this data element
is therefore necessary to enable users of ClinicalTrials.gov to
understand why some participants (or units) were excluded from the
analysis of Demographic and baseline characteristics. These data
elements in final Sec. 11.48(a)(2) are consistent with section
402(j)(3)(C)(i) of the PHS Act and are promulgated pursuant to our
authority under section 402(j)(3)(D)(iii)(IV) of the PHS Act.
We invited comments on whether the lists of proposed choices for
Measure Type and Measure of Dispersion were adequate, but we did not
receive any specific comments on this topic. However, based on our
experience with submitted results information and routine queries from
users of ClinicalTrial.gov, we have identified two issues with the
following limited list of options for Measure Type proposed in the NPRM
preamble: ``Number,'' ``mean,'' ``median,'' ``least squares mean,''
``geometric mean,'' and ``log mean.'' First, because the ``log mean''
option is not needed, we have excluded it from the limited list of
options for Measure Type. Of the more than 22,000 records with posted
results on ClinicalTrials.gov as of July 2016, only 3 indicated ``log
mean'' in Baseline Measure Information, and in each case the data were
the mean of log transformed data (rather than a logarithmic mean) and
should have been specified as a Measure Type of ``mean'' instead.
Second, as discussed in this preamble for Outcome measures and
statistical analyses, we also add ``geometric least squares mean'' to
the list of options for Measure Type. Third, the ``number'' option is
not sufficiently granular to allow for discrimination among different
methods of aggregation that use ``number'' for Measure Type (such as
count of participants or percentage of participants). To address this,
we are adding two additional options to Measure Type to specify whether
the number is a ``count of participants'' or a ``count of units.''
These choices will improve the clarity of results data by making such
counts unambiguous, thereby ensuring that these data are properly
interpreted by human users as well as (semi-) automated systems.
Final Rule
Taking into consideration the comments, our experience with the
ClinicalTrials.gov data bank, and the statutory requirements for
clinical trial results information, we are modifying the NPRM approach
for Baseline Measure Information to specify that Demographic and
baseline characteristics includes a new requirement to provide race and
ethnicity information, if collected, or indicate that it was not
collected, and modifies the requirement to provide other measures
assessed at baseline to those used in the analysis of a primary outcome
measure. In addition, based on our operational experience and routine
queries from users, we add provisions in final Sec. 11.48(a)(2)(ii),
Baseline Analysis Population Information to address how the responsible
party provides demographic and baseline characteristics when the unit
of analysis is not human subjects and how to describe the analysis
population, if needed. Final Sec. 11.48(a)(2)(v) also explains how to
specify the number of baseline participants (and units) analyzed, if
different from the Overall Number of Baseline Participants or Units
Analyzed. Additional elaboration
[[Page 65083]]
is provided on the information required to be submitted as a brief
description of each arm/group (a similar omission was described for
Sec. 11.48(a)(1)), the use of ``categories'' used to submit Baseline
Measure Data, and options for specifying Measure Type. We have made
minor revisions to clarify the Name and description of the measure in
final Sec. 11.48(a)(2)(iii)(A) to indicate that the information must
include ``any categories that are used to submit Baseline Measure
Data'' (revised from the proposed broader phrasing of ``any categories
that are used in submitting results''). We also have revised the
description of the population for whom Baseline Measure Data is
provided in Sec. 11.48(a)(2)(iv) (proposed ``human subjects who
participated in the clinical trial'') to be consistent with a similar
description for Overall Number of Baseline Participants in Sec.
11.48(a)(2)(ii)(A) (``human subjects for whom baseline characteristics
were measured''). Final Sec. 11.48(a)(2) requires the submission of
the following demographic and baseline characteristic information: (i)
Baseline Characteristics Arm/Group Information; (ii) Baseline Analysis
Population Information; (iii) Baseline Measure Information; (iv)
Baseline Measure Data; and (v) Number of baseline participants (and
units), if different from Overall Number of Baseline Participants or
Units Analyzed.
ClinicalTrials.gov will use the Arm Information, Intervention Name,
and Intervention Description data elements (submitted as clinical trial
registration information) as well as Participant Flow Arm Information
to provide the responsible party with options for pre-populating table
column names and descriptions for Baseline Characteristics Arm/Group
Information (described in final Sec. 11.48(a)(2)(i)). The responsible
party will review and edit the information as needed to ensure that it
appropriately and accurately reflects the baseline arms/groups for the
clinical trial, or the responsible party may instead define new groups
to reflect how baseline information was analyzed. As described in the
discussion of the term ``comparison group'' in Sec. 11.10(a) of the
preamble, the reference to comparison groups recognizes that when data
collected during clinical trials are analyzed, the data are often
aggregated into groupings of human subjects (i.e., comparison groups)
other than the arms to which the subjects were assigned for the study.
It is expected that Baseline Characteristics Arm/Group Information will
be the same as Participant Flow Arm Information, unless human subjects
were analyzed in groups that are different from those to which they
were assigned. In this situation, there must be sufficient detail to
understand how the arm(s) or comparison groups used for submitting
Baseline Characteristics Arm/Group Information were derived from
Participant Flow Arm Information. In general, Baseline Characteristics
Arm/Group Information must include all participants assessed at
baseline, with each participant belonging to only one arm or comparison
group, as specified in the pre-specified protocol and/or SAP. Baseline
Characteristics Arm/Group Information must also include sufficient
detail to understand the intervention strategy being described in that
arm/group, similar to what is described in this preamble for
Participant Flow Arm Information in Sec. 11.48(a)(1).
Baseline Analysis Population Information, as described in final
Sec. 11.48(a)(2)(ii), consists of (A) Overall Number of Baseline
Participants, (B) Overall Number of Units Analyzed, and (C) Analysis
Population Description. Baseline Analysis Population Information is
similar to that described for Analysis Population Information for
outcome measures in Sec. 11.48(a)(3)(ii). The Overall Number of
Baseline Participants is defined as the ``[t]he total number of human
subjects for whom baseline characteristics were measured, by arm or
comparison group, and overall.'' Overall Number of Baseline
Participants is necessary to indicate whether some subjects enrolled in
the clinical trial were not measured at baseline (e.g., because they
dropped out of the clinical trial before that point in time) and to
help ensure that results information is submitted for all subjects who
were measured at baseline. If any of the demographic or baseline
characteristics are based on a unit other than human subjects (e.g.,
lesions, eyes, implants), the responsible party is also required to
provide the Overall Number of Units Analyzed, which is defined as ``. .
. a description of the unit of analysis and the number of units for
which baseline measures were measured and analyzed, by arm or
comparison group and overall.'' In addition, the Analysis Population
Description in baseline must be used ``[i]f the Overall Number of
Baseline Participants (or units) differs from the number of human
subjects (or units) assigned to the arm or comparison group and
overall, [with] a brief description of the reason(s) for the
difference.''
Baseline Measure Information, as described in Sec.
11.48(a)(2)(iii), consists of ``[a] description of each baseline or
demographic characteristic measured in the clinical trial, including
age, sex/gender, race, ethnicity (if collected under the protocol), and
any other measure(s) that were assessed at baseline and are used in the
analysis of the primary outcome measure(s) in accordance with Sec.
11.48(a)(3).'' If any Baseline Measure Information (described in Sec.
11.48(a)(2)(iii)) is not measured in the clinical trial (e.g., age,
sex/gender, race and ethnicity), ClinicalTrials.gov will provide a
mechanism for the responsible party to indicate that such information
was not collected. A responsible party must submit demographic and
baseline characteristics using the following limited list of options
for Baseline Measure Information: ``Age,'' ``sex/gender,'' ``race and
ethnicity,'' ``region of enrollment'' (if assessed at baseline), and
``study-specific measure(s),'' by arm or comparison group and overall
for the clinical trial. Age information must be submitted as ``age,
continuous'' (e.g., for Measure Types of ``mean'' or ``median''),
``age, categorical'' (pre-defined categories of <18 years, 18 to 65
years, and >65 years), or ``age, customized'' (age categories defined
by responsible party). For sex/gender data, the responsible party must
submit using ``sex, male, female'' (pre-formatted categories of male
and female) and/or ``gender, customized'' (gender categories defined by
the responsible party). The responsible party may use the description
of the measure to provide additional, free-text information about the
collection and/or reporting methods used for sex and/or gender
information. Race and ethnicity data must be submitted as ``race (NIH/
OMB),'' ``ethnicity (NIH/OMB),'' or ``race/ethnicity, customized.'' The
options that reference NIH/OMB reflect the classification system of the
Office of Management and Budget (OMB) (see 62 FR 58782, Oct. 30, 1997),
which has been adopted by Federal agencies, including NIH.
Alternatively, the responsible party may select ``race/ethnicity,
customized'' in order to customize race and ethnicity categories for
consistency with how information was collected in the protocol for the
clinical trial, if different from the NIH/OMB classification. If region
of enrollment information is provided, the measure information will be
pre-filled with the countries described for Facility Information in
Sec. 11.28(a)(2)(iii)(C), but this information can be edited as
needed. Responsible parties must select from this limited list of
options for Baseline Measure Information to ensure that the required
information is
[[Page 65084]]
provided and to allow for the identification of such information in a
search by users of the public site. In addition, ClinicalTrials.gov
accommodates the submission of information to describe an unlimited
number of customized demographic and baseline characteristics (using
the ``study-specific measure'' option). In general, we cannot specify
in advance which other demographic and baseline characteristics would
be provided for a particular clinical trial. Only those conducting the
clinical trial will know which characteristics are important for their
clinical trial and which were actually collected. Important demographic
and baseline characteristics are those that a responsible party
determines are useful for comparing participants across comparison
groups and for describing the population enrolled in the clinical
trial. Although we cannot specify these characteristics in advance, we
do believe it is important that baseline measures include any
characteristic used in assessing primary outcome measure(s). For
example, if an outcome measure compares a subject's blood pressure
after 6 weeks of receiving a particular intervention, the baseline
measure of blood pressure must be submitted. Similarly, if a clinical
trial includes a statistical analysis of a primary outcome measure that
uses baseline data from participants enrolled in the clinical trial as
part of the calculation (e.g., a regression analysis), it is necessary
to submit the relevant baseline data. The use of these baseline data in
analyzing the primary outcome measure indicates that these data would
have been collected during the clinical trial and would be important to
the interpretation of results. In the limited circumstance in which
Baseline Characteristics Arm/Group Information is different from the
Arms/Groups used in the analysis of the primary outcome measure(s), it
is acceptable to provide the relevant Baseline Measure Information only
as part of Outcome Measure Information.
For each measure, Baseline Measure Information in Sec.
11.48(a)(2)(iii) must include the following elements: ``(A) Name and
description of the measure, including any categories that are used to
submit Baseline Measure Data; (B) Measure Type and Measure of
Dispersion [for] each baseline measure submitted, an indication of the
type of data to be submitted and the associated measure of dispersion;
[and] (C) Unit of Measure.'' Providing Baseline Measure Information in
this structured manner is intended to ensure that the information is
meaningful to users, ensure that submitted information is complete, and
improve the comparability of information across clinical trials. With
respect to the categories that are used to submit Baseline Measure
Data, in our experience operating ClinicalTrials.gov, we have observed
that responsible parties use categories for two general types of
information: Either a list of mutually exclusive and exhaustive
categories to which each participant belongs to one and only one (e.g.,
participants with history of smoking, no history of smoking, unknown)
or a list of items that are not mutually exclusive and exhaustive for
which a single participant may be represented in more than one row (or
not all) (exposure to ``A,'' ``B,'' and/or ``C''). To distinguish these
two different types of information and to allow for improved options
for validation (e.g., the system can ensure that the sum of
participants in mutually exclusive and exhaustive categories is the
same as the overall number of baseline participants), responsible
parties may indicate which information type is being reported. When
specifying the Measure Type, the responsible party is required to
select one option from the following limited list of options: ``Count
of participants,'' ``count of units,'' ``number,'' ``mean,''
``median,'' ``least squares mean,'' ``geometric mean,'' and ``geometric
least squares mean.'' When specifying the associated Measure of
Dispersion, the responsible party is required to select one option from
the following limited list of options: ``Standard deviation,'' ``inter-
quartile range,'' ``full range,'' and ``not applicable'' (which would
be permitted only if the specified measure type is ``count of
participants,'' ``count of units,'' or ``number''). No ``other'' option
is available for either Measure Type or Measure of Dispersion, but
responsible parties have the option of voluntarily providing additional
information about the baseline measures as part of a free-text
description of the baseline measure. Unit of Measure describes what is
being quantified by the data (e.g., blood pressure in ``millimeters of
mercury'' or ``participants''). Each baseline measure can have only one
Unit of Measure.
Final Sec. 11.48(a)(2)(iv) specifies that Baseline Measure Data
consists of ``[t]he value(s) for each submitted baseline measure, by
arm or comparison group and for the entire population of human subjects
. . .'' Section 11.48(a)(2)(v) indicates that, for each submitted
baseline measure, the number of baseline participants (and units) must
be specified if different from the Overall Number of Baseline
Participants or Overall Number of Units Analyzed (e.g., a participant
was unable to complete one of the baseline assessments). The ``[n]umber
of baseline participants (and units)'' is provided ``by arm or
comparison group and overall'' as part of Baseline Measure Data.
Sec. 11.48(a)(3)--Outcomes and Statistical Analyses
Overview of Proposal
Proposed Sec. 11.48(a)(3) addressed the statutory requirement for
the submission of outcomes and statistical analyses as part of clinical
trial results information. Section 402(j)(3)(C)(ii) of the PHS Act
specifies that a responsible party must submit ``[t]he primary and
secondary outcome measures as submitted under paragraph
(2)(A)(ii)(I)(ll), and a table of values for each of the primary and
secondary outcome measures for each arm of the clinical trial,
including the results of scientifically appropriate tests of the
statistical significance of such outcome measures'' (79 FR 69640).
Consistent with this section of the PHS Act, the Agency proposed in
Sec. 11.48(a)(3) to require ``[i]nformation for completing a table of
data for each primary and secondary outcome measure by arm or
comparison group, including the result(s) of scientifically appropriate
statistical analyses that were performed on the outcome measure data,
if any.'' The NPRM noted that the information must include the
following: (i) Outcome Measure Arm/Group Information; (ii) Analysis
Population Information; (iii) Outcome Measure Information, to include
the Name of the specific measure, Description of the metric, Time
point(s) at which the measurement was assessed, Outcome Measure Type,
Outcome Measure Reporting Status, Measure Type, to include type of data
and related measure of dispersion or precision, and Unit of measure;
(iv) Outcome Measure Data; and (v) Statistical Analyses information for
results of scientifically appropriate statistical analyses. The NPRM
included options that could be selected to describe the type of data
and related measure of dispersion or precision and invited public
comment on whether the proposed options were sufficient for collecting
data from the full range of clinical trials that would be subject to
the proposed rule. Statistical Analyses were proposed to be defined as
``[r]esult(s) of scientifically appropriate statistical analyses, if
any . . .'' The criteria for what would be considered scientifically
appropriate were proposed in Sec. 11.48(a)(3)(v) as ``including any
statistical analysis that is: (A) Pre-
[[Page 65085]]
specified in the protocol and/or statistical analysis plan [SAP] that
was performed on the outcome measure data, (B) Made public by the
sponsor or responsible party prior to the date on which results
information is submitted for all primary and secondary outcome measures
studied in the clinical trial, or (C) Conducted in response to a
request made by the U.S. Food and Drug Administration prior to the date
on which complete clinical trial results information is submitted for
all of the primary outcome measures studied in the clinical trial.'' We
invited public comment on these and other criteria that the Agency
should consider when determining what constitutes a scientifically
appropriate statistical analysis. Finally, the NPRM described
approaches for reporting information for outcome measures and
statistical analyses in the following situations: (1) When a trial is
terminated before data are collected for one or more of the pre-
specified outcome measures and (2) when outcome measure data are
collected, but the actual enrollment falls well below the target
enrollment. We invited public comments on other way to highlight the
limitations of the submitted data when either situation occurs (79 FR
69643).
Comments and Response
Commenters addressed specific aspects of the proposed requirements
for Outcomes and statistical analyses in Sec. 11.48(a)(3). Most of the
commenters addressed the proposed criteria for determining when a
statistical analysis would be considered scientifically appropriate.
Many of these commenters expressed concern that the proposal may
require statistical analyses for exploratory outcome measures described
in the protocol and/or SAP to be reported. Other commenters indicated
that some statistical analyses associated with a primary or secondary
outcome measure are considered exploratory, post-hoc, or of sub-groups,
rather than primary, and they requested clarification on which of these
would be required to be reported. We clarify that the proposal was
intended to require the submission of statistical analyses for only
primary and secondary outcome measures and, therefore, would not have
the effect of requiring statistical analyses for other pre-specified or
post-hoc outcome measures (including for sub-groups) not considered
primary or secondary outcome measures in the protocol and/or SAP.
Similarly, we interpret Sec. 11.48(a)(3)(v) to exclude statistical
analyses considered exploratory, even if they are pre-specified in the
protocol and/or SAP for primary and secondary outcome measures. In
addition, the requirement to submit statistical analyses is limited to
those that inform the interpretation of the primary and secondary
Outcome Measure Information and Outcome Measure Data that are
submitted. Alternatively stated, if the statistical analysis does not
rely on data that are specified as primary or secondary outcome measure
information in Sec. 11.48(a)(3)(i)-(iv), that analysis does not need
to be submitted. For example, if a statistical analysis is requested by
FDA for a primary outcome measure based on a different analysis
population or is limited to certain sub-groups not summarized in the
primary or secondary Outcome Measure Information or Outcome Measure
Data, that analysis would generally not meet this requirement. To help
the public understand when a reported statistical analysis is pre-
specified or post-hoc, the responsible party may voluntarily provide
additional information in the accompanying free-text fields as needed
to support an understanding of the nature of the analysis.
One commenter suggested that the statistical analysis requirements
be applied only to the primary outcome measure(s). Section
402(j)(3)(C)(ii) of the PHS Act requires the submission of ``the
results of all scientifically appropriate tests of statistical
significance of [primary and secondary] outcome measures.'' However,
based on our interpretation of which statistical tests are
scientifically appropriate, we are limiting some statistical analysis
reporting requirements to primary outcome measures, as described below.
Other commenters suggested that scientifically appropriate analyses
done in response to an FDA request be limited to the primary outcome
measure(s), with one noting that not all FDA-requested analyses are
determined to be relevant; another commenter expressed concern that
reporting statistical analyses without proper context could be
confusing to the public, particularly if analyses requested by FDA were
not originally specified in the protocol or analysis plan. This
commenter also indicated that clinical trial results presented on
ClinicalTrials.gov should always be based on the CSR submitted to FDA
or other health authorities. For the purposes of results information
reporting under the final rule, the results of all scientifically
appropriate statistical analyses (as defined in Sec. 11.48(a)(3)(v))
for all pre-specified primary and secondary outcome measures must be
reported to ClinicalTrials.gov. When these analyses are the same as
analyses reported to other regulatory authorities in CSRs, it would be
reasonable to use the CSR as the source document for reporting. We
further clarify that the requirement for reporting statistical analyses
made public by the sponsor or responsible party is limited to analyses
of primary outcome measure(s) conducted prior to the date on which
clinical trial information about that primary outcome measure is
submitted to ClinicalTrials.gov. We clarify that the requirement for
reporting statistical analyses conducted in response to a request by
FDA, which is already limited to analyses of the primary outcome
measures, is further limited to those analyses of primary outcome
measures for which results information has not yet been submitted to
ClinicalTrials.gov. That is, primary outcome measures are not required
to be updated under Sec. 11.64(a) with statistical analyses conducted
in response to a request made by FDA, if such analyses are conducted
after clinical trial results information is submitted for the primary
outcome measure(s) to which the statistical analysis applies.
In addition, as previously stated, the requirement is limited to
statistical analyses that rely on the outcome measure data submitted.
We also note that ClinicalTrials.gov includes optional free-text fields
to allow responsible parties the option to provide additional
descriptive information about any submitted statistical analysis,
including information regarding why the analysis was done, why it is
being reported (e.g., in the case of an FDA-requested analysis), and
any limitations of the analysis. This descriptive information should
generally not include interpretations of results or conclusions about
the analyses because of concerns regarding the introduction of bias
discussed in greater detail elsewhere in the preamble. One commenter
indicated that statistical analyses requested by FDA may contain
confidential commercial information and suggested that the results of
statistical analyses should be required to be submitted only when pre-
specified in the protocol or SAP. As such, the final rule retains the
proposed criteria, with the clarification that statistical analyses
conducted in response to a request from FDA are limited to those
performed on primary outcome measures. We believe that these criteria
identify those statistical analyses that either the responsible party
or FDA considers scientifically appropriate. We believe that excluding
from the requirement analyses that were
[[Page 65086]]
prespecified as ``exploratory'' or that were requested by FDA on
outcomes other than the primary outcome measure(s) appropriately
balances the reporting burden with the informational benefit.
Several commenters suggested that the proposed structure of, and
drop-down choices for, the Statistical Analysis Overview, Statistical
Test of Hypothesis, and Method of Estimation elements are too rigid for
non-drug/device studies and smaller studies. We note that the scope of
this rule is limited to studies of drug products (including biological
products) and device products. To help ensure that all required
statistical analyses can be fully accommodated, we will provide a
general ``other'' option that can be used to describe and report the
results of statistical analyses that cannot be submitted using the
options available for Statistical Test of Hypothesis and Method of
Estimation. In addition, the list of options for describing the
procedure for Statistical Test of Hypothesis and the estimation
parameter for Method of Estimation both include an ``other'' option,
and free-text fields are provided for additional explanation, as
needed. Commenters suggested that the proposed options for type of
statistical test conducted (as part of Statistical Analysis Overview)
be expanded from ``superiority,'' ``non-inferiority,'' ``equivalence,''
and ``not applicable'' to include ``estimation'' (e.g., rate of events
in a given arm) and ``descriptive'' (e.g., safety analyses). We note
that EMA's EudraCT results data bank has a similar data element named
``Analysis type'' and uses the following list of options:
``equivalence,'' ``non-inferiority,'' ``superiority,'' and ``other''
[Ref. 98a]. To accommodate these comments and align with EudraCT more
closely, we are modifying the list of options for the type of
statistical test conducted by replacing ``not applicable'' with
``other'' and requiring a description of the type of analysis if the
``other'' option is selected. One commenter suggested that, based on
deficiencies in reporting found in their analysis [Ref. 14], the final
rule should require the specification of the non-inferiority or
equivalence margin. We note that although this recommendation is
consistent with the proposal in section IV.C.4 of the NPRM, the
proposed codified provision inadvertently omitted mention of the
equivalence analysis. This has been corrected in the final rule. One
commenter provided general support for the proposed requirement for
Analysis Population Description as part of Analysis Population
Information.
We invited comments on whether the list of proposed choices for
Measure Type and Measure of Dispersion or Precision was adequate. One
commenter requested that ``geometric least squares mean'' be added to
the list of choices. We know from a similar request from a
ClinicalTrials.gov user that this measure is useful when summarizing
data evaluating pharmacokinetics. Based on this comment and our
experience, we are adding ``geometric least squares mean'' to the list
of choices for Measure Type in both Demographic and baseline
characteristics and Outcomes and statistical analyses. In addition,
based on operational experience and routine queries from users, we have
identified two other issues with the proposed list of options for
Measure Type (i.e., ``number,'' ``mean,'' ``median,'' ``least squares
mean,'' ``geometric mean,'' and ``log mean.'' As described in the
Comments and Response section for Sec. 11.48(a)(2), we have excluded
the ``log mean'' option from the list of options in the final rule
because it is not needed. Second, as also described in this preamble
for Sec. 11.48(a)(2), the ``number'' option is not sufficiently
granular to allow for discrimination among different methods of
aggregation that use ``number'' as the Measure Type (such as count of
participants or percentage of participants). To address this, we are
adding two options to Measure Type to allow responsible parties to
specify whether the number is a ``count of participants'' or a ``count
of units''. We note that this modification more closely aligns the data
fields with the EMA's EudraCT results data bank [Ref. 98a], which
distinguishes between ``countable'' and ``measurable'' types of data.
The final rule also updates ``Measure Type'' to ``Measure Type and
Measure of Dispersion or Precision'' for consistency with the similar
data element ``Measure Type and Measure of Dispersion'' in Sec.
11.48(a)(2)(iii)(B).
We also requested comments on the proposed approach for reporting
outcome measure information when (1) a trial is terminated before data
are collected for one or more of the pre-specified outcome measures and
(2) when outcome measure data are collected but the actual enrollment
falls well below the target enrollment. For the first situation, we
proposed that the responsible party may specify zero (``0'') for the
Number of Participants Analyzed and that Outcome Measure Data would not
need to be submitted. The responsible party would still be expected to
provide the clinical trial results information in proposed Sec.
11.48(a)(1),(2), and (4) (79 FR 69642). For the second situation, we
proposed that collected results information for the primary or
secondary outcome measure must be submitted but statistical analysis
information would not be expected to be submitted because it would not
be considered scientifically valid (79 FR 69643). We received comments
supporting full reporting of results information for terminated or
withdrawn studies. A study with an Overall Recruitment Status of
``withdrawn'' does not include any enrolled participants and would not
require results information submission. We received one comment on the
second situation, in which outcome measure data are required to be
submitted for a clinical trial in which actual enrollment falls well
below the target enrollment. The commenter was concerned about the
misinterpretation of such results and suggested that the final rule
require the responsible party to provide additional information about
the limitations of the data. We note that, in this particular
situation, the posted study record would clearly reflect that the trial
was terminated (i.e., the responsible party submitted the Overall
Recruitment Status as ``terminated''), and we intend to include
information on the posted study record so that the public can easily
see when actual enrollment was below the target enrollment goals (using
information from the Enrollment data element and submitted estimated
and actual values). We believe that this information will make it
easier for the public to consistently identify across studies the
specific limitations raised by the commenter, thereby reducing the need
to make this a requirement. However, we agree that providing additional
information about the limitations of the clinical trial and/or the
collected data may be helpful in this and other situations, and we
strongly encourage responsible parties to use the related free-text
fields and/or the optional Limitations and Caveats data element to
provide such information, when appropriate. Additional relevant
comments were received in the context of waivers and are addressed in
Sec. 11.54, accordingly.
Final Rule
Taking into consideration the comments, our experience operating
the ClinicalTrials.gov data bank, and the statutory requirements for
clinical trial results information, the final rule modifies the
proposed approach for Outcome measures and statistical analyses. We
clarify in Sec. 11.48(a)(3)(v) that one type of scientifically
[[Page 65087]]
appropriate statistical analysis is an analysis that is conducted on a
primary outcome measure, in response to an FDA request. In the same
section, we correct an error that suggested that the submission of
statistical analysis information applied only to the information in
proposed Sec. 11.48(a)(3)(v)(C). Additional elaboration is also
provided on the information required to be submitted as a brief
description of each arm/group (a similar omission was described for
Sec. 11.48(a)(1) and (a)(2)). We remove the requirement to submit
Outcome Measure Reporting Status (see proposed Sec.
11.48(a)(3)(iii)(E)) because a more streamlined approach makes this
item obsolete (i.e., the submission of Measure Type and Measure of
Dispersion or Precision, Unit of Measure, and Outcome Measure Data are
sufficient for determining that Outcome Measure Information and Outcome
Measure Data are intended to be posted). We explain how to specify, as
part of Outcome Measure Data, whether the number of participants (or
units) analyzed in a category differs from the overall Number of
Participants Analyzed and Number of Units Analyzed in Sec.
11.48(a)(3)(ii). We have also updated the options available for
specifying the type of statistical test in the Statistical Analysis
Overview as well as the Measure Type and Measure of Dispersion or
Precision (includes additional options for counts of participants or
units and for specifying a confidence interval). Finally, minor changes
have been made for consistency with similar data items in Demographic
and baseline characteristics in Sec. 11.48(a)(2). Final Sec.
11.48(a)(3) otherwise retains the following outcomes and statistical
analyses information as proposed: (i) Outcome Measure Arm/Group
Information, (ii) Analysis Population Information, (iii) Outcome
Measure Information, (iv) Outcome Measure Data, and (v) Statistical
Analyses.
As discussed in Section IV.B.4 of this preamble, primary and
secondary outcome measures are submitted as part of the registration
process. ClinicalTrials.gov was designed to display the results of each
outcome measure in separate tables organized by arm or comparison
group. The responsible party determines the rows and columns for each
outcome measure table; columns represent arms or comparison groups, and
rows represent data categories (e.g., for categorical data types). The
responsible party populates the table cells with data from the clinical
trial. Attributes such as measure type (e.g., mean), measure of
dispersion or precision (e.g., standard deviation), and unit of measure
(e.g., milliseconds) provide context for interpreting the numerical
data. In this way, the system can accommodate either continuous or
categorical data, as desired by the responsible party based on the
design and analysis of the clinical trial as specified in the protocol
and SAP. For example, time-to-event data could be provided as either a
continuous measure (e.g., median time to response) or as categorical
data (e.g., number of participants with response by year 5).
In order to enhance the ability of users to understand and
interpret the submitted clinical trial results information and help
ensure that submitted information is complete, Sec. 11.48(a)(3)(i)-(v)
requires the responsible party to submit information for completing a
table of data for each primary and secondary outcome measure, by arm or
comparison group, including the results of scientifically appropriate
tests of the statistical significance. This is done by submitting the
following information, which is used to create and populate the outcome
data tables:
(1) Outcome Measure Arm/Group Information, which is described in
Sec. 11.48(a)(3)(i) as ``[a] brief description of each arm or
comparison group used for submitting an outcome measure for the
clinical trial, including a descriptive title to identify each arm or
comparison group.'' As discussed in Section IV.C.4 of this preamble on
Demographic and baseline characteristics, this information describes
the grouping of human subjects for the purposes of analysis, whether by
arm of the clinical trial or another comparison group.
ClinicalTrials.gov will use the Arm Information, Intervention Name, and
Intervention Description data elements (submitted as clinical trial
registration information), as well as Participant Flow Arm Information
and Baseline Characteristics Arm/Group Information, to provide the
responsible party with options for pre-populating table column names
and descriptions for Outcome Measure Arm/Group Information. The
responsible party must review and edit the information as needed to
ensure that it appropriately and accurately reflects the outcome
measure arms/groups for the clinical trial, or the responsible party
may instead define new groups to reflect how outcome measure
information was analyzed. As described in the discussion of the term
``comparison group'' in Sec. 11.10(a) of the preamble, the reference
to comparison groups recognizes that when data collected during
clinical trials are analyzed, the data are often aggregated into
groupings of human subjects (i.e., comparison groups) other than the
arms to which the subjects were assigned for the study. It is expected
that Outcome Measure Arm/Group Information will be the same as
Participant Flow Arm Information, unless human subjects were analyzed
in groups different from those to which they were assigned. In this
situation, there must be sufficient details for users to understand how
the arm(s) or comparison groups used for submitting outcome measures
were derived from Participant Flow Arm Information. In general, the
Outcome Measure Arm/Group Information must be inclusive of all arms or
comparison groups, based on the pre-specified protocol and/or SAP. The
Outcome Measure Arm/Group Information must also include sufficient
details for users to understand the intervention strategy being
described in that arm/group, similar to what is described in this
preamble for Participant Flow Arm Information in Sec. 11.48(a)(1).
(2) Analysis Population Information, as described in Sec.
11.48(a)(3)(ii), consists of the following: (A) Number of Participants
Analyzed, (B) Number of Units Analyzed, and (C) Analysis Population
Description. Number of Participants Analyzed means ``[t]he number of
human subjects for whom an outcome was measured and analyzed, by arm or
comparison group.'' If the analysis is based on a unit other than
participants (e.g., lesions, eyes, implants), the responsible party is
also required to provide the Number of Units Analyzed, which is defined
as ``. . . a description of the unit of analysis and the number of
units for which an outcome was measured and analyzed, by arm or
comparison group.'' In addition, if the Number of Participants Analyzed
or Number of Units Analyzed in an arm or comparison group differs from
the number of human subjects or units assigned to the arm or comparison
group, the responsible party is also required to provide an Analysis
Population Description, which is explained as ``a brief description of
the reason(s) for the difference.'' For example, if some participants
assigned to arms drop out before one of the outcome measures is
assessed or if some participants are otherwise ineligible for analysis,
the responsible party would include an explanation in the Analysis
Population Description. Similarly, if a clinical trial enrolled
participants but was terminated before outcome measure data were
collected, the entry would explain why the Number of Participants
Analyzed is zero even though
[[Page 65088]]
participants had been assigned to the relevant arm or comparison group.
(3) Outcome Measure Information, as described in Sec.
11.48(a)(3)(iii), includes the following components: (A) Name of the
specific outcome measure, including the titles of any categories into
which Outcome Measure Data in Sec. 11.48(a)(3)(iv) are aggregated; (B)
Description of the metric used to characterize the specific outcome
measure; (C) Time point(s) at which the measurement was assessed for
the specific metric; (D) Outcome Measure Type, which indicates whether
the outcome measure is one of the following types of outcome measures:
primary, secondary, other pre-specified, or post-hoc; (E) Measure Type
and Measure of Dispersion or Precision, which indicates the type of
data submitted and the measure of dispersion or precision; and (F) Unit
of Measure (e.g., blood pressure in ``millimeters of mercury'' or
``participants''). As described Section IV.B.4 of this preamble for
Sec. 11.28(a)(2)(i)(W) and (X), when an attribute such as blood
pressure is summarized using more than one metric or method of
aggregation (e.g., mean and median) and/or summarized at more than one
time point (e.g., 3 months, 6 months, 9 months), each of these is
considered a different outcome measure. In addition, the description of
the time point(s) of assessment must be specific to the submitted
outcome measure and is generally the specific duration of time over
which each human subject is assessed (not the overall duration of the
trial). As described in this section of this preamble for Baseline
Measure Information, when responsible parties submit information using
categories, they may indicate which information type is being reported
(participants in mutually exclusive and exhaustive categories or a list
of items for which participants may be represented in more than one
row) to allow for improved options for data validation (e.g., the
system can ensure that the sum of participants in mutually exclusive
and exhaustive categories is the same as Number of Participants
Analyzed).
In specifying the type of data to be submitted as part of Measure
Type and Measure of Dispersion or Precision, the responsible party is
required to select one option from the following limited list of
options for Measure Type: ``count of participants,'' ``count of
units,'' ``number,'' ``mean,'' ``median,'' ``least squares mean,''
``geometric mean,'' and ``geometric least squares mean.'' In specifying
the Measure of Dispersion or Precision, the responsible party is
required to select one option from the following limited list of
options: ``standard deviation,'' ``standard error,'' ``inter-quartile
range,'' ``full range,'' ``geometric coefficient of variation'' (which
is permitted only if the specified Measure Type is ``geometric mean''
or ``geometric least squares mean''), ``not applicable'' (which is
permitted only if the specified Measure Type is ``count of
participants,'' ``count of units,'' ``number''), ``80% confidence
interval,'' ``90% confidence interval,'' ``95% confidence interval,''
``97.5% confidence interval,'' ``99% confidence interval,'' and ``other
confidence interval level'' (which must also include a specification of
the numerical value of the confidence interval level). There is no
general ``other'' option for either the Measure Type or Measure of
Dispersion or Precision entries, but responsible parties may optionally
provide additional descriptive information as part of the free-text
Outcome Measure Description. Collecting Measure Type and Measure of
Dispersion or Precision in this format improves the ability of users'
to compare submitted information across clinical trials and also
ensures complete data submission. For example, if the responsible party
indicates that the measure of dispersion is inter-quartile range,
ClinicalTrials.gov can prompt the submission of the two values
corresponding to the upper and lower bounds of the inter-quartile
range, instead of only the single value needed to submit a standard
deviation. Unit of Measure describes what is quantified by the data
(e.g., blood pressure in ``millimeters of mercury'' or
``participants''). Each outcome measure can only have one unit of
measure.
In most cases, Name of the specific outcome measure, Description of
the metric, Time point(s), and Outcome Measure Type (Sec.
11.48(a)(3)(iii)(A), (B), (C), and (D)) for the primary and secondary
outcome measures would have been submitted at the time of clinical
trial registration, as specified in Sec. 11.28(a)(2)(i)(W) and (X),
and updated during the course of the clinical trial, as specified in
Sec. 11.64. Final Sec. 11.64(a) specifically requires responsible
parties to update information submitted during registration at the time
they submit results. To ensure consistent data entry and reduce the
data entry burden on responsible parties, ClinicalTrials.gov will
automatically pre-populate the results data tables with the previously
submitted (and updated) registration information and will allow the
responsible party to make further updates as necessary or desired
(e.g., to provide clarification that would enable users to better
interpret the submitted results values). If data were not collected for
an outcome measure in a clinical trial (i.e., Number of Participants
Analyzed in all arms or comparison groups is zero for that outcome
measure), the responsible party is not required to submit Measure Type
and Measure of Dispersion or Precision and Unit of Measure (Sec.
11.48(a)(3)(iii)(E) and (F)) for that outcome measure, as no Outcome
Measure Data in Sec. 11.48(a)(3)(iv) would be submitted. This
situation may occur, for example, if a clinical trial is terminated
before data are collected for a pre-specified primary or secondary
outcome measure.
(4) Outcome Measure Data, which is described in Sec.
11.48(a)(3)(iv), consists of ``[t]he measurement value(s) for each
outcome measure for which data are collected, by arm or comparison
group and by category (if specified).'' The information provided for
Outcome Measure Data must use the Unit of Measure and correspond to the
Measure Type and Measure of Dispersion or Precision submitted as
described in Sec. 11.48(a)(3)(iii)(E) and (F). In addition, the
responsible party may specify the number of participants (and units, if
applicable), by arm or comparison group, if different in any category
from the Number of Participants Analyzed or Number of Units Analyzed in
Sec. 11.48(a)(3)(ii)(A) or (B).
(5) Statistical Analyses are specified in Sec. 11.48(a)(v) as the
``[r]esults of scientifically appropriate tests of the statistical
significance of the primary and secondary outcome measures, if any.''
In implementing this requirement, we clarify the meaning of
``scientifically appropriate'' as it relates to Statistical Analyses
for the purposes of this regulation only. In this final rule, we
specify in Sec. 11.48(a)(3)(v)(A) that a statistical analysis is
required to be submitted if it meets any one of the following three
criteria in the context of a particular applicable clinical trial:
A statistical analysis that is pre-specified in the
protocol and/or SAP and was performed on primary or secondary outcome
measure data. Statistical analyses that are pre-specified in the
protocol for a primary or secondary outcome measure, but are considered
exploratory, are excluded from these requirements.
A statistical analysis for a primary or secondary outcome
measure that is made public by the sponsor or responsible party, where
``made public'' is considered to be when the statistical analysis is
available in written form (e.g., journal publication, scientific
abstract, press release). We believe that the decision by the sponsor
or responsible party to publicly disseminate a statistical analysis for
a
[[Page 65089]]
primary or secondary outcome measure implicitly indicates that an
assessment of the scientific appropriateness of the analysis has been
made. The fact that the Agency is adopting this approach in the
regulation does not reflect the Agency's agreement that such
statistical analyses are necessarily scientifically valid. Recognizing
that the time at which an analysis is made public and the submission
requirements under this rule may not overlap, this criterion is limited
to analyses made public before clinical trial results information is
submitted for the primary outcome measure(s) studied in the clinical
trial.
A statistical analysis conducted on a primary outcome
measure in response to a request made by FDA. We limit the requirement
regarding FDA-requested statistical analyses to those analyses
requested by FDA for a primary outcome measure prior to the submission
of clinical trial results information for all primary outcome measures.
This avoids requiring a responsible party to submit FDA-requested
analyses if such analyses would be based on results information that
was submitted to ClinicalTrials.gov prior to FDA's request.
Statistical analyses that meet any of these criteria must be
submitted to ClinicalTrials.gov at the time of results or partial
results information submission. In addition, we clarify that these
criteria apply only to statistical analyses that rely on information
and data that are specified as primary or secondary outcome measure
information in Sec. 11.48(a)(3)(i)-(iv). This limitation is necessary
because statistical analyses are only interpretable in the context of
the summary outcome measure information that forms the basis for the
analysis. These criteria, therefore, do not have the effect of
requiring a responsible party to submit primary or secondary outcome
measure information in Sec. 11.48(a)(3)(i)-(iv) that is not otherwise
required to be submitted.
We specify in Sec. 11.48(a)(3)(v)(B) that the information that a
responsible party must submit for statistical analyses of primary and
secondary outcome measures is as follows:
(1) Statistical Analysis Overview, which identifies the arms or
comparison groups compared in the statistical analysis (by selecting
the arms or comparison groups already defined for the outcome measures)
and specifies the type of analysis conducted. The type of analysis
conducted would be selected from the following limited set of options:
``superiority,'' ``non-inferiority,'' ``equivalence,'' or ``other''
(which must also include a description of the analysis type). The
``other'' option would be appropriate for a single group analysis or
other descriptive statistics, for example. If the type of analysis
selected is ``non-inferiority'' or ``equivalence,'' the responsible
party is also required to provide a free-text description of key
parameters of the statistical analysis to include, at minimum,
information about the power calculation and the non-inferiority or
equivalence margin. An additional comment field is offered to provide
the responsible party with the opportunity to submit optional
additional information about the statistical analysis.
(2) The Responsible Party must provide either the Statistical Test
of Hypothesis or the Method of Estimation, as applicable. If the
statistical analysis performed cannot be submitted using the
Statistical Test of Hypothesis or Method of Estimation options, a
general ``other'' option is available for submitting any other
scientifically appropriate tests of statistical significance.
Statistical Test of Hypothesis consists of the p-value and the
procedure used for statistical analysis of the outcome data. For
convenience in specifying the procedure used for the statistical
analysis, ClinicalTrials.gov includes the following list of commonly
used statistical tests for calculating p-values from which responsible
parties may select: ``ANCOVA;'' ``ANOVA;'' ``Chi-squared;'' ``Chi-
squared, Corrected;'' ``Cochran-Mantel-Haenszel;'' ``Fisher Exact;''
``Kruskal-Wallis;'' ``Log Rank;'' ``Mantel Haenszel;'' ``McNemar;''
``Mixed Models Analysis;'' ``Regression, Cox;'' ``Regression, Linear;''
``Regression, Logistic;'' ``Sign Test;'' ``t-Test, 1-sided;'' ``t-Test,
2-sided;'' and ``Wilcoxon (Mann-Whitney).'' Responsible parties may
also select the ``other'' option and provide the name of another
method. Additional comment fields are available to provide the
responsible party with an opportunity to submit optional additional
information about the statistical test of hypothesis, such as a
description of the null hypothesis, adjustments for multiple
comparisons, a priori thresholds for statistical significance, and
degrees of freedom. Method of Estimation consists of the estimation
parameter, estimated value, and confidence interval (if calculated).
For convenience in describing Method of Estimation, ClinicalTrials.gov
includes the following list of more than a dozen commonly used
estimation parameters from which responsible parties may select: ``Cox
Proportional Hazard;'' ``Hazard Ratio (HR);'' ``Hazard Ratio, log;''
``Mean Difference (Final Values);'' ``Mean Difference (Net);'' ``Median
Difference (Final Values);'' ``Median Difference (Net);'' ``Odds Ratio
(OR);'' ``Odds Ratio, log;'' ``Risk Difference (RD);'' ``Risk Ratio
(RR);'' ``Risk Ratio, log;'' and ``Slope.'' Responsible parties may
also select the ``other'' and provide the name of another estimation
parameter. If a confidence interval was calculated, the responsible
party will submit the confidence level, indicate whether the confidence
interval is one-sided or two-sided, and provide the upper and/or lower
limits of the confidence interval. A responsible party could specify
that the confidence interval is one-sided and provide only the upper or
lower limit. If one of the limits of a two-sided confidence interval
cannot be calculated, the responsible party is required to specify that
limit as ``Not Available'' and provide a brief narrative explanation
(e.g., because an insufficient number of clinical trial participants
reached the event at the final time point for assessment). A
responsible party may also submit, on an optional basis, a dispersion
value. If a dispersion value is submitted, the responsible party is
required to specify the parameter of dispersion by selecting one of the
following options: ``standard deviation'' or ``standard error of the
mean.'' No ``other'' option for the parameter of dispersion is
available. An additional comment field is available to provide the
responsible party with an opportunity to submit optional additional
information about the method of estimation, such as the direction of
the comparison (e.g., for a relative risk). The requirements for
submitting statistical analysis information attempt to balance the
benefits of structured data with minimal narrative text with the need
to describe what was evaluated in the statistical analysis. For the
reasons discussed in section III.C., in addition to the information
specified above, responsible parties also have the option of
voluntarily submitting additional, free-text information in order to
provide a more complete description of the statistical analyses. This
free-text information should not include an interpretation of results
or conclusions, just a description of the statistical test(s)
conducted. Submitted statistical analyses are linked to each submitted
outcome measure. Although a responsible party is not limited in the
number of statistical analyses that can be submitted for each outcome
measure, only statistical analyses that rely on submitted outcome
measure information
[[Page 65090]]
and data can be described. Specifically, the requirement is limited to
statistical analyses that rely on the summary outcome information and
data submitted, including Outcome Measure Arm/Group Information,
Analysis Population Information, Outcome Measure Information, and
Outcome Measure Data. Statistical analyses that use data external to
the clinical trial or different analysis populations or are limited to
certain sub-groups would generally not meet this requirement unless,
for example, the summary sub-group data were submitted as part of the
primary or secondary outcome measure (e.g., using categories or
comparison groups).
In specifying requirements for outcome measures and statistical
analyses under Sec. 11.48(a)(3), two situations merit further
clarification. The first involves a clinical trial terminated before
data are collected for one or more of the pre-specified outcome
measures. Certain information is still required to be submitted for
outcome measures for which data were not collected. Under Sec.
11.48(a)(3)(ii) the responsible party would be required to submit the
Number of Participants Analyzed, which would be zero (``0'') for an
outcome measure for which no data were collected. The responsible party
is not required to submit the Measure Type and Measure of Dispersion or
Precision, and Unit of Measure data elements specified in Sec.
11.48(a)(3)(iii)(E) and (F), for any outcome measure for which data
were not collected but would be required to provide the other elements
of Outcome Measure Information specified in Sec. 11.48(a)(3)(iii)(A),
(B), (C), and (D). As specified in Sec. 11.48(a)(3)(iv), the
responsible party is not required to submit Outcome Measure Data for
the outcome measure(s) for which no data were collected but is required
to submit Outcome Measure Data for any other primary and secondary
outcomes for which data were collected. For terminated trials, the
responsible party must still meet the requirements specified in Sec.
11.48(a)(1), (2), and (4) for the submission of results information for
the Participant Flow, Demographic and baseline characteristics, and
Adverse event information modules. If a clinical trial enrolls no
participants, the information to be updated for the Enrollment data
element under Sec. 11.64(a) would be zero (``0'') and no results
information would be required to be submitted for that clinical trial.
The second situation involves a clinical trial for which outcome
measures are collected but the actual enrollment falls well below the
target enrollment. This could occur, for example, if a clinical trial
is terminated due to poor enrollment after only some participants are
enrolled but outcomes are measured. Even in such situations, collected
results information must be submitted to ClinicalTrials.gov as
specified in this rule (taking into account the privacy considerations
discussed in section III.C.16 of the NPRM preamble (79 FR 69591) if
actual enrollment is very small). The submission and posting of results
information for such a clinical trial would be consistent with section
402(j) of the PHS Act and provide a way of tracking the progress of the
clinical trial and demonstrating what happened to the human subjects
who were enrolled. If the clinical trial was terminated because of
safety concerns or efficacy, the results information would be of
considerable interest to users interested in human health and safety
information. In order to reduce the chances that users of
ClinicalTrials.gov might misinterpret submitted results information, we
encourage the responsible party to submit additional optional
information about the clinical trial in the Analysis Population
Description data element and/or in the Limitations and Caveats module
of ClinicalTrials.gov. This additional information could highlight that
enrollment in the clinical trial did not reach the target number of
subjects needed to achieve target power and was insufficient to produce
statistically reliable results. If the trial was terminated, the posted
study record will clearly reflect that the trial was terminated (i.e.,
the responsible party indicates Overall Recruitment Status as
``terminated''), and we intend to include information on the posted
study record to allow the public to easily see when actual enrollment
was below the target enrollment goals (using information from the
Enrollment data element and submitted expected and actual values). We
believe that this information will make it easier for the public to
consistently identify across studies when a trial was terminated and/or
actual enrollment was below the target enrollment goals. We expect
that, in most of these situations, no statistical analysis information
would be submitted for the affected outcome measure(s) because no
statistical analyses would have been performed or would be considered
scientifically appropriate.
Sec. 11.48(a)(4)--Adverse Event Information
Overview of Proposal
The proposal for submitting adverse event information in Sec.
11.48(a)(4) was based on the information required to complete the two
tables specified as additional results information in sections
402(j)(3)(I)(iii)(I) and (II) of the PHS Act, with modifications to
further assist users in understanding and interpreting submitted
adverse event information. Specifically, section 402(j)(3)(I)(i) of the
PHS Act requires the Secretary, by regulation, to ``determine the best
method for including in the registry and results data bank appropriate
results information on serious adverse and frequent adverse events for
applicable clinical trials . . . in a manner and form that is useful
and not misleading to patients, physicians, and scientists.'' Section
402(j)(3)(I)(ii) of the PHS Act specifies that if regulations are not
issued by the date that is 24 months after the date of the enactment of
FDAAA (i.e., by September 27, 2009), the requirement to submit results
information necessary to complete the two tables specified in sections
402(j)(3)(I)(iii)(I) and (II) of the PHS Act would take effect as
stated in section 402(j)(3)(I)(ii). The statutorily mandated adverse
event reporting provisions require the submission of two tables of
information, as follows: (1) ``[a] table of anticipated and
unanticipated serious adverse events grouped by organ system, with
number and frequency of such event in each arm of the clinical trial''
(section 402(j)(3)(I)(iii)(I) of the PHS Act), referred to hereinafter
as the ``serious adverse events table'' and (2) ``[a] table of
anticipated and unanticipated adverse events that are not included in
the [serious adverse events table] . . . that exceed a frequency of 5
percent within any arm of the clinical trial, grouped by organ system,
with number and frequency of such event in each arm of the clinical
trial'' (section 402(j)(3)(I)(iii)(II) of the PHS Act). In the NPRM and
in the ClinicalTrials.gov data bank, we refer to adverse events that do
not fit the definition of a serious adverse event as ``other adverse
events,'' and we refer to the adverse events table in item (2) above as
the ``other adverse events table'' (79 FR 69588).
Consistent with this section of the PHS Act, the Agency proposed in
Sec. 11.48(a)(4)(i) to require ``[i]nformation for completing two
tables summarizing adverse events collected during an applicable
clinical trial: (A) Table of all serious adverse events, grouped by
organ system, with the number and
[[Page 65091]]
frequency of each event by arm or comparison group; (B) Table of all
adverse events, other than serious adverse events, that exceed a
frequency of 5 percent within any arm of the clinical trial, grouped by
organ system, with the number and frequency of each event by arm or
comparison group.'' Proposed Sec. 11.48(a)(4)(ii) further specified
that information for each table must include the following: (A) Adverse
Event Arm/Comparison Group Information; (B) Total Number Affected by
Arm or Comparison Group; (C) Total Number at Risk by Arm or Comparison
Group; (D) Total Number Affected by Organ System; (E) Total Number at
Risk by Organ System; (F) Adverse Event Information, to include a
descriptive term for the adverse event and organ system associated with
the adverse event; (G) Adverse Event Data, to include for each adverse
event the number of human subjects affected and at risk; and (H)
Additional Adverse Event Description. The NPRM also indicated in
proposed Sec. 11.48(a)(4)(iii) that information provided by organ
system must be grouped using the organ system classification
established on ClinicalTrials.gov. These data elements (with the
exception of the new Total Number Affected by Organ System and Total
Number at Risk by Organ System data elements) were first made available
in September 2008 as optional data elements; they became required as of
September 27, 2009. The Additional Adverse Event Description data
element has been available as an optional data element since September
2008 (named Adverse Event Reporting Additional Description) with the
following other optional data elements: Time Frame for Adverse Event
Reporting, Assessment Type (i.e., collection approach), Source
Vocabulary Name (for specifying a standard vocabulary), and Number of
Events (for number of occurrences of an adverse event). The NPRM
proposal and request for comment on additional data elements was also
based on our operational experience with adverse event information
since 2008.
In section III.C.15 of the NPRM, we requested comments on all
aspects of the proposed requirements for submission of adverse event
information. This included considerations of the following: (1) Benefit
and burden of the proposed modifications to the statutorily mandated
adverse event reporting provisions (i.e., number of participants
affected and at risk for adverse events at the organ system level); (2)
benefit and burden of additional information considered but not
included in the proposal, including the time frame for collecting
adverse events, the collection approach (systematic or non-systematic),
all-cause mortality information, a standard vocabulary for submitted
adverse event terms, number of occurrences of an adverse event and
attribution of an adverse event to the intervention(s) under study; (3)
ways to reduce the data submission burden without reducing the value of
the data; and (4) approaches to increasing standardization in the
vocabularies used for adverse event information (79 FR 69591). The
Agency also specifically requested comments on whether the organ system
classification is sufficient and whether additional categories or an
``other'' option are necessary (79 FR 69644).
Comments and Response
Most of the commenters who addressed the requirements for adverse
event information were generally supportive of the requirements that
were consistent with current practice and the statutorily mandated
adverse event reporting provisions. Some commenters expressed support
for the proposal for adverse event information, including the
submission of additional information and the data elements on adverse
events on which we sought comment. One commenter expressed overall
support for the proposal but generally indicated that it is a change
from current practice in academic medical centers and expressed concern
about the burden of the requirements. Many commenters addressed issues
related to specific data elements and opposed the proposal to require
the submission of adverse event information aggregated by the total
number of participants affected and at risk for adverse events for each
organ system. Commenters expressed opposition to these requirements
because they considered the requirements to be beyond the statutorily
mandated adverse event reporting provisions and they questioned the
Agency's legal authority to require information not specified in those
provisions.
We first address the general issue of the Agency's legal authority
to require adverse event information not specified in the statutorily
mandated adverse event reporting provisions. The adverse event
information proposed to be required in Sec. 11.48(a)(4) is based on
the provisions in sections 402(j)(3)(I)(iii)(I) and (II) of the PHS
Act, with some modifications. We interpret the provision as providing
the Secretary with authority to modify the required information, by
regulation, under section 402(j)(3)(D)(v)(VI) of the PHS Act, which
specifies that the regulations shall establish ``additions or
modifications to the manner of reporting of the data elements
established under [section 402(j)(3)(C) of the PHS Act].'' Section
402(j)(3)(I)(v) of the PHS Act deems adverse event information to be
``clinical trial information included in [the] data bank pursuant to .
. . [section 402(j)(3)(C) of the PHS Act].'' We also interpret that
this clinical trial information is therefore included in the ``data
elements established under . . . [section 402(j)(3)(C) of the PHS
Act]'' referred to in section 402(j)(3)(D)(v)(VI) of the PHS Act.
Therefore, we conclude that the Secretary has the authority, under
section 402(j)(3)(D)(v)(VI) of the PHS Act, to modify the statutorily
mandated adverse event reporting provisions for the submission of
adverse event information via regulation, because such modifications
represent ``additions or modifications to the manner of reporting
[adverse event information] . . .''
The modifications to the statutorily mandated adverse event
reporting provisions in this final rule represent modifications to the
``manner of reporting'' required adverse event information. As
described above, section 402(j)(3)(D)(v)(VI) of the PHS Act authorizes
the Secretary to make ``additions or modifications to the manner of
reporting of the data elements established under [section 402(j)(3)(C)
of the PHS Act]'' by regulation. We interpret the ``manner of reporting
of the data elements'' to include specific content requirements for
reporting information in the categories of information under section
402(j)(3)(C) of the PHS Act. For example, section 402(j)(3)(C) of the
PHS Act identifies certain content requirements for data elements, such
as ``Primary and Secondary Outcomes.'' If the ``manner of reporting of
the data elements established under [section 402(j)(3)(C) of the PHS
Act]'' does not include the content requirements for these categories,
then ``additions or modifications'' would be strangely limited to
changing only how the information must be submitted (e.g., on paper or
electronically), not what information must be submitted. This
interpretation would leave us in the untenable situation, which we
believe was not Congress' intent, of having to limit ``additions or
modifications'' to changes only in how information must be submitted,
not to what information must be submitted. Section 402(j)(3)(I)(i) of
the PHS Act also informs this question by directing the Secretary
within 18 months to determine by
[[Page 65092]]
regulation ``the best method for including in the registry and results
data bank appropriate results information on serious adverse and
frequent adverse events . . . in a manner and form that is useful and
not misleading to patients, physicians, and scientists.'' Because the
``manner'' and ``form'' must be ``useful and not misleading,'' it would
not be reasonable to conclude that such regulations could only specify
the means of submitting and displaying the adverse event information,
but not the information content. Finally, we believe Congress intended
the Agency to have broad rulemaking authority to add to the information
requirements of the data bank, as demonstrated in section
402(j)(3)(D)(i) of the PHS Act, which directs that the data bank be
expanded by rulemaking ``[t]o provide more complete results information
and to enhance patient access to and understanding of the results of
clinical trials.'' In this section, we explain the modifications made
to the statutorily mandated adverse event reporting provisions and
clarify how these modifications represent ``additions or modifications
to the manner of reporting'' adverse event information.
Commenters were concerned about the burden of providing adverse
event information aggregated by the total number of participants
affected and at risk for adverse events for each organ system,
particularly for studies at academic medical centers and, in general,
because this information is not routinely summarized for adverse events
occurring during a trial. Some were concerned about adverse event data
being reported differently on ClinicalTrials.gov as compared to EMA,
FDA labeling, and other summary reports available on the FDA Web site
(e.g., 510(k) summary). One commenter was supportive of the proposal
only if it meant that all participants affected by an adverse event
(whether serious or not) would be summarized by system organ class.
Having considered the comments, the Agency is not including a
requirement in this final rule to submit the total number of
participants affected and at risk for adverse events by organ system.
This data element was proposed as a new requirement; it was not part of
other adverse event data elements that were implemented in 2009 as
optional or required information. The comments helped us understand the
extent to which such information is not routinely aggregated in this
manner and the potential burdens associated with the requirement. We
note that, in general, there will be differences between the
information reported on ClinicalTrials.gov and in other reports, such
as those submitted to FDA, because of differences in the underlying
statutory framework and the requirements of the related regulations and
elaborations provided in guidance.
There were comments on the proposal to provide adverse event
information by system organ class, based on the use of an organ system
classification established in ClinicalTrials.gov. Most of these
comments were in the context of the proposed requirement to summarize
the total number of participants affected and at risk for adverse
events for each organ system, which is not included in the final rule.
The NPRM preamble described this organ system classification as based
on the Medical Dictionary for Regulatory Affairs (MedDRA) [Ref. 99] (79
FR 69589) As a standardized medical terminology, MedDRA is used
internationally for the reporting of drug and biologic regulatory
information and was adopted by ICH [Ref. 100]. Commenters indicated
that at academic institutions there are not institution-wide systems
established for the collection of adverse event information in a
standard manner that would include MedDRA's organ system classification
and that investigator-sponsors may not have access to MedDRA. In
addition, commenters indicated that the requirements should be kept
simple and ``consistent with current practice.'' One commenter
requested an extended transition period for ongoing studies to allow
for the incorporation of MedDRA into their processes. Some commenters
also requested implementation of a new PRS feature to assist
investigators who are responsible parties in classifying adverse events
using MedDRA system organ classes. Although the final rule no longer
includes the proposal to require the total number of participants
affected and at risk by organ system, there is still a requirement to
provide, for each adverse event, the ``[o]rgan system associated with
the adverse event.''
The proposal to require this organ system information is derived
from the statutorily mandated adverse event reporting provisions that
specified that adverse events need to be ``grouped by organ system.''
The organ system classification used to describe a specific adverse
event submitted to ClinicalTrials.gov has been based on MedDRA organ
system classes since the adverse events module was made available in
September 2008 (and was required in September 2009). Thus, the final
rule is consistent with current practice. Our experience indicates that
responsible parties are able to use these classes effectively and that
a single set of organ system classes provides a consistent way to
display information about adverse events among the tables for a single
trial and across trials. We also note that there are publicly available
resources for mapping to MedDRA system organ classes, such as the NCI's
thesaurus [Ref. 101], ``a widely recognized standard for biomedical
coding and reference, used by a broad variety of public and private
partners both nationally and internationally including the Clinical
Data Interchange Standards Consortium Terminology (CDISC), the U.S.
Food and Drug Administration (FDA), the Federal Medication
Terminologies (FMT), and the National Council for Prescription Drug
Programs (NCPDP).'' In the final rule, to clarify the circumstances in
which the organ system is relevant, we have removed the general
provision from the codified that stated that the information ``must be
grouped according to the organ system classification established in
ClinicalTrials.gov.'' Instead, when submitting the organ system
associated with the adverse event, as specified in final Sec.
11.48(a)(4)(iii)(D)(2), the responsible party is required to select one
option describing the organ system from a list of options established
on ClinicalTrials.gov. This approach improves consistency with other
data elements in which the format (also described in Section IV.A.4) is
to select from menu options. The use of this particular list for organ
system class is based on our experience with voluntary and mandatory
adverse events submission since September 2008, which indicates that
responsible parties are able to use these classes effectively and that
a single set of organ system classes provides a consistent way to
display information about adverse events among the tables for a single
trial and across trials.
Two commenters indicated that, for certain trials of devices, the
protocol specifies adverse event reporting only for organ systems that
may be affected by the device. We note that we do not intend for these
regulations to result in requiring an investigator to collect adverse
event information of any type or in any way that is not specified in
the protocol. Therefore, if adverse events were collected for only some
organ systems, as pre-specified in the protocol, the responsible party
would need to submit only those adverse events to ClinicalTrials.gov.
The Additional Adverse Events Description data element (renamed
``Adverse Event
[[Page 65093]]
Reporting Description'' in the final rule) could be used to describe
the methods for adverse event collection, including any organ system
classes that were not evaluated. We also note that since the
publication of the NPRM, MedDRA version 19.0 was released, which
includes a new system organ class called ``product issues.'' We will
add this to the classification on ClinicalTrials.gov, bringing the
total number of organ system classes to 27. Although we requested
comments on whether an ``other'' option is necessary for the organ
system class, no specific comments were received.
Commenters requested that instead of the proposed requirement to
report other adverse events that exceed a frequency of 5 percent within
any arm of the clinical trial, the final rule require all other adverse
events to be reported (i.e., other adverse events that exceed a
frequency of 0 percent). These commenters were concerned that the 5
percent threshold for reporting other adverse events did not have a
clear scientific basis and potentially would allow some findings to go
unreported. Similarly, one commenter requested that ``all adverse
events occurring in five percent or more of patients across arms
receiving the investigational product'' be required to be reported,
based on a concern that if there are multiple arms with the
investigational product, the overall frequency of adverse events among
participants receiving the investigational product may be higher than 5
percent. Another commenter suggested that the 5 percent threshold could
be used for differentiating expected and unexpected adverse events. Our
proposal for reporting anticipated and unanticipated other adverse
events that exceed a frequency of 5 percent within any arm of the trial
is based on section 402(j)(3)(I)(iii)(II) of the PHS Act. As stated in
the NPRM (79 FR 69588), we will allow the submission of other adverse
events with a frequency of 5 percent or less on an optional basis, as
many responsible parties are currently doing. This allows responsible
parties to determine whether a threshold of 5 percent or less is
scientifically appropriate for their study. We believe that this
approach strikes an appropriate balance between the potential burden of
reporting all adverse events for all applicable clinical trials and the
scientific value of allowing responsible parties to report adverse
events occurring below the 5 percent threshold for a particular
clinical trial. If a responsible party chooses to report adverse events
that occur at a lower frequency (i.e., 5 percent or less), the specific
threshold must be identified (e.g., 3 percent) and used for reporting
all adverse events in each arm of the trial. This approach helps avoid
the type of reporting bias that occurs when the reporting threshold
varies by adverse event or by arm. Similarly, not permitting the
threshold to be higher than 5 percent, which is consistent with section
402(j)(3)(I)(iii)(II) of the PHS Act, avoids another type of reporting
bias that could occur if the threshold was allowed to be set at any
value (i.e., higher thresholds in some trials but not others could
exclude the submission of important adverse event information).
Therefore, we maintain the approach described in the NPRM to require
the reporting of all other adverse events, other than serious adverse
events, that exceed a frequency of 5 percent within any arm of the
clinical trial.
We invited comments on the benefits and burdens of requiring
additional adverse event information, including time frame, collection
approach, all-cause mortality information, and a standard vocabulary
for adverse event terms (79 FR 69590). Some commenters were in favor of
adding a requirement to submit the adverse event reporting time frame;
one reason given was that the provision of this information would help
avoid inappropriate comparisons across clinical trials that used
different time frames. We agree that the time frame is important for
comparing information across trials, and we note that it is also
important for interpreting clinical trial results information within
the context of a single trial, since the time frames for data
collection for primary outcome measures, secondary outcome measures,
and adverse events may all be different. Similarly, we note that Sec.
11.44(d) describes partial results information submission deadlines
based on when final data collection occurs for primary outcome
measures, secondary outcome measures, and additional adverse event
information. In this context, it is particularly important to have a
description of the adverse event reporting time frame so that it is
clear what time frame for assessment applies to adverse event
information submitted as partial results. In the NPRM, we noted that
responsible parties provided time frame information for more than half
of the results information submitted in 2012 for probable applicable
clinical trials (79 FR 69590). (See the explanation of probable
applicable clinical trial in section IV.B.2). In 2015, nearly 60
percent of results submitted for probable applicable clinical trials
included information for the time frame data element. Based on the
current use of this data element and the implications for interpreting
adverse event information in the context of a single clinical trial and
across trials, we are adding adverse event reporting time frame as a
requirement in the final rule. As explained in detail earlier in this
section, we consider this required information to represent a
modification to the ``manner of reporting'' in section
402(j)(3)(D)(v)(VI) of the PHS Act; the information helps elucidate the
adverse event information in the statutorily mandated reporting
provisions.
Commenters who addressed the issue of collection approach for
adverse event information were generally in favor of adding a
requirement to submit this information, suggesting that such contextual
information is important for interpreting the benefits and harms of an
intervention evaluated in a trial and for comparing adverse event
information across trials. Collection approach information includes an
indication of the type of approach taken to collect adverse event
information, either a systematic assessment or a non-systematic
assessment. In the NPRM, we explained that a ``systematic assessment''
involves the use of a specific method of ascertaining the presence of
an adverse event (e.g., the use of checklists, questionnaires,specific
laboratory tests at regular intervals), and a ``non-systematic
assessment'' relies on the spontaneous reporting of adverse events,
such as unprompted self-reporting by participants (79 FR 69590). [Ref.
102] One commenter suggested that the information be provided in a
free-text field (instead of as a binary indication) to allow the
responsible party to describe how adverse events were collected and
adjudicated. We acknowledge that this can be a complex issue; however,
we believe that the binary, structured indication of either a
systematic or non-systematic assessment provides users of
ClinicalTrials.gov with a consistent way of understanding what was done
in the clinical trial. We also note that the free-text field for
Adverse Event Reporting Description can be used by the responsible
party to describe the methods for adverse event collection and provide
any further details about adjudication. The submission of the protocol,
as described in Sec. 11.48(a)(5), also would typically provide
additional supporting information that is important for interpreting
the collection approach and the submitted adverse event information.
Another commenter requested clarification ``on the classification of
routine investigator assessment of adverse events (when an
[[Page 65094]]
investigator asks if the subject has had an adverse event) as a
Systematic Assessment.'' We interpret this routine investigator
assessment to mean that the investigator asks a general question about
whether a participant had any adverse events at prespecified intervals,
rather than more targeted questions about specific categories or types
of adverse events. We clarify that such a routine, general assessment
would be considered a ``non-systematic assessment.'' However, if more
specific questions were asked about adverse events at regular
intervals, this approach could be considered a ``systematic
assessment.'' We agree with the commenters that knowledge of the
collection approach affects comparability of information across
clinical trials and we believe that such information is similarly
important for interpreting adverse event information for a single
clinical trial. As we noted in the NPRM, clinical trials using non-
systematic assessment approaches typically record fewer adverse events
than those using a systematic assessment approach [Ref. 102]. We also
noted in the NPRM that, of the results for probable applicable clinical
trials submitted to ClinicalTrials.gov in 2012, 76 percent voluntarily
included information about the approach to collecting adverse events
(79 FR 69590). In 2015, reporting was about the same, with 74 percent
of results submitted for probable applicable clinical trials including
information on the collection approach for adverse events. Based on the
current use of this data element and the importance of this information
for interpreting adverse event information, we require this information
in the final rule. As explained in detail earlier in this section, this
required information constitutes a modification to the ``manner of
reporting'' in section 402(j)(3)(D)(v)(VI) of the PHS Act; this
information helps elucidate the adverse event information in the
statutorily mandated adverse event reporting provisions.
Commenters who addressed the topic of including all-cause mortality
information supported requiring the submission of such information,
with the exception of one commenter. Commenters who supported the
requirement stated that accurate information about the number of deaths
in each arm of the clinical trial was critical for interpreting the
trial's results. One of these commenters suggested that it would be
misleading to have a statement specific to all-cause mortality
information that explains that deaths may not be related to the
intervention evaluated because this is actually what randomized trials
are designed to understand. In addition, if there were such a
statement, it would apply equally to other results, including outcomes.
Some commenters (including some who supported the requirement)
expressed concern about the interpretation of all-cause mortality
information, particularly in the absence of information about
attribution (i.e., whether the deaths were considered related to the
intervention). The commenter opposed to the requirement expressed
concern that the reporting of all-cause mortality information would
increase the risk of re-identification of participants in the clinical
trial, leading to requests for waivers of the clinical trial results
information submission requirements, but the commenter did not provide
further explanation of how the risk of re-identification would
increase.
We have considered these comments and require in the final rule the
submission of all-cause mortality information in addition to the
serious adverse events and other adverse events tables. This required
information constitutes a modification to the ``manner of reporting''
in section 402(j)(3)(D)(v)(VI) of the PHS Act; this information helps
elucidate the adverse event information in the statutorily mandated
adverse event reporting provisions. Specifically, although other
clinical trial results information may include information about
deaths, the total number of deaths that occurred during the clinical
trial might not be readily apparent (e.g., submitted serious adverse
event information indicates the number of subjects who experienced a
myocardial infarction, but it would not necessarily indicate how many
of the subjects died from the event).
As noted in the NPRM, submission of all-cause mortality information
would be consistent with other clinical trial reporting guidelines (79
FR 69590) [Ref. 56, 103]. The all-cause mortality information is
described in Sec. 11.48(a)(4)(ii) of the final rule as being provided
by the responsible party in a separate table. This approach allows the
responsible party to use the Adverse Event Arm/Group Information as the
table columns and, for each arm/group (i.e., separate column), to
specify the overall number of human subjects affected by death due to
any cause and the overall number of human subjects included in the
assessment as a table row. The information will then be displayed as a
row in the serious adverse events table in the posted study record. As
with serious and other adverse event information, we will make
available an optional data element for providing descriptive
information that the responsible party deems appropriate.
We acknowledge the concerns expressed by some of the commenters
about potential misinterpretation of adverse event information. To
address those concerns, we intend to provide standard explanatory
information on each posted record that will help the public understand
the definition of ``all-cause mortality'' and that will further explain
that all-cause mortality information, serious adverse events, and other
adverse events appearing on ClinicalTrials.gov are generally reported
regardless of attribution. Similarly, in the context of all results
information, a standard statement on the posted record will indicate
that results of a single clinical trial may not be representative of
the overall efficacy and safety profile of the product and that the
FDA-approved product labeling should be consulted for information for
approved drug products (including biological products) and device
products. In response to the comment about waivers, we note that the
NPRM indicated that a high risk of re-identification would be an
appropriate reason for requesting that the requirement for submitting
all-cause mortality information be waived, using the process described
in proposed Sec. 11.54. However, because adverse event information is
summary data provided in aggregate, we expect that waivers would be
requested and granted in a very limited number of situations.
Comments were mixed on the issue of whether attribution of an
adverse event to a specific intervention evaluated in a study should be
provided. Some commenters were opposed to providing information about
attribution because of a lack of consensus about the optimal
methodology for making such determinations, leading to concerns about
the potential for tremendous variability and subjectivity across
clinical trials regarding how decisions about attribution were made.
Commenters indicated that attribution can only be assessed after a
trial is completed (e.g., by comparing rates of events across arms of
the clinical trial), and even then, decisions about attribution based
on a single clinical trial may be incorrect. Similarly, one of these
commenters cited FDA guidance to reviewers that instructs them to
``discount'' attribution information [Ref. 104]. One commenter
suggested that because of the challenges in correctly assigning
attribution, such information should be prohibited. One commenter
suggested that a disclaimer be added to adverse event information to
explain
[[Page 65095]]
that the data do not necessarily reflect a conclusion by the sponsor or
FDA that the event was caused or contributed to by the intervention.
Some commenters were in favor of the submission of attribution
information because they thought it was necessary to prevent
misunderstandings about the safety of study interventions, including
devices, and the risks of trial participation. One commenter indicated
that the requirements for adverse event submission should be limited to
only those serious adverse events and adverse events considered related
to the intervention. In addition to the concerns raised by the
commenters, we note that providing information on attribution would add
an additional burden on responsible parties. Given the challenges
described by commenters in accurately assigning attribution within the
context of a single clinical trial, as well as similar concerns that we
raised in the NPRM (79 FR 69589), we are not including attribution
information in the final rule. We recognize that the monitoring of
adverse events during a clinical trial has an important role in
identifying the risks and benefits for human subjects participating in
the clinical trial. [Ref. 105]. Attempts to determine attribution of an
intervention to each individual adverse event, however, may be
subjective (and potentially misleading), particularly after study
completion when aggregate adverse event information is available to
make objective quantitative assessments of the potential attribution of
the intervention to the adverse event. [Ref. 106, 107, 108]. As noted
in the discussion for all-cause mortality, we intend to include a
standard statement on ClinicalTrials.gov to help the public understand
that all-cause mortality information, serious adverse events, and other
adverse events are generally reported regardless of attribution. We
received one comment in support of requiring the submission of the
number of occurrences of an adverse event (in addition to the number of
participants affected by the adverse event). This optional data element
has been available to responsible parties since the adverse events
module was released in September 2008, and we will continue to make it
available as an optional data element.
A few commenters addressed the topic of whether we should require
the submission of adverse event terms using a standard vocabulary. One
of the commenters was opposed, citing in particular the burden that
would be imposed if that particular vocabulary had not been used in a
trial from the outset. Another commenter recommended that a standard
vocabulary for adverse events be used, noting that emerging
technologies could potentially take advantage of standard
terminologies. We also interpret many of the comments received on using
the MedDRA classification system for summarizing the total number of
participants affected and at risk for adverse events by organ system as
opposition to requiring a specific vocabulary. We did not receive any
other suggested approaches for standardizing the vocabularies used for
adverse event information. Taking into consideration the burden and the
potential for this requirement to cause a responsible party to report
or collect adverse event information in any way that is not specified
in the protocol, we do not include in the final rule a requirement to
submit adverse event terms using a standard vocabulary. We will,
however, continue to provide optional data elements to allow
responsible parties to describe the standard vocabulary that was used,
if applicable.
We also received some comments in response to our request for
additional input on ways to reduce the data submission burden without
reducing the value of the data. Commenters requested tools (in addition
to XML) for uploading datasets for the adverse event tables. In the
preamble of this final rule describing the format required for
submitting clinical trial information in Sec. 11.8, we note that the
PRS has allowed the submission of adverse event information in a
spreadsheet format (e.g., Microsoft Excel) since 2013. We will continue
to support uploading of adverse event information that uses this format
and meets the technical specifications.
Some commenters suggested that the regulations explicitly state
that only adverse event information collected ``per protocol'' is
required to be submitted. The requirements in the final rule are not
intended to cause an investigator to collect information of a type or
in a way not specified in the protocol. However, situations may arise
during the conduct of a trial in which the responsible party collects
and reports certain relevant adverse events that were not anticipated
in the protocol and/or that occur in participants thus not following
the protocol. Therefore, we maintain the proposed language in the final
rule (i.e., ``collected during'') to cover all relevant situations. But
we reiterate that the requirements in the final rule do not impose data
collection requirements for an applicable clinical trial. One commenter
suggested that adverse event information requirements should be less
rigorous for products not being conducted under an IND/IDE because the
safety and efficacy has already been established. We do not agree that
the reporting of adverse event information for clinical trials not
being conducted under an IND/IDE should be less rigorous. We believe
that the purpose of the ClinicalTrials.gov database to make information
available to the public is best achieved by requiring the same adverse
event reporting requirements for all applicable clinical trials.
Final Rule
Final Sec. 11.48(a)(4) generally maintains the NPRM approach, but
we are making the following changes in the final rule: First, we remove
the proposed requirement that the overall number of participants
affected and at risk, by arm or comparison group, be reported by organ
system class. Second, we add a requirement to submit all-cause
mortality information by arm or comparison group. Third, we add a
requirement to provide the time frame for adverse event data
collection. Fourth, we add a requirement to provide the collection
approach (systematic or non-systematic) for adverse events. In
addition, in developing the final rule we have identified a few issues
that would benefit from further clarification, based on our operational
experience and routine queries from users. Specifically, we are
clarifying the additional information required to be provided including
a brief description of each arm/group (a similar omission was described
for Sec. 11.48(a)(1), (2), and (3)). We have renamed the proposed
Additional Adverse Event Description data element to ``Adverse Event
Reporting Description'' and included it as Sec. 11.48(4)(i)(B) with
the other requirements added in the final rule (i.e., Time Frame and
Collection Approach) that also pertain to information about methods for
adverse event collection. In addition, this name change is intended to
reduce the potential for misinterpreting the data element as relating
to a specific adverse event, rather than to definitions related to
adverse event reporting overall. The change also better aligns the name
of this data element with the optional data element in place on
ClinicalTrials.gov prior to the final rule.[Ref. 97]. In addition,
minor changes have been made for consistency with terms used in the
statute and with similar data items in Demographic and baseline
characteristics specified in Sec. 11.48(a)(2) and Outcomes and
statistical analyses in Sec. 11.48(a)(3).
[[Page 65096]]
Final Sec. 11.48(a)(4) requires the submission of summary
information on anticipated and unanticipated adverse events that
occurred during an applicable clinical trial. This includes a table of
all serious adverse events; a table of adverse events other than
serious adverse events that exceed a frequency of 5 percent within any
arm of the clinical trial; and a table of all-cause mortality
information, which will be displayed as a row in the serious adverse
event table. Such information is considered part of results
information. The requirements derive from the statutorily mandated
adverse event reporting provisions in sections 402(j)(3)(I)(ii)-(iii)
of the PHS Act and include the following additional requirements
intended to assist users in understanding and interpreting the
submitted adverse event information: Arm/group description, adverse
event reporting description, time frame, collection approach, and all-
cause mortality information.
We interpret modifications to the ``manner of reporting'' in
section 402(j)(3)(d)(v)(VI) of the PHS Act to include, among other
things, information that helps elucidate the adverse event information
required by the statutorily mandated adverse event reporting
provisions. The definitions of ``adverse event'' and ``serious adverse
event'' are provided in Sec. 11.10(a).
Final Sec. 11.48(a)(4)(i) requires the responsible party to submit
information that describes the methods for collecting adverse event
information. The Time Frame data element, as specified in Sec.
11.48(a)(i)(A), describes the time period over which the submitted
adverse event information was collected as well the overall period of
time for which additional adverse event information was, is being, or
will be collected (e.g., primary outcome measure data and adverse
events collected over the same time period as the primary outcome are
submitted, but secondary outcome measure and additional adverse event
data collection is ongoing). Similar to the information provided for
outcome measures on the time points of assessment (Sec.
11.48(a)(3)(iii)(C)), the time frame for adverse event reporting is
generally the specific duration of time over which each human subject
is assessed for adverse events. Time frame information is a ``manner of
reporting'' adverse event information and helps elucidate the adverse
event information required by the statutorily mandated adverse event
reporting provisions.
In cases in which the protocol specifies the collection of only a
limited set of adverse events (e.g., unanticipated adverse reactions),
the responsible party is still required to submit three tables of
information that summarize the information collected during the
clinical trial with respect to serious adverse events, other adverse
events (other than serious adverse events) that exceed a frequency of 5
percent within any arm of the trial, and all-cause mortality. The all-
cause mortality information will be displayed as a row in the serious
adverse event table. As specified in Sec. 11.48(a)(4)(i)(B), if the
adverse event information collected in the trial is collected based on
a definition of ``adverse event'' and/or ``serious adverse event'' that
is diffrerent from the definitions in Sec. 11.10(a), the responsible
party must use the Adverse Event Reporting Description data element to
explain the differences. Similarly, the responsible party must use the
Adverse Event Reporting Description data element to explain whether
these definitional differences include adverse event collection methods
that exclude certain types of adverse events required to be reported in
Sec. 11.48(a)(4) (e.g., protocol specified that other adverse events
are not to be collected, only serious adverse events are collected).
This explanation facilitates the understanding of required adverse
event information in situations where different definitions or methods
of collection are used. Adverse Event Reporting Description constitutes
a ``manner of reporting'' adverse event information that facilitates
understanding the nature of the events being reported. Responsible
parties may also use the Adverse Event Reporting Description data
element, on an optional basis, to provide general information that they
deem important for explaining methods of adverse event collection and
reporting, including additional details about the collection approach.
Collection Approach, specified in Sec. 11.48(a)(i)(C), allows the
responsible party to identify whether a ``systematic assessment'' or
``non-systematic assessment'' approach was taken to collect adverse
event information during the trial. Responsible parties must specify
the assessment type for adverse event information as a whole or for
each adverse event in each table. Systematic assessment involves the
use of a specific method of ascertaining the presence of an adverse
event (e.g., the use of checklists, questionnaires, or specific
laboratory tests at regular intervals). Non-systematic assessment
relies on spontaneous reporting of adverse events, such as unprompted
self-reporting by participants. This information explains how the
statutorily mandated adverse event information was obtained and
constitutes a ``manner of reporting'' this information authorized to be
required by section 402(j)(3)(D)(v)(VI) of the PHS Act. We note that
the requirements are not intended to cause an investigator to collect
adverse event information of any type or in any way not specified in
the protocol.
Final Sec. 11.48(a)(4)(ii) specifies that responsible parties must
submit three tables summarizing information on all serious adverse
events, other adverse events with a frequency higher than 5 percent in
any arm or comparison group of the clinical trial, and all-cause
mortality. Final Sec. 11.48(a)(4)(iii) specifies that there must be a
description of each arm or comparison group for which adverse event
information was collected and the overall number of human subjects
affected by and at risk must be described for each of the following
tables: (1) Serious adverse events, (2) adverse events other than
serious adverse events that exceed a frequency threshold of 5 percent
within any arm, and (3) deaths due to any cause. We note that the death
of a human subject could be reflected in information included in the
serious adverse event table and in the all-cause mortality table. For
example, a death separately identified in the serious adverse event
table with a descriptive term for the adverse event such as
``myocardial infarction'' (as specified Sec. 11.48(a)(4)(iii)(D)(1))
would also be included in the overall number of human subjects affected
in the all-cause mortality table. The all-cause mortality information
required by this rule is simply another meaningful way to aggregate and
report one important type of serious adverse event (i.e., those that
led to death). The all-cause mortality information is a ``manner of
reporting'' the adverse event information authorized to be required by
section 402(j)(3)(D)(v)(VI) of the PHS Act.
The arm and comparison group information is provided once by the
responsible party and is used for all three tables. As similarly
discussed in this section under Demographic and baseline
characteristics and Outcomes and statistical analyses, the Adverse
Event Arm/Group Information data element describes the grouping of
human subjects for the purposes of summarizing adverse event
information. These descriptions are necessary to understand the
statutorily mandated adverse event reporting information. Adverse Event
Arm/Group Information is another ``manner of reporting'' the
[[Page 65097]]
adverse event information authorized to be required by section
402(j)(3)(D)(v)(IV) of the PHS Act. ClinicalTrials.gov will use the Arm
Information, Intervention Name, and Intervention Description data
elements (submitted as clinical trial registration information), as
well as Participant Flow Arm Information, Baseline Characteristics Arm/
Group Information, and Outcome Measure Arm/Group Information, to
provide the responsible party with options for pre-populating table
column names and descriptions for Adverse Event Arm/Group Information.
The responsible party must review and edit the information as needed to
ensure that it appropriately and accurately reflects the adverse event
arms/groups for the clinical trial, or the responsible party may
instead define new groups to reflect how adverse event information was
analyzed. As described in the discussion of the term ``comparison
group'' in Sec. 11.10(a) of the preamble, the reference to comparison
group recognizes that when data collected during clinical trials are
analyzed, the data are often aggregated into groupings of human
subjects (i.e., comparison groups) other than the arms to which the
subjects were assigned for the study. It is expected that Adverse Event
Arm/Group Information will be the same as Participant Flow Arm
Information, unless human subjects were analyzed in groups that are
different from those to which they were assigned. In this situation,
there must be sufficient detail to understand how the arm(s) or
comparison groups used for submitting adverse events were derived from
Participant Flow Arm Information. In general, Adverse Event Arm/Group
Information must be inclusive of all arms or comparison groups, based
on the pre-specified protocol and/or SAP. Adverse Event Arm/Group
Information must also include sufficient details to understand the
intervention strategy being described for that arm/group, similar to
that which is described in Sec. 11.48(a)(1) for Participant Flow Arm
Information.
For each of the serious and other adverse events tables described
in Sec. 11.48(a)(4)(ii)(A) and (B), respectively, the responsible
party must provide a descriptive term for each serious adverse event
and other adverse event with a frequency higher than 5 percent in any
arm of the clinical trial (Sec. 11.48(a)(4)(iii)(D)(1)), along with
the organ system that is associated with the adverse event (Sec.
11.48(a)(4)(iii)(D)(2)), number of participants experiencing the
adverse event (Sec. 11.48(a)(4)(iii)(E)(1)), and number of
participants at risk for the adverse event (Sec.
11.48(a)(4)(iii)(E)(2)). In most cases, the number of participants at
risk for the adverse event will equal the number of participants who
started that arm of the clinical trial. However, the number of
participants at risk could differ if, for example, participants were
assigned to an arm but did not receive the intervention (e.g., because
they dropped out of the clinical trial) or because a comparison group
combines participants from multiple arms of the trial. The number of
participants at risk for each adverse event will generally be the same
as the overall number of participants at risk in the arm or comparison
group. To minimize the burden of data entry, the overall number of
participants at risk will be pre-populated for each adverse event term.
However, if these numbers are not the same (e.g., certain adverse
events were only systematically evaluated in a sub-group of human
subjects enrolled in the clinical trial), the responsible party can
modify the number of participants at risk for each adverse event, as
needed. Using the data submitted for the number of participants that
experienced the adverse event and the number of participants at risk,
ClinicalTrials.gov will automatically calculate the frequency
(percentage of participants who experienced the event). This approach
helps reduce calculation errors and helps users interpret the frequency
information in those cases in which the full study population may not
have been at risk for a specific adverse event or when the number of
participants at risk is different across comparison groups.
Adverse events described in Sec. 11.48(a)(4)(iii)(D)(1) must be
submitted with an indication of the organ system associated with the
adverse event (as described in Sec. 11.48(a)(4)(iii)(D)(2)) using the
classification scheme specified on ClinicalTrials.gov, which includes
the following 27 items adapted from the MedDRA version 19.0: Blood and
lymphatic system disorders; Cardiac disorders; Congenital, familial and
genetic disorders; Ear and labyrinth disorders; Endocrine disorders;
Eye disorders; Gastrointestinal disorders; General disorders;
Hepatobiliary disorders; Immune system disorders; Infections and
infestations; Injury, poisoning and procedural complications;
Investigations; Metabolism and nutrition disorders; Musculoskeletal and
connective tissue disorders; Neoplasms benign, malignant and
unspecified (including cysts and polyps); Nervous system disorders;
Pregnancy, puerperium and perinatal conditions; Product issues;
Psychiatric disorders; Renal and urinary disorders; Reproductive system
and breast disorders; Respiratory, thoracic and mediastinal disorders;
Skin and subcutaneous tissue disorders; Social circumstances; Surgical
and medical procedures; and Vascular disorders organ classes [Ref. 99].
No ``other'' option is included. ``Product issues'' is not an organ
class (like most of the other categories), but this term is used in
MedDRA for issues with ``product quality, devices, product
manufacturing and quality systems, supply and distribution, and
counterfeit products'' [Ref. 109]. ``Social circumstances'' is also not
an organ class but is used in MedDRA to accommodate the classification
of some types of adverse events that are not specific to an organ
system, such as an automobile accident, a homicide, or a fall. Adverse
events that affect multiple systems must be reported only once (to
avoid over-counting), preferably under the organ system class that is
considered primary. If there is no primary organ system class, the
event should be listed under ``General disorders,'' and additional
information may be provided in the optional free-text field, Adverse
Event Term Additional Description.
Finally, we note that the Agency interprets section 402(j)(3)(I)(v)
of the PHS Act to deem the adverse event information required under
section 402(j)(3)(I) of the PHS Act as clinical trial results
information not only for all applicable clinical trials but also for
all voluntarily-submitted clinical trials under section 402(j)(4)(A) of
the PHS Act. Therefore, responsible parties who submit clinical trial
information subject to section 402(j)(4)(A) of the PHS Act must submit
adverse event information in accordance with Sec. 11.48(a)(4).
Additional information on the clinical trial information requirements
for voluntarily-submitted clinical trials under section 402(j)(4)(A) of
the PHS Act, is described in Section IV.D.1.
Sec. 11.48(a)(5)--Protocol and Statistical Analysis Plan
Section 11.48(a)(5) adds a requirement to submit the protocol and
statistical analysis plan as part of clinical trial results
information. The proposal, comments and response, and final rule
requirements are discussed in detail in Section III.D.
Sec. 11.48(a)(6)--Administrative Information
Overview of Proposal
Proposed Sec. 11.48(a)(5)(i) implemented section 402(j)(3)(C)(iii)
of the PHS Act,
[[Page 65098]]
which requires that ``a point of contact for scientific information
about the clinical trial results'' be submitted as part of clinical
trial results information, and specified the submission of the
following information to allow users of ClinicalTrials.gov to inquire
about the results of a clinical trial: (1) Name or official title of
the point of contact, (2) name of affiliated organization, and (3)
telephone number and email address of the point of contact (79 FR
69644). This proposal reflects the Results Point of Contact data
element used on ClinicalTrials.gov since the results database was first
launched in September 2008 [Ref. 97].
Proposed Sec. 11.48(a)(5)(ii) implemented section 402(j)(3)(C)(iv)
of the PHS Act, which requires responsible parties to indicate
``whether there exists an agreement . . . between the sponsor or its
agent and the principal investigator . . . that restricts in any manner
the ability of the principal investigator, after the primary completion
date of the trial, to discuss the results of the trial at a scientific
meeting or any other public or private forum, or to publish in a
scientific or academic journal information concerning the results of
the trial.'' The statutory provision also provides that this
requirement does not apply to an agreement between a sponsor or its
agent and the principal investigator solely to comply with applicable
provisions of law protecting the privacy of participants in the
clinical trial. We explained in the proposed rule preamble that in
accordance with proposed Sec. 11.48(a)(5)(ii), we required responsible
parties to indicate (yes/no) whether the principal investigator is an
employee of the sponsor. If the principal investigator is an employee
of the sponsor (yes), no further information must be provided, although
it may be provided voluntarily. If the principal investigator is not
(no), the responsible party would be required to indicate (yes/no)
whether an agreement (other than one solely to comply with applicable
provisions of law protecting the privacy of human subjects
participating in the clinical trial) exists between the sponsor or its
agent and the principal investigator that restricts in any manner the
ability of the principal investigator, after the primary completion
date of the clinical trial, to discuss the results of the clinical
trial at a scientific meeting or any other public or private forum or
to publish in a scientific or academic journal information concerning
the results of the clinical trial. We also proposed to permit
responsible parties to provide additional optional information about
existing agreements. The proposal reflected the Certain Agreements data
element used on ClinicalTrials.gov since the results component of the
database was first launched in September 2008 [Ref. 97]. We invited
public comment on the proposed approach, on any experience to date with
the current approach, and on other information that might be collected
on a voluntary basis (e.g., types of principal investigator disclosure
restrictions) (79 FR 69644).
Comments and Response
Regarding the results point of contact in proposed Sec.
11.48(a)(5)(i), a few commenters suggested that the final rule not
require the submission and posting of information that would identify
an individual employee. One commenter proposed to instead require a
general facility email address or contact form. We generally agree with
these comments and note that the proposed approach, which is retained
in the final rule, did not require the disclosure of an individual's
name or specific contact information, but permitted the use of an
official title and a general organizational phone number or email
address. While the name of a specific individual and contact
information for that individual are not required, a responsible party
must provide sufficient information to allow users to reach a contact
able to provide additional scientific information about the clinical
trial results found on a posted record.
Some commenters addressed the certain agreements provision in
proposed Sec. 11.48(a)(5)(ii). One commenter suggested the addition of
another category to the existing three optional choices currently
available on ClinicalTrials.gov, to help viewers understand
restrictions related to multi-site trials. For example, a sponsor may
limit or prohibit individual-site principal investigators from
disclosing single-site results before the overall results aggregated
from all sites of a multi-center trial are disclosed. Another commenter
proposed that such agreements be nullified in the event that clinical
trial information submitted by a sponsor without the consent or
knowledge of the principal investigator is found to be misrepresented
or in the event of any legal proceedings arising from false or
misleading data. In response to the first commenter, the Agency will
consider the suggestion when deciding in the future whether to modify
or restructure the optional principal investigator Disclosure
Restriction Type component of the Certain Agreements data element. In
response to the second commenter, the legal status of agreements
between a sponsor or its agent and the principal investigator is
outside the scope of this rulemaking. Final Sec. 11.48(a)(6)(ii)
provides the mechanism for mandatory reporting of the existence of such
agreements for applicable clinical trials under this part.
Final Rule
Taking into consideration the commenters' suggestions and the
statutory requirements for the submission of additional components of
clinical trial results information, the final rule maintains the
approach proposed in Sec. 11.48(a)(5). Final Sec. 11.48(a)(6)(i)
requires the submission of the following information for a point of
contact for scientific information about the results information for a
clinical trial: Name or official title, name of the affiliated
organization, and the telephone number and email address. We note that
point of contact information is required to be submitted even if it is
the same as the information for the responsible party, because we do
not plan to make public the responsible party's contact information.
Final Sec. 11.48(a)(6)(ii) requires the submission of information
about certain agreements between the principal investigator and the
sponsor. The responsible party must indicate whether the principal
investigator is an employee of the sponsor. If the principal
investigator is not an employee, the responsible party must indicate
whether any agreement exists that restricts the principal investigator
from disclosing the results of the clinical trial after the primary
completion date. Consistent with the definition of ``principal
investigator'' in Sec. 11.10, we interpret this provision as applying
to a principal investigator who has oversight of the entire applicable
clinical trial, not to site-specific investigators or other
investigators (such as those on grant-funded studies) who may be
referred to as principal investigators in other contexts but who do not
meet the definition of ``principal investigator'' under this part. We
clarify that when the responsible party for a clinical trial is a
sponsor-investigator, for the purposes of submitting information about
certain agreements in Sec. 11.48(a)(6)(ii), we interpret that the
sponsor-investigator is both the sponsor and the principal investigator
and is therefore considered an employee of the sponsor for the purposes
of this section. We also clarify that the information about certain
agreements that is required to be submitted under this regulation must
accurately represent the status at the time of initial results
[[Page 65099]]
information submission, and if that information has changed since the
previous submission of partial clinical trial results information, the
responsible party must submit information to reflect the new status of
certain agreements between the principal investigator and the sponsor
at the time of the subsequent submission of partial results
information, in accordance with Sec. 11.44(d)(3)(ii). For example, if
the principal investigator had been an employee of the sponsor prior to
results information submission but is no longer employed by the sponsor
at the time of initial results information submission, the principal
investigator would not be considered an employee of the sponsor for the
purposes of submitting partial results information about certain
agreements. However, if the principal investigator's employment status
subsequently changes and he or she becomes an employee of the sponsor
prior to the submission of final results information, the certain
agreements information would need to be included when submitting
partial results information as specified in Sec. 11.44(d)(3)(ii). Note
that the Certain Agreements results data element specified in Sec.
11.48(a)(6)(ii) is excluded from the update requirements specified in
Sec. 11.64(a)(2).
Additionally, in our interactions with responsible parties and
consultations with stakeholders, we have learned that certain
agreements of the nature described in section 402(j)(3)(C)(iv) of the
PHS Act are routine in the clinical trials community, although they may
vary in their terms and the duration of their limitations on the
principal investigator. Such agreements, as we understand them,
typically permit the sponsor or its delegate to review results
communications prior to public release and impose a short-term embargo
of 60 days or less, from the date that the communication is submitted
to the sponsor for review, although other agreements may impose
restrictions that are much longer in duration or broader in scope [Ref.
110]. In order to allow responsible parties to provide additional
information about the agreements in place between the sponsor or its
delegate and the principal investigator, we permit the submission of
optional, structured information about the agreement. These optional
data elements, which are separate and distinct from the two data
elements required as part of clinical trial results information, as
previously discussed, are: (1) Whether the principal investigator is an
employee of the sponsor and, if not, (2) whether any agreement exists
that restricts the principal investigator from discussing or publishing
the results of the clinical trial after the primary completion date.
Thus, currently on ClinicalTrials.gov, a responsible party who wishes
to provide this additional information may choose from among the
following:
(1) The only disclosure restriction on the principal investigator
is that the sponsor can review results communications prior to public
release and can embargo communications regarding clinical trial results
for a period that is less than or equal to 60 days from the date that
the communication is submitted to the sponsor for review. The sponsor
cannot require changes to the communication and cannot unilaterally
extend the embargo.
(2) The only disclosure restriction on the principal investigator
is that the sponsor can review results communications prior to public
release and can embargo communications regarding clinical trial results
for a period that is more than 60 days but less than or equal to 180
days from the date that the communication is submitted to the sponsor
for review. The sponsor cannot require changes to the communication and
cannot unilaterally extend the embargo.
(3) Other disclosure agreement that restricts the right of the
principal investigator to disclose, discuss or publish clinical trial
results after the trial is completed. The responsible party may provide
an additional description of the disclosure agreement.
Based on our experience operating ClinicalTrials.gov, the usage of
these optional responses suggests that they provide an acceptable way
to describe these agreements in a consistent format. These categories
of optional information may be modified over time to reflect
information that we learn about changes in clinical trials practice or
to provide other information of interest to users. As permitted by law,
we may make these changes without notice and comment rulemaking.
However, we will provide prior notice and seek public comment on any
proposed changes of a substantive nature to the format of required
results information submission information (see Sec. 11.8 and the
discussion in Section IV.A.4 of this preamble).
Sec. 11.48(a)(7)--Additional Clinical Trial Results Information for
Applicable Device Clinical Trials of Unapproved or Uncleared Device
Products
Overview of Proposal
Proposed Sec. 11.48(a)(6)(i) enumerated additional descriptive
information that responsible parties would need to submit as part of
the clinical trial results information for applicable device clinical
trials of unapproved or uncleared devices for display on the posted
record. For applicable device clinical trials of unapproved or
uncleared devices subject to delayed posting of registration
information in proposed Sec. 11.35(b)(2)(i), the results information
specified in proposed Sec. 11.48(a)(1) through (5) can be submitted as
specified in proposed Sec. 11.44(c) and publicly posted as required by
proposed Sec. 11.52 prior to the date on which clinical trial
registration information is publicly posted (79 FR 69645).
In proposing Sec. 11.48(a)(6)(i), we exercised the authority
granted under sections 402(j)(3)(D)(ii)(II) and 402(j)(3)(D)(iii) of
the PHS Act to require responsible parties of applicable device
clinical trials of unapproved or uncleared devices to submit, as part
of results information, certain additional descriptive information that
is similar to the type of information submitted at the time of
registration. In particular, section 402(j)(3)(D)(ii)(II) of the PHS
Act authorizes the Secretary to determine through rulemaking whether
responsible parties for applicable clinical trials of unapproved
products would be subject to the results information submission
requirements under proposed subpart C. Additionally, section
402(j)(3)(D)(iii)(IV) of the PHS Act grants the Secretary wide
discretion in determining what information can be required through
rulemaking to be submitted as part of results information, stating that
the regulations ``shall require, in addition to the elements described
in [section 402(j)(3)(C)] . . . [s]uch other categories as the
Secretary determines appropriate.'' Therefore, the Secretary can
require, through rulemaking, submission of not only the results
information required under section 402(j)(3)(C) of the PHS Act, but
also ``such other categories'' of information as the Secretary
determines appropriate. We noted in the NPRM that we interpret ``such
other categories'' of results information for applicable device
clinical trials of unapproved or uncleared device products to include,
among other things, certain descriptive information that is similar to
the type of information required to be submitted
[[Page 65100]]
under section 402(j)(2)(A)(ii) of the PHS Act. We pointed out that if
clinical trial registration information is not available until after
the posting of results information, users of ClinicalTrials.gov would
lack access to certain descriptive information necessary to enhance
access to and understanding of, the submitted results information and
to determine whether the required results information has been
submitted (e.g., for all arms of the study). Therefore, this
descriptive information, as a component of clinical trial results
information for unapproved or uncleared devices, would be posted based
on the timeline specified in Sec. 11.52 (79 FR 69645).
To make submission of the necessary descriptive information easier
and to reduce the risk of inconsistency or error, Sec. 11.48(a)(6)(ii)
proposed to require responsible parties to affirm the accuracy of the
descriptive information that is similar to the type of information
submitted when the trial is registered by verifying and updating it as
necessary and then affirming that this descriptive information is ready
to be posted with the results information. Once affirmed, the proposed
rule explained, ClinicalTrials.gov would automatically populate the
clinical trial results descriptive information data elements using the
previously submitted clinical trial registration elements that are
similar to the type of information to be submitted when the trial is
registered. The proposed approach would decrease the burden on
responsible parties, reduce inconsistencies between information
previously submitted at registration and information submitted with
results, and increase administrative efficiency by reducing the need
for the Agency to conduct a wholly-new quality control review of the
submitted information (79 FR 69645).
Comments and Response
We did not receive any specific comments about the proposal to
require additional descriptive results information for applicable
device clinical trials of unapproved or uncleared devices in proposed
Sec. 11.48(a)(6). We did receive comments concerning the submission of
any results information for unapproved or uncleared devices, and these
comments are addressed in Section III.B. of this preamble.
Final Rule
Final Sec. 11.48(a)(7)(i) specifies the additional results
information necessary to enhance access to and understanding of the
results of applicable clinical trials of unapproved or uncleared device
products consistent with the proposed rule. However, this section
clarifies that this requirement is limited to applicable clinical
trials of unapproved or uncleared device products for which clinical
trial registration information has not been posted publicly by the
Director on ClinicalTrials.gov in accordance with Sec. 11.35(b)(2)(i).
This section also includes minor modifications to the names of data
elements for consistency with modifications to the data elements in
Sec. 11.10(b). Additionally, final Sec. 11.48(a)(7) clarifies that
``device'' means ``device product.''
Final Sec. 11.48(a)(7)(ii) states that responsible parties must
submit all the results information specified in Sec. 11.48(a)(7)(i).
We clarify that this applies to all applicable device clinical trials
of unapproved or uncleared device products that are subject to Sec.
11.48(a)(7)(i), regardless of when the trial was initiated. We also
clarify that if a responsible party indicates to the Director that it
is authorizing the Director, in accordance with Sec. 11.35(b)(2)(ii),
to publicly post its clinical trial registration information on
ClinicalTrials.gov prior to the date of FDA approval or clearance of
the device product, the applicable device clinical trial of its
unapproved or uncleared device product is not subject to Sec.
11.48(a)(7)(i).
Section 11.48(a)(7)(ii) additionally requires responsible parties
to submit an affirmation that any information previously submitted to
ClinicalTrials.gov for the data elements listed in paragraph Sec.
11.48(a)(7)(i) of this section have been updated in accordance with
Sec. 11.64(a) and are to be included as clinical trial results
information. As described above, to make submission of the necessary
descriptive information under Sec. 11.48(a)(7)(i) easier and to reduce
the risk of inconsistency or error, ClinicalTrials.gov will
automatically populate the clinical trial results descriptive
information data elements using the previously submitted clinical trial
registration elements that are similar to the type of information
submitted when the trial is registered. This automatic population
approach is intended to decrease the burden on responsible parties,
reduce inconsistencies between information previously submitted and
information submitted with results, and increase administrative
efficiency. The affirmation in Sec. 11.48(a)(7)(ii) therefore applies
to the previously submitted information that will be used to populate
the data elements listed in Sec. 11.48(a)(7)(i). The responsible party
must enter any additional descriptive information that has not been
automatically populated, as Sec. 11.48(a)(7)(ii) requires the
submission of all results information specified in Sec.
11.48(a)(7)(i).
Sec. 11.48(b)--Results Information for a Pediatric Postmarket
Surveillance of a Device Product That Is Not a Clinical Trial
Overview of Proposal
Proposed Sec. 11.48(b) specified the results information that must
be submitted to ClinicalTrials.gov for a pediatric postmarket
surveillance of a device that is not a clinical trial. We proposed that
the final report submitted to FDA according to 21 CFR 822.38 (or any
successor regulation) must be submitted to ClinicalTrials.gov in a
common electronic document format and must include redactions of
personally identifiable information and commercial confidential
information. We invited public comment on the proposed approach (79 FR
69646).
Comments and Response
Commenters addressed the proposal for a pediatric postmarket
surveillance of a device that is not a clinical trial in proposed Sec.
11.48(b). Commenters recommended that the final rule alternatively
allow for the submission of a study summary in place of a redacted
final report, suggesting that the redacted final report ``might be
confusing and virtually unreadable.'' One commenter indicated that a
pediatric postmarket surveillance of a device that is not a clinical
trial should be required to provide the same clinical trial results
information (as for a clinical trial) identified in proposed Sec.
11.48(a). As noted in the NPRM, ``pediatric postmarket surveillances
under section 522 of the FD&C Act can take various forms [other than a
clinical trial], including a detailed review of the complaint history
and the scientific literature, non-clinical testing, observational
studies . . .'' (79 FR 69576). As such, it may not always be possible
or appropriate for the responsible party for a pediatric postmarket
surveillance of a device that is not a clinical trial to provide all of
the specified results data elements or data tables required for
clinical trials in proposed Sec. 11.48(a). Regarding the suggested
submission of a study summary, it is not clear, based on the comments,
which specific items would be included in such a summary and how the
components could be described in the context of this final rule.
Because of the broad spectrum of types of studies that may be
considered pediatric
[[Page 65101]]
postmarket surveillances of a device, it is not possible to fully
elucidate the items that should be present in such a summary that would
apply to all types of studies. On the other hand, the final report
submitted to FDA would include the results information that was deemed
important by FDA. Therefore, we maintain the approach in the final rule
that the responsible party is required to provide a copy of the final
report submitted to FDA. This approach ensures that the information and
requirements are consistent for all types of pediatric postmarket
surveillances of a device product that are not clinical trials. We
have, however, modified the requirement as described in the NPRM, in
that we are not requiring that the final report be redacted. Upon
further consideration, we believe that it is appropriate to leave
decisions about information to be redacted to the discretion of the
responsible party.
Final Rule
Taking into consideration the commenters' suggestions and the
statutory requirements for the submission of clinical trial results
information for a pediatric postmarket surveillance of a device that is
not a clinical trial, we maintain in the final rule the approach
proposed in Sec. 11.48(b), but we remove the requirement to redact
information from the final report submitted to FDA and clarify that
``device'' means ``device product.''
Final Sec. 11.48(b) specifies the results information that must be
submitted to ClinicalTrials.gov for a pediatric postmarket surveillance
of a device product that is not a clinical trial. We recognize that a
pediatric postmarket surveillance of a device product may take any of
several forms, including prospective surveillance studies and
historical reviews of the health records of those who have received a
device as an intervention, and may not meet the definition of a
``clinical trial'' under this part. For this reason, it is not possible
to specify particular data elements or tables of data for all types of
pediatric postmarket surveillances of a device product that are not
clinical trials. For each pediatric postmarket surveillance of a device
product that is not a clinical trial, the final report submitted to FDA
according to 21 CFR 822.38 (or any successor regulation) is required to
be submitted to ClinicalTrials.gov. The responsible party may redact
names, addresses, and other personally identifiable information, as
well as any proprietary information (i.e., trade secrets and/or
confidential commercial information) contained in the report, but the
redacted information should not include any of the information required
to be submitted under Sec. Sec. 11.28(a) or 11.48(a) of this part. The
final report is required to be submitted in a common electronic
document format specified on ClinicalTrials.gov at https://prsinfo.clinicaltrials.gov (or successor site).
5. Sec. 11.52--By when will the NIH Director post submitted clinical
trial results information?
Overview of Statutory Provisions and Proposal
According to section 402(j)(3)(G) of the PHS Act, for applicable
clinical trials, the Director of NIH is required to post results
information ``publicly in the registry and results database not later
than 30 days after such submission.'' Proposed Sec. 11.52 implemented
this provision, stating that NIH will post publicly ``clinical trial
results information submitted under this subpart at ClinicalTrials.gov
not later than 30 calendar days after the date of submission'' (79 FR
69646).
Comments and Response
The comments received on the provisions specified in Sec. 11.52
for posting of clinical trial results information pertained to the
proposed quality control procedures (described in section III.C.12 of
the NPRM and proposed Sec. 11.66) and the timing of posting in
relationship to those procedures. These comments are addressed in full
in Section IV.D.3 of this preamble which addresses the requirements for
corrections in Sec. 11.64(b)(1) (which now includes the provisions
proposed in Sec. 11.66). We describe here the comments specific to the
timeline for posting. Some commenters supported the proposal for
posting, however, a number of commenters favored the quality control
review of information and suggested that information on both
registration and results should be posted only after quality control
review process has concluded. Commenters expressed concern about the
potential to misinform those using the public record and suggested only
posting sections that have fulfilled quality control criteria. Some
commenters suggested that the harm of posting information before the
quality control review process has concluded is greater than the
benefit of posting the information in a timely manner. While we
understand these concerns, we interpret the statutory posting deadline
to be a clearly delineated timeline between submission and posting. In
addition, in the event that a study record is posted in accordance with
the statutory posting deadline and the quality control review process
has not concluded, the clinical trial record will contain information
that will be visible to those viewing the record on ClinicalTrials.gov
to make it clear that the quality control review process has not
concluded for the posted clinical trial information.
Final Rule
Taking into consideration the commenters' concerns and the
statutory requirements for posting clinical trial results information,
we maintain the NPRM proposal in the final rule. For clarity, we have
modified the title of Sec. 11.52 such that it is now ``By when will
the NIH Director post submitted clinical trial results information?''
As discussed further in the preamble for Sec. 11.10, we clarified that
clinical trial results information means the data elements the
responsible party is required to submit to ClinicalTrials.gov as
specified in the PHS Act or as specified in these regulations, as
applicable. Thus, we have clarified Sec. 11.52 by removing the phrase
``submitted under this subpart.'' We have also clarified that the
requirement does not apply to information submitted under section
402(j)(4)(A) of the PHS Act and Sec. 11.60.
Section 11.52 applies only to clinical trial results information
required to be submitted to ClinicalTrials.gov. Reflecting section
402(j)(2)(C) of the PHS Act, as codified in Sec. 11.42, clinical trial
results information is required to be submitted for certain applicable
clinical trials ``for which clinical trial registration information is
required to be submitted'' (see Sec. 11.42(a) and (b)). Section 11.22
specifies which applicable clinical trials must be registered. For such
trials that voluntarily register with ClinicalTrials.gov, regardless of
whether they are subject to the requirements for voluntary submission
under Sec. 11.60 or are subject to the requirements in Sec.
11.60(a)(2)(ii), we intend to post results information as soon as
practicable after clinical trial results information has been submitted
and after the issues identified during quality control are corrected or
adequately addressed.
6. Sec. 11.54--What are the procedures for requesting and obtaining a
waiver of the requirements for clinical trial results information
submission?
Overview of Proposal
Section 402(j)(3)(H) of the PHS Act provides that ``[t]he Secretary
may
[[Page 65102]]
waive any applicable requirements of this paragraph [(3) of the PHS
Act] for an applicable clinical trial, upon written request from the
responsible party, if the Secretary determines that extraordinary
circumstances justify the waiver and that providing the waiver is
consistent with the protection of public health or in the interest of
national security . . .'' The statute also stipulates that if such a
waiver is granted, the Secretary will notify the appropriate
congressional committees that the waiver has been granted and explain
why it has been granted, not later than 30 calendar days after the
waiver has been granted. Proposed Sec. 11.54 implemented this
provision by outlining procedures by which a responsible party may
submit a written request for a waiver from the requirements of subpart
C for an applicable clinical trial. Proposed Sec. 11.54(a) specified
the details for the submission and content of the waiver request,
including that the request identify the specific requirement(s) for
which the waiver is requested. Proposed Sec. 11.54(b) specified the
procedures and deadlines for appealing a denied waiver request, and
Sec. 11.54(c) provided that the Director would include a notation in
the clinical trial record for the waived results submission requirement
and that the Secretary would notify the appropriate congressional
committees of the waiver and why it was granted (79 FR 69646).
The proposed rule noted that we expected that waivers would be
requested and granted in only a very limited number of situations, and
we described an example of a situation in which a waiver might be
granted, namely if results information could be submitted only in a
manner that would likely enable the re-identification of clinical trial
participants. We invited public comments on other situations in which a
waiver might be granted and would be consistent with the protection of
public health or in the interest of national security. With regard to
the notation on the clinical trial record, we explained that it was
intended to inform users of ClinicalTrials.gov that the absence of
certain results information does not constitute a failure to comply
with the statute and implementing regulation. We also explained that
because the waiver would be based on extraordinary circumstances that
could include considerations of public health and/or national security,
we proposed that we would not publicly post information describing the
reason for the waiver. We invited public comment on this proposal as
well (79 FR 69646).
Comments and Response
Several commenters addressed the Agency's proposed procedures for
handling waiver requests. Commenters suggested additional examples of
situations that they thought would warrant a waiver of the results
information submission requirements. Several commenters suggested that
a waiver was warranted when the principal investigator could no longer
serve as the responsible party such as when the investigator relocates
or in the event of their death or disability. Commenters suggested that
a waiver would relieve the institution of the burden of having to
fulfill the responsible party's obligations to submit results
information. We do not consider a principal investigator's inability to
fulfill their responsibilities as an extraordinary circumstance that
would satisfy the statutory standard. Section 11.4(c)(3) provides for
the reassignment of the responsible party function when the principal
investigator no longer meets or is no longer able to meet all of the
requirements for designation as the responsible party or in the event
of the principal investigator's death or incapacity. Other comments
emphasized the importance of maintaining flexibility in the process of
considering requests for waivers for results information reporting and
asserted that without flexibility in the system, waiver requests may be
unnecessarily denied. We believe that the proposed rule provides the
necessary mechanisms and the flexibility for considering waivers while
also protecting public health and national security.
Comments were also received suggesting that the proposed rule's 15
calendar day deadline for data submission following waiver denial or
appeal denial should be extended, including a proposal to allow the
waiver request to be submitted 60 calendar days before the results
information submission deadline, allowing the Secretary 30 calendar
days to transmit a decision and an additional 60 calendar days for an
appeal resolution. We agree with the comments that longer timeframes
are appropriate and have included 30-calendar day deadlines in the
final rule.
Commenters also supported the use of justified waiver requests as
well as a publicly posted notation on the clinical trial record if
results information submission is waived. Other commenters suggested
making the waiver request and appeal public and allowing the public to
appeal a reason given in a waiver request by a responsible party. Since
the waiver would be based on extraordinary circumstances that could
include considerations of public health and/or national security, the
Agency will retain the proposed approach of not posting information
describing the reason for the waiver.
Final Rule
Taking into consideration the public comments and the statutory
requirements set forth in section 402(j)(3)(H) of the PHS Act, the
final rule retains the proposed rule with the exception of the
timeframes for submitting results information after a waiver denial,
for appealing a waiver denial, and for submitting results information
after a denial of the waiver on appeal. These timeframes have been
extended from 15 calendar days to 30 calendar days. The final rule also
clarifies in Sec. 11.54(d) that for an applicable clinical trial with
a primary completion date before the effective date of the rule, the
responsible party may submit a waiver request as specified in section
402(j)(3)(H) of the PHS Act. This is consistent with the differing
requirements that apply to applicable clinical trials, depending on the
primary completion date of the applicable clinical trial, as discussed
further in Section IV.F of this preamble. Section 11.54 of the rule
outlines procedures by which a responsible party may submit a request
for a waiver from any or all requirements of results information
submission. We expect that waivers will be requested and granted only
for extraordinary circumstances that could include the need to protect
the public health and/or the interests of national security. The Agency
will issue guidance on how to submit such waiver requests.
Section 11.54(a) of the rule specifies that waiver requests must be
submitted by the responsible party to the Secretary or a delegated
official in the format specified at https://prsinfo.clinicaltrials.gov/
(or successor site) and indicate the NCT number, Brief Title, and Name
of the Sponsor of the applicable clinical trial. This information is
necessary to ensure accurate identification of the specific trial for
which the waiver is requested (i.e., the combination of NCT number and
Brief Title will assist in identifying mistyped NCT numbers) and the
key parties involved (i.e., sponsor and responsible party). Since the
statute grants the Secretary the authority to waive ``any applicable
requirements'' for the submission of results information if justified
by ``extraordinary circumstances,'' the rule
[[Page 65103]]
requires the responsible party to identify the specific provisions(s)
for which a waiver is requested and provide a description of the
extraordinary circumstances that are believed to justify the waiver.
The responsible party will not be required to comply with the results
information submission provisions in subpart C for which the waiver is
granted. Such provisions could include all or just some of the
provisions for which the waiver is requested. The responsible party
will continue to be required to comply with any remaining provisions of
subpart C for which the waiver is not requested or not granted. It is
important to note, however, that a responsible party may still need to
provide certain information in the PRS to indicate that the results
information submission requirement was waived for that information.
After a waiver is granted, the Agency will work with the responsible
party to address the specific requirements that are waived. In some
cases, for example, the responsible party may need to enter ``0
participants'' with an explanation that a waiver was provided for such
information. While a waiver request is pending, the responsible party
will not be required to submit other required clinical trial results
information. The deadline for submitting results information to
ClinicalTrials.gov is the later of the original submission deadline or
30 calendar days after a notification denying the waiver is sent to the
responsible party.
Section 11.54(b) details the process by which a responsible party
may appeal a denied waiver request to the Secretary or delegated
official and indicates that additional information about the format of
the appeal will be specified at https://prsinfo.clinicaltrials.gov/ (or
successor site). If this responsibility is delegated to a Department or
Agency official, the delegated official will, as a matter of practice,
differ from the delegated official for reviewing the initial waiver
request. As with the original request, the responsible party is not
required to comply with specific provisions of subpart C for which the
waiver is granted upon appeal. For the provisions for which a waiver is
not granted upon appeal, the responsible party is required to submit
results information by the later of the original results information
submission deadline or 30 calendar days after the notification denying
the appeal is sent to the responsible party. Of note, we have replaced
the word ``transmitted,'' used in the proposed rule, with the phrase
``sent to the responsible party'' in final Sec. 11.54(b)(1) and added
the phrase ``to the responsible party'' in final Sec. 11.54(b)(3).
Although these changes do not alter the meaning of these provisions, we
believe they further clarify that the responsible party has 30 calendar
days from the date the notification is sent from the Agency as
evidenced by the date stamp on the notification.
Section 11.54(c)(1) requires the Director to include a notation in
the clinical trial record that specified elements of the results
information submission requirements have been waived. This notation is
intended to inform users of ClinicalTrials.gov that the absence of
certain results information does not necessarily constitute a failure
to comply with the statute and implementing regulation. Section
11.54(c)(2) implements section 402(j)(3)(H) of the PHS Act by requiring
the Secretary, if a waiver is granted, to notify the appropriate
congressional committees that the waiver has been granted and explain
why it has been granted, not later than 30 calendar days after any part
of the waiver is granted. Since the waiver would be based on
extraordinary circumstances that could include considerations of public
health and/or national security, the Agency will not post publicly
information describing the reason for the waiver.
Section 11.54(d), as described above, states that a responsible
party for an applicable clinical trial with a primary completion date
before the effective date of the rule may request a waiver from any of
the applicable requirement(s) for clinical trial results information
submission in accordance with the procedures specified in section
402(j)(3)(H) of the PHS Act.
D. Subpart D--Additional Submissions of Clinical Trial Information
1. Sec. 11.60--What requirements apply to the voluntary submission of
clinical trial information for clinical trials of FDA-regulated drug
products (including biological products) and device products?
Overview of Proposal
Proposed Sec. 11.60 described requirements that would apply to
voluntary submissions of information for certain clinical trials not
otherwise subject to the registration and results information
submission requirements of section 402(j) of the PHS Act. Section
402(j)(4)(A) of the PHS Act specified that ``[a] responsible party for
a clinical trial that is not an applicable clinical trial, or that is
an applicable clinical trial that is not subject to paragraph (2)(C),
may submit complete clinical trial information described in paragraph
(2) or paragraph (3) [of the PHS Act] provided the responsible party
submits clinical trial information for each applicable clinical trial
that is required to be submitted under section 351 [of the PHS Act] or
under section 505, 510(k), 515, or 520(m) of the Federal Food, Drug,
and Cosmetic Act in an application or report for licensure, approval,
or clearance of the drug or device for the use studied in the clinical
trial.'' Based on this provision, the proposed rule described two types
of clinical trials of FDA-regulated drugs or devices for which
submission of information is not otherwise required: (1) Clinical
trials that do not meet the definition of an applicable clinical trial;
and, (2) clinical trials that are applicable clinical trials but are
not required to register under proposed section Sec. 11.22(a) (i.e.,
clinical trials that are applicable clinical trials that were initiated
on or before September 27, 2007, and that reached their completion
dates before December 26, 2007) (79 FR 69647).
Under proposed Sec. 11.60, if a responsible party voluntarily
submitted clinical trial information for either type of clinical trial
for which submission of information is not otherwise required, the
responsible party would be required to submit registration information
as specified in proposed Sec. 11.60(a)(2)(i)(A) or results information
as specified in proposed Sec. 11.60(a)(2)(i)(B) for the voluntarily
submitted clinical trial. In addition, proposed Sec. 11.60(a)(2)(ii)
and Sec. 11.60(a)(2)(iii) described additional applicable clinical
trials (i.e., ``triggered'' trials) for which clinical trial
information would be required to be submitted if a responsible party
voluntarily submitted clinical trial information for a clinical trial
not otherwise required to be registered. In this context, ``triggered''
trials referred to ``each applicable clinical trial that is required to
be submitted under section 351 [of the PHS Act] or under section 505,
510(k), 515, or 520(m) of the [FD&C] Act in an application or report
for licensure, approval, or clearance of the drug or device for the use
studied in the clinical trial'' as specified in section 402(j)(4)(A) of
the PHS Act. Requiring the submission of information for ``triggered''
trials helps prevent selective voluntary submissions of results
information from clinical trials that only show positive results for a
particular product, but not from those applicable clinical trials that
show negative or uncertain results for the same product (79 FR 69648).
Additionally, proposed Sec. 11.60(a)(2)(iv) provided deadlines
applying to voluntary submissions and proposed Sec. 11.60(a)(2)(v)
specified that
[[Page 65104]]
all voluntary submissions would be subject to the update and
corrections requirements proposed in Sec. Sec. 11.64 and 11.66,
respectively. Finally, proposed Sec. 11.60(b) provided a statement to
accompany applicable clinical trial information that was submitted
voluntarily as specified in section 402(j)(3)(D)(v)(V) of the PHS Act
(79 FR 69649).
Comments and Response
Several commenters addressed proposed Sec. 11.60. Some commenters
supported the proposed requirements, while one suggested that the scope
of the mandatory submission requirements should be modified to
encompass all trials covered by the proposed voluntary submissions
requirements, including those of currently marketed drugs and devices
completed before the enactment of FDAAA. The Agency appreciates these
comments and the underlying sentiment for broad trial registration and
results information reporting policies. We note that responsible
parties have always been able to submit voluntarily the registration
and/or results information for clinical trials of currently marketed
drugs and devices that were completed before the enactment of FDAAA. We
also note that Sec. 11.60 of the final rule provides that, as of
September 27, 2007, responsible parties who make such voluntary
submissions and are manufacturers of the studied product must also
submit clinical trial information for all ``triggered'' applicable
clinical trials required to be provided to FDA in a marketing
application or premarket notification, in order to avoid selective
disclosure of information about a product on ClinicalTrials.gov.
Other commenters suggested that the Agency consider including fewer
requirements in the final rule to encourage more voluntary submissions,
while another requested the removal of proposed requirements for
updating and correcting voluntarily submitted trial information because
of concerns that such a burden may have the unintended consequence of
discouraging voluntary submissions. In response, the Agency has
reviewed proposed Sec. 11.60(a) and determined that each requirement
is necessary to ensure that voluntary submissions would be provided in
accordance with the statute. Further, we have added the Study
Completion Date data element, as defined in Sec. 11.10 of the final
rule and discussed in Section IV.A.5 of this preamble, to the list of
required additional results data elements that must be provided when
the responsible party voluntarily submits clinical trial results
information for a clinical trial for which the clinical trial
registration information specified in Sec. 11.60(b)(2)(i)(B), and
11.60(c)(2)(i)(B) have not been submitted. The Study Completion Date is
needed to identify that the requirements for voluntary partial results
information submission in Sec. 11.60(a)(2)(iv)(A), 11.60(b)(2)(iv)(A),
and 11.60(c)(2)(iv)(A), and obligations for updates and corrections in
Sec. Sec. 11.60(c)(2)(v) and 11.64 have been fulfilled. That is, even
though a responsible party for a trial may need to submit partial
results information several times voluntarily in order to meet
different deadlines (i.e., because of different dates for final data
collection for primary and/or secondary outcome measures or for the
pre-specified time frame for collecting adverse events), that
responsible party's obligation for voluntary results information
submission is only completely fulfilled after all required results
information is submitted not later than 1 year following the Study
Completion Date. With regard to the updating and correction
requirements in proposed Sec. 11.60, section 402(j)(4)(A) of the PHS
Act provides that voluntary submissions of information must consist of
``complete'' clinical trial registration and/or results information.
The updating requirements help ensure that any subsequent changes in
clinical trial information for a voluntarily submitted trial (e.g.,
overall recruitment status) are reflected in the data bank.
Additionally, the error correction requirements provide for the timely
revision of submitted clinical trial information. As with mandatory
submissions, these requirements are intended to help assure that all
voluntary submissions are complete and accurate.
A commenter expressed concerns over a statement to accompany
applicable clinical trials submitted voluntarily in proposed Sec.
11.60(b). The commenter suggested that submitted statements may be
written in language too technical for the public to understand and
recommended several approaches to clarifying the meaning, such as
providing a hyperlink to a page containing an explanation written in
non-technical language or amending the statement directly with non-
technical language. The Agency agrees that the proposed language was
too technical and has modified the statement in the final rule by
adding a non-technical first sentence and placing the original
technical statement in parenthesis for clarity: ``This clinical trial
information was submitted voluntarily under the applicable law and,
therefore, certain submission deadlines may not apply. (That is,
clinical trial information for this applicable clinical trial was
submitted under section 402(j)(4)(A) of the Public Health Service Act
and 42 CFR 11.60 and is not subject to the deadlines established by
sections 402(j)(2) and (3) of the Public Health Service Act or 42 CFR
11.24 and 11.44.)''
In addition, a few commenters requested clarification on additional
issues. In particular, one commenter requested clarification of the
word ``triggered'' as used in the preamble section of the proposed
rule. In the preamble of the proposed rule and this final rule, we use
the term ``triggered'' to refer to the statutory requirement that a
responsible party who has voluntarily submitted clinical trial
information for a clinical trial that is not an applicable clinical
trial or that is an applicable clinical trial that is not subject to
the registration requirements, and who is the manufacturer of the FDA-
regulated drug product (including a biological product) or device
product being studied, must also submit clinical trial information for
each applicable clinical trial required to be submitted to FDA in a
marketing application or premarket notification for approval,
licensure, or clearance of the drug product (including a biological
product) or device product for the use studied in the voluntarily
submitted trial. However, the term ``triggered'' is not used in the
regulatory text of the final rule in Sec. 11.60.
Another commenter expressed concern that proposed Sec. 11.60 could
be used for the voluntary submission of clinical trial information for
studies of unproven stem cell and cell based therapy interventions to
ClinicalTrials.gov as ``phase 1'' trials for promoting medical tourism
and other activities. The comment further suggested that the Agency
consider additional requirements for voluntary submissions in the final
rule, such as review of the approval status for each submitted
intervention by the relevant competent authorities. The Agency
appreciates these comments and the underlying sentiment for trial
registration and results reporting information. Nevertheless, allowing
voluntary submissions for clinical trials not otherwise subject to
submission requirements under section 402(j) of the PHS Act or this
final rule increases public access to information about clinical trials
regardless of the apparent nature, quality, or other characteristics of
a clinical trial. Making the clinical research enterprise more
transparent allows the public to track ongoing trials and informs
decision makers involved
[[Page 65105]]
with clinical trial policies and practices (Section I of this preamble
discusses public health benefits of registration and results
reporting).
One commenter suggested that the Agency develop results templates
for observational studies, which some sponsors may want to report at
ClinicalTrials.gov. Observational studies that are not pediatric
postmarket surveillances of a device are not subject to section 402(j)
of the PHS Act. In the future, we may consider developing tools to
assist sponsors who provide optional results information for
observational studies (other than certain pediatric postmarket
surveillances of a device product that are not a clinical trial), which
are outside the scope of this rule. The Agency does provide online
access to results templates for interventional studies to assist and
guide responsible parties in submitting results information under
section 402(j) of the PHS Act [Ref. 111].
Another commenter sought clarification about whether linking study
results that have been published or posted on another Web site would be
permitted for clinical trials that were voluntarily submitted with
registration information only. ClinicalTrials.gov currently provides a
number of optional data elements such as Citations and Links, which can
be used to link a record to relevant trial results cited in
publications or are available at a another Web site, respectively.
These optional data elements will continue to be available on
ClinicalTrials.gov. Note that, as discussed in greater detail in
Section III.B of this preamble, such links to other studies and Web
sites from ClinicalTrials.gov do not constitute a government
affirmation or verification that the information within or referenced
in the database, or communications that rely on that information, are
truthful and non-misleading.
Final Rule
Taking into consideration the commenters' suggestions and the
statutory requirements for voluntary submissions, the final rule
retains the requirements as proposed in Sec. 11.60(a), but modifies
the statement from proposed Sec. 11.60(b) to accompany voluntarily
submitted applicable clinical trials and clarifies that ``drug'' means
``drug product'' and ``device'' means ``device product.'' In addition,
consistent with the discussion in Section IV.F of this preamble, we
have made revisions to address the differing requirements that apply to
applicable clinical trials (and, if voluntarily submitted, other
clinical trials).
Section 11.60(a) applies to clinical trials initiated before the
effective date of the final rule and that have a primary completion
date before the effective date of the final rule. Consistent with the
discussion in Section IV.F, below, those clinical trials would be
subject to the registration requirements specified in section
402(j)(2)(A)(ii) of the PHS Act and subject to results information
submission requirements specified in sections 402(j)(3)(C) and
402(j)(3)(I) of the PHS Act. Section 11.60(b) applies to clinical
trials initiated before the effective date of the final rule and that
have a primary completion date on or after the effective date of the
final rule. Consistent with the discussion in Section IV.F, below,
those clinical trials would be subject to the registration requirements
specified in section 402(j)(2)(A)(ii) of the PHS Act and subject to
results information submission requirements specified in 42 CFR part
11. Section 11.60(c) applies to clinical trials initiated on or after
the effective date of the final rule and that have a primary completion
date on or after the effective date of the final rule. Consistent with
the discussion in Section IV.F, below, those clinical trials would be
subject to the registration and results information submission
requirements specified in 42 CFR part 11.
Section 11.60(a)(1), (b)(1), and (c)(1) specify that the
requirements for voluntary submission of clinical trial information
apply to two types of clinical trials for which submission of
information is not otherwise required, as follows: (1) Clinical trials
of FDA-regulated drug products (including biological products) or
device products that do not meet the definition of an applicable
clinical trial (e.g., a phase 1 drug trial or small feasibility device
study); and, (2) clinical trials that are applicable clinical trials
that were initiated on or before September 27, 2007, and that reached
their completion dates before December 26, 2007 (i.e., applicable
clinical trials not required to be registered under section
402(j)(2)(C) of the PHS Act or Sec. 11.22(a), as applicable). We
interpret section 402(j)(4)(A) of the PHS Act in a way that is
consistent with the scope of FDA's regulatory authorities and the scope
of this regulation. Thus, Sec. 11.60 applies only to clinical trials
of FDA-regulated drug products (including biological products) and
device products. For example, this section applies to a phase 1 trial
of an FDA-regulated drug product (including a biological product) or a
small clinical trial that evaluates the feasibility of an FDA-regulated
device product, but does not apply to a clinical trial that studies
only behavioral interventions that are not drug products (including
biological products) or device products.
In addition, as explained in the proposed rule, we interpret the
phrase ``applicable clinical trial that is not subject to [the
mandatory registration requirement of] paragraph (2)(C),'' in section
402(j)(4)(A) of the PHS Act, to mean a clinical trial that meets the
definition of an applicable clinical trial, as specified in section
402(j)(1)(A) of the PHS Act and this part, but that was initiated on or
before September 27, 2007, and that reached its completion date prior
to December 26, 2007 (79 FR 69647).
In considering the information that must be submitted to
ClinicalTrials.gov for a voluntarily submitted clinical trial, we
interpret section 402(j)(4)(A) of the PHS Act as permitting a
responsible party to voluntarily submit registration information for a
clinical trial, results information, or both. Thus, Sec.
11.60(a)(2)(i), (b)(2)(i), and (c)(2)(i) expressly permit the voluntary
submission of registration information, results information, or both.
When a responsible party voluntarily submits only registration
information for a clinical trial, Sec. 11.60(a)(2)(i)(A),
(b)(2)(i)(A), and (c)(2)(i)(A) establish that registration information
specified in section 402(j)(2)(A)(ii) of the PHS Act or specified in
Sec. 11.28(a) (as applicable) must also be submitted.
For clinical trials with a primary completion date on or after the
effective date, Sec. 11.60(b)(2)(i)(B) and (c)(2)(i)(B) specify that
when a responsible party voluntarily submits results information for a
clinical trial for which registration information is specified in
section 402(j)(2)(A)(ii) of the PHS Act or specified in Sec. 11.28(a)
(as applicable) has not been submitted, results information as
specified in Sec. 11.48(a), as well as additional descriptive
information set forth in Sec. 11.60(b)(2)(i)(B) and (c)(2)(i)(B) and
defined in Sec. 11.10(b), must be submitted. We believe that such
additional descriptive information is necessary to enhance access to
and understanding of the results of a clinical trial of a drug product
(including a biological product) or device product (e.g., Study Phase
is necessary to enable a user to understand the relative stage of
development of an experimental drug product (including a biological
product) studied in a clinical trial). Further, we believe that several
other data elements must be submitted with voluntarily submitted
results information in order for the Agency to confirm that a clinical
[[Page 65106]]
trial for which information is voluntarily submitted is not an
applicable clinical trial subject to mandatory registration or results
information submission under this part (e.g., Product Manufactured in
and Exported from the U.S., and U.S. Food and Drug Administration IND
or IDE Number). For situations in which a responsible party submits
voluntarily only clinical trial results information under section
402(j)(4)(A) of the PHS Act, the Agency is using its authority under
section 402(j)(3)(D)(iii)(IV) of the PHS Act to interpret results
information to include the data elements under Sec. 11.60(a)(2)(i)(B)
and (c)(2)(i)(B) in addition to the data elements set forth in Sec.
11.48(a). We have added Sec. 11.60(a)(2)(i)(C), (b)(2)(i)(C), and
(c)(2)(i)(C) to clarify that a responsible party who voluntarily
submits registration information and voluntarily submits results
information for a clinical trial must submit registration information
as specified in section 402(j)(2)(A)(ii) of the PHS Act or specified in
Sec. 11.28(a) (as applicable) and results information specified in
sections 402(j)(3)(C) and 402(j)(3)(I) of the PHS Act or specified in
Sec. 11.48(a) (as applicable).
Sections 11.60(a)(2)(ii), (b)(2)(ii), and (c)(2)(ii) require that a
responsible party who submits clinical trial information voluntarily
for a clinical trial must additionally submit clinical trial
information for any applicable clinical trial (including those
initiated on or before September 27, 2007, and reached their completion
date prior to December 26, 2007) that is required to be submitted in a
marketing application or premarket notification to FDA for approval,
licensure, or clearance of the drug product (including a biological
product) or device product for the use studied in the voluntarily
submitted clinical trial. The final rule maintains the approach in the
proposed rule by clarifying that this statutory requirement applies to
(1) applications or premarket notifications submitted to the FDA by a
manufacturer on or after September 27, 2007; and (2) when the
responsible party for the voluntarily submitted clinical trial is also
the manufacturer submitting the marketing application or premarket
notification, thereby avoiding the situation in which a responsible
party would be required to submit information for triggered applicable
clinical trials for which they are not the responsible party and do not
have access to the relevant data. While the Agency encourages
submissions of registration information and results information for all
types of clinical trials, regardless of whether they are subject to
section 402(j) of the PHS Act, responsible parties should consider the
above requirements before deciding whether to register a clinical trial
or submit results information voluntarily.
In the final rule, Sec. 11.60(a)(2)(iii), (b)(2)(iii), and
(c)(2)(iii) specify that the clinical trial information required to be
submitted for a triggered applicable clinical trial is, at minimum, the
same as that for the voluntarily submitted clinical trial. That is, if
a responsible party voluntarily submits registration information for a
clinical trial pursuant to Sec. 11.60(a), the responsible party must
submit registration information specified in section 402(j)(2)(A)(ii)
of the PHS Act for any triggered applicable clinical trial(s).
Similarly, if a responsible party voluntarily submits clinical trial
results information for a clinical trial pursuant to Sec. 11.60(a),
then the responsible party must submit results information specified in
sections 402(j)(3)(C) and 402(j)(3)(I) of the PHS Act for any triggered
applicable clinical trial(s). Since the submission of clinical trial
information for a triggered applicable clinical trial is a condition of
voluntary submission, the Agency does not propose to treat the
submission of such information as a voluntary submission under Sec.
11.60(a)(2)(ii), (b)(2)(ii), and (c)(2)(ii) that itself could trigger
the submission of clinical trial information for other applicable
clinical trials. In other words, the submission of information for an
applicable clinical trial that is triggered under section 402(j)(4)(A)
of the PHS Act and subject to Sec. 11.60 would not, in turn, itself
trigger the requirement to submit information for additional applicable
clinical trials under that section. For example, voluntary submission
of information for trial X may trigger the submission of information
for applicable clinical trials Y and Z that were required to be
included in FDA marketing application 001, as required under Sec.
11.60(a)(2)(ii), (b)(2)(ii), and (c)(2)(ii). However, submission of
information for applicable clinical trials Y and Z would not further
trigger the requirement to submit information for additional applicable
clinical trials (e.g., even if applicable clinical trial Y were used to
support marketing application 002, the applicable clinical trials
required to be included in 002 would not be triggered).
In general, an initial voluntary submission is not subject to any
regulatory deadlines in Sec. Sec. 11.24 and 11.44 and so may be
submitted at any time in relation to the conduct of the trial (e.g.,
before, during, or after the study start date or primary completion
date). However, when a voluntary submission is made, Sec.
11.60(a)(2)(iv), (b)(2)(iv), and (c)(2)(iv) establish two deadlines
that apply to voluntary submissions of results information. Sections
11.60(a)(2)(iv)(A), (b)(2)(iv)(A), and (c)(2)(iv)(A) specify that if
data collection for the secondary outcome measure(s) or the pre-
specified timeframe for collecting adverse event information for such
clinical trials is not completed by the primary completion date of the
voluntarily submitted clinical trial, then results information for the
secondary outcome measure(s) and/or adverse event information must be
submitted by the later of either the date that the results information
is voluntarily submitted for the primary outcome measure(s) or 1 year
after the date on which (1) the final subject was examined or received
an intervention for the purposes of final collection of data for the
secondary outcome measure(s) or (2) after the final subject was
observed for adverse events, whether the clinical trial was concluded
according to the pre-specified protocol or was terminated. We clarify
that while initial voluntary submission of partial results information
is permitted (pending completion of data collection for secondary
outcomes and/or the pre-specified time frame for collecting adverse
events information according to the reporting deadlines specified in
Sec. 11.60(a)(2)(iv)(A), (b)(2)(iv)(A), and (c)(2)(iv)(A)), the
responsible party is required to submit the clinical trial results
information specified in sections 402(j)(3)(C) and 402(j)(3)(I) or
specified in Sec. 11.48(a) (as applicable) that is otherwise available
when submitting partial results information. This means that, with
respect to adverse event information, a responsible party would be
required to submit information summarizing serious and frequent adverse
events recorded to-date each time results information for a secondary
outcome is submitted, until all the adverse event information required
by this part has been submitted. This clarification is now included in
the final rule in Sec. 11.60(a)(2)(iv)(A)(2), (b)(2)(iv)(A)(2), and
(c)(2)(iv)(A)(2). We emphasize, however, this provision does not impose
requirements on the design or conduct of the clinical trial or on the
data that must be collected during the clinical trial.
Sections 11.60(a)(2)(iv)(B), (b)(2)(iv)(B), and (c)(2)(iv)(B)
specify that clinical trial information for triggered applicable
clinical trials must be submitted not later than the date on which the
application or premarket notification is submitted to FDA or the
[[Page 65107]]
date on which clinical trial information is submitted for the
voluntarily submitted clinical trial to ClinicalTrials.gov, whichever
is later. This approach prevents a responsible party from having to
submit information for a clinical trial that is not subsequently
included in the marketing application or premarket notification.
Section 11.60(c)(2)(v) specifies that responsible parties who
voluntarily submit clinical trial information to ClinicalTrials.gov
would be required to update and correct submitted information,
including information submitted for triggered trials, in accordance
with Sec. 11.64 (as applicable).
Section 11.60(d) specifies the text of the statement to accompany
voluntarily submitted applicable clinical trials to clarify that the
voluntary submission was not subject to the deadlines imposed by
section 402(j) of the PHS Act for mandatory submission of registration
and results information. The required statement would apply to any
applicable clinical trial, including any triggered applicable clinical
trial, submitted under section 402(j)(4)(A) of the PHS Act and Sec.
11.60(a), (b), and (c). Accordingly, the statement will be as follows:
``This clinical trial information was submitted voluntarily under the
applicable law and, therefore, certain submission deadlines may not
apply. (That is, clinical trial information for this applicable
clinical trial was submitted under section 402(j)(4)(A) of the Public
Health Service Act and 42 CFR 11.60 and is not subject to the deadlines
established by sections 402(j)(2) and (3) of the Public Health Service
Act or 42 CFR 11.24 and 11.44.)''
2. Sec. 11.62--What requirements apply to applicable clinical trials
for which submission of clinical trial information has been determined
by the Director to be necessary to protect the public health?
Overview of Proposal
The NPRM, in accordance with section 402(j)(4)(B) of the PHS Act,
proposed in Sec. 11.62 to require submission of clinical trial
information if the Director determines that the posting of such
information on ClinicalTrials.gov is necessary to protect the public
health. Section 402(j)(4)(B)(i) of the PHS Act specifically authorizes
the Secretary to ``require by notification'' of the submission of
clinical trial information ``in any case in which the Secretary
determines for a specific clinical trial [. . . .] that posting in the
registry and results data bank of clinical trial information for such
clinical trial is necessary to protect the public health.'' This
authority has been delegated to the Director (74 FR 19973, Apr. 30,
2009). If the Director so determines, clinical trial information must
be submitted for that clinical trial in accordance with sections
402(j)(2) and (3) of the PHS Act, except with regard to timing
requirements. With respect to timing, such clinical trial information
must be submitted to ClinicalTrials.gov ``not later than 30 days after
the date specified by the [Director] in the notification,'' unless the
responsible party submits a certification for delayed results
information submission under section 402(j)(3)(E)(iii) of the PHS Act
(see section 402(j)(4)(B)(i)(II) of the PHS Act).
The NPRM proposed in Sec. 11.62(a) to implement this provision by
requiring the responsible party for an applicable clinical trial who
receives notification pursuant to section 402(j)(4)(B) of the PHS Act
that the Director has determined that posting of clinical trial
information is necessary to protect the public health to submit such
information to ClinicalTrials.gov in accordance with proposed Sec.
11.62(c) (79 FR 69650).
The NPRM proposed in Sec. 11.62(b) to implement section
402(j)(4)(B)(ii) of the PHS Act, which specifies that the types of
clinical trials subject to this provision are limited to those that
are: (1) ``an applicable clinical trial for a drug that is approved
under section 505 of the Federal Food, Drug, and Cosmetic Act or
licensed under section 351 of [the PHS Act] or for a device that is
cleared under section 510(k) of the Federal Food, Drug, and Cosmetic
Act or approved under section 515 or section 520(m) of [the FD&C Act],
whose completion date is on or after the date 10 years before the date
of the enactment of the Food and Drug Administration Amendments Act of
2007'' (i.e., September 27, 1997) or (2) an applicable clinical trial
that is subject to registration under section 402(j)(2)(C) of the PHS
Act and studies a drug or device that is unapproved, unlicensed, or
uncleared regardless of whether or not approval, licensure, or
clearance was sought as described in section 402(j)(3)(D)(ii)(II) of
the PHS Act (79 FR 69650).
Section 11.62(c) of the NPRM specified that such clinical trial
information must be submitted to ClinicalTrials.gov not later than 30
calendar days after the date specified by the Director in the
notification, unless the responsible party submits a certification for
delayed results submission, as specified in Sec. 11.44(b) or (c). It
further proposed that if the responsible party submitted clinical trial
registration information prior to the date on which the notification is
sent to the responsible party, the responsible party must then make all
necessary updates, if any, to the submitted information not later than
30 calendar days after the date specified in the notification (79 FR
69650). The Agency invited public comment on the types of situations in
which the posting of clinical trial information might be necessary to
protect the public health and on the criteria that the Director should
consider when making such a determination, but no comments were
received on the types of trials that should be included.
Comments and Response
One commenter addressed proposed Sec. 11.62. The comment suggested
that the Agency should describe the criteria to be used by the Director
to determine when applicable clinical trials subject to Sec. 11.62
would be required to submit clinical trial information to
ClinicalTrials.gov. The Agency will issue guidance at a later date on
factors that the Director intends to consider in determining whether
clinical trial information subject to Sec. 11.62 must be posted on
ClinicalTrials.gov. We expect this authority to be rarely invoked and
limited to extraordinary circumstances including those in the interest
of public health or in the interest of national security.
Final Rule
Taking into consideration the commenter's suggestion and the
statutory requirements for applicable clinical trials for which
submission of clinical trial information has been determined by the
Director to be necessary to protect the public health, the final rule
maintains the proposed Sec. 11.62 approach, except we clarify that
``drug'' means ``drug product'' and ``device'' means ``device product''
in final Sec. 11.62(b)(1) and 11.62(b)(2). We also clarify in final
Sec. 11.62(b)(2) that the applicable clinical trial is subject to this
section ``regardless of whether approval, licensure, or clearance was,
is, or will be sought, and that is not otherwise subject to results
information submission in accordance with the regulation.'' As
explained in the discussion of Sec. 11.10 of this preamble (Section
IV.A.5), approval status of a product studied in an applicable clinical
trial (i.e., either ``unapproved, unlicensed, or uncleared'' or
``approved, licensed, or cleared'') is interpreted to be the approval
status of the product on the primary completion date. In this context,
the approval status
[[Page 65108]]
of the product is the approval status on the estimated or actual
primary completion date on the date that the Director notifies the
responsible party that clinical trial information must be submitted to
ClinicalTrials.gov for an applicable clinical trial under Sec. 11.62.
The clinical trials specified in Sec. 11.62(b)(1) would consist of
applicable clinical trials of approved, licensed, or cleared drugs
(including biological products) or devices that reached their primary
completion dates on or after September 27, 1997. We note that this set
of clinical trials would include applicable clinical trials that reach
their primary completion dates on or after the date of enactment of
FDAAA, many of which already would be subject to the registration and
results information submission requirements of section 402(j) of the
PHS Act, with the exception of applicable clinical trials that were
initiated prior to the date of enactment of FDAAA (i.e., September 27,
2007) and were not ongoing as of December 26, 2007.
The clinical trials specified in Sec. 11.62(b)(2) would consist of
applicable clinical trials that are required to register at
ClinicalTrials.gov pursuant to Sec. 11.22(a) of this rule and that
study drugs (including biological products) or devices that are
unapproved, unlicensed, or uncleared by the FDA (regardless of whether
or not approval, licensure, or clearance was sought). This set of
clinical trials would consist of registered applicable clinical trials
that would not otherwise be required to submit clinical trial results
information to ClinicalTrials.gov.
Section 11.62(c) specifies which information must be submitted to
ClinicalTrials.gov and the timelines for submitting such information.
In general, we interpret the references to ``clinical trial
information'' and submission ``in accordance with paragraphs (2) and
(3)'' in section 402(j)(4)(B)(i)(I) of the PHS act to mean registration
information and results information as required in Sec. Sec. 11.28(a)
and 11.48(a), respectively. Consistent with section 402(j)(4)(B)(i)(II)
of the PHS Act, such information must generally be submitted not later
than 30 calendar days after the date specified by the Director in the
notification. We note that section 402(j)(4)(B)(i)(II) of the PHS Act
permits an exception to the submission deadline for results information
if a responsible party submits a certification for delayed results
information submission not later than 30 days after the submission date
specified by the Director in the notification. We also note that if the
responsible party has submitted such a certification under Sec.
11.44(b) or (c), only the submission of results information will be
delayed. Accordingly, if a responsible party for an unregistered
applicable clinical trial subject to Sec. 11.62 submits a
certification not later than 30 calendar days after the submission date
specified in the Director's notification, the responsible party still
would be required to submit registration information not later than 30
calendar days after the submission date specified in the notification,
although results information would be required to be submitted by the
applicable deadline established under Sec. 11.44(b) or (c).
To clarify the submission requirement in situations in which
registration information was submitted to ClinicalTrials.gov before a
notification was sent to the responsible party, Sec. 11.62(c)(3)
indicates that the registration information must be updated, if
necessary, not later than 30 calendar days after the submission date
specified in the notification. Notwithstanding this initial update, the
requirements of Sec. 11.64 would apply to clinical trial information
submitted pursuant to Sec. 11.62.
All clinical trial information submitted to ClinicalTrials.gov
under Sec. 11.62 will be subject to the quality control procedures
described in Sec. 11.64(b)(1). The Agency intends to post such
information as soon as practicable after it has completed the quality
control review process. The timeline for posting would apply to all
clinical trial information submitted under Sec. 11.62, including
registration information for an applicable clinical trial of a device
that has not previously been approved or cleared by the FDA. Section
402(j)(4)(B) of the PHS Act applies equally to applicable clinical
trials of drugs and devices that are approved, licensed, or cleared or
are unapproved, unlicensed, or uncleared. It applies to ``any case'' in
which the Director, as delegated by the Secretary, determines that
posting of clinical trial information on ClinicalTrials.gov (not just
submission of the information to ClinicalTrials.gov) is necessary to
protect public health. Although section 402(j)(4)(B) of the PHS Act
specifically allows for a delay in submission of results information if
the responsible party submits a certification for delayed results
information submission under section 402(j)(3)(E)(iii) of the PHS Act,
it does not specifically delay or prohibit posting submitted
registration information until a device is cleared or approved.
Therefore, the Agency believes that registration information for all
applicable clinical trials under Sec. 11.62 may be posted after
quality control review has concluded, regardless of the approval,
licensure, or clearance status of the device products studied. Of note,
we do not interpret section 402(j)(4)(B) of the PHS Act to permit a
responsible party to request a waiver of the requirement to submit
clinical trial information pursuant to a notification from the Director
under Sec. 11.62. The language of section 402(j)(4)(B) of the PHS Act
states ``Notwithstanding paragraphs (2) and (3)'' (note that waivers
are in paragraph (3)), and only makes the exception for trials with a
certification for delayed results information submission, as described
above. Therefore, it does not make an exception for trials for which a
waiver was granted.
3. Sec. 11.64--When must clinical trial information submitted to
ClinicalTrials.gov be updated or corrected?
Proposed Sec. Sec. 11.64 and 11.66, which described the
requirements and procedures for clinical trial information updates and
corrections respectively, are combined in the final rule under the new
Sec. 11.64--When must clinical trial information submitted to
ClinicalTrials.gov be updated or corrected?, described herein.
Overview of Proposal
When must clinical trial information submitted to ClinicalTrials.gov be
updated?
Section 402(j)(3)(D)(v)(IV) of the PHS Act provides that the
regulations shall also establish ``the appropriate timing and
requirements for updates of clinical trial information, and whether
and, if so, how such updates should be tracked.'' Section 402(j)(4)(C)
of the PHS Act separately requires responsible parties to submit
updates of clinical trial registration information to
ClinicalTrials.gov not less than once every 12 months (except for
certain specified data elements for which more rapid updates are
required) and the Director to post such updates publicly in the data
bank. With regard to the requirement in section 402(j)(3)(D)(v)(IV) of
the PHS Act to establish, by regulation, ``the appropriate timing and
requirements for updates of clinical trial information . . .,'' we
noted in the NPRM that we interpret the term ``clinical trial
information'' to mean both clinical trial registration information and
clinical trial results information, consistent with the definition of
``clinical trial information'' in section 402(j)(1)(A)(iv) of the PHS
Act. In addition, our proposed requirements for updates
[[Page 65109]]
apply to adverse event information because adverse event information is
deemed to be clinical trial results information under section
402(j)(3)(I)(v) of the PHS Act (79 FR 69587).
Proposed Sec. 11.64(a)(1) established a general requirement for
responsible parties to update clinical trial information not less than
once every 12 months if there are changes to any of the data elements
previously submitted. Section 11.64(a)(2) emphasized that this
requirement to update clinical trial information not less than once
every 12 months includes a requirement to update the estimated Primary
Completion Date data element, unless there have been no changes in the
preceding 12 months. We noted that, in our view, the public should be
able to rely upon the accuracy of this date to assist them in
determining when results information may be available on
ClinicalTrials.gov. In general, we recommended that the complete
clinical trial record on ClinicalTrials.gov be reviewed not less than
once every 12 months to help ensure that the clinical trial information
it contains remains accurate. Proposed Sec. 11.64(a)(3) specified that
updates to clinical trial information must be submitted until the date
on which all required clinical trial results information has been
submitted to ClinicalTrials.gov, meaning results for all primary and
secondary outcome measures and all adverse events collected in
accordance with the protocol. After that time, the proposed rule
stated, submitted clinical trial information would continue to be
subject to the corrections provisions in proposed Sec. 11.66 of the
NPRM, and responsible parties would be required to submit corrected
information when the responsible party or the NIH becomes aware of any
errors or needed corrections in the clinical trial information (79 FR
69651).
Proposed Sec. 11.64(b) identified data elements that must be
updated not later than 30 calendar days after a change occurs,
including those already specified in section 402(j)(4)(C)(i) of the PHS
Act (i.e., Recruitment Status and Clinical Trial Completion Status).
Additional data elements identified for more frequent updates were:
Study Start Date; Intervention Name(s); Availability of Expanded
Access; Expanded Access Status; Overall Recruitment Status and, if the
status changes to suspended, terminated, withdrawn, an explanation
about why the study was stopped; and if the status change is terminated
or active, not recruiting, the actual enrollment data; Individual Site
Status; Human Subjects Protection Review Board Status; Completion Date;
Responsible Party, by Official Title; and Responsible Party Contact
Information. Furthermore, Sec. 11.64(b) proposed an even more frequent
update timeline of not later than 15 calendar days for updating the
U.S. FDA Approval, Licensure, or Clearance data element, and stated
that the Record Verification Date must be updated any time the
responsible party reviews the complete record for accuracy, even if no
other updates are submitted at that time (79 FR 69653). It also
specified that if a protocol is amended in such a manner that changes
are communicated to participants in the clinical trial, updates to
relevant clinical trial information must be submitted no later than 30
calendar days after the protocol amendment is approved by the human
subjects protection review board (79 FR 69587).
We noted that the above exceptions to the 12-month period for
updates are considered important for patients using the data bank to
search for clinical trials for which they might qualify and for the
Agency in administering other provisions of section 402(j) of the PHS
Act. In addition, proposed Sec. 11.64(c) would require a responsible
party to update, as necessary, any previously submitted clinical trial
information at the time results information is submitted to
ClinicalTrials.gov (the responsible party would then be required to
update the Record Verification Date data element). The NPRM suggested
that doing so will improve the accuracy of information that is used by
ClinicalTrials.gov to automatically prepopulate some elements of
results information. As set forth in proposed Sec. 11.64(d)(2),
submitted clinical trial information that is posted in accordance with
Sec. Sec. 11.35 and 11.52, including past updates of posted
submissions, are tracked in the ClinicalTrials.gov archive, in which
the history of changes to clinical trial information for any clinical
trial is accessible to the public (79 FR 69587).
What are the requirements for corrections of clinical trial
information?
Proposed Sec. 11.66 of the NPRM set out requirements for
responsible parties to correct clinical trial information submitted to
ClinicalTrials.gov. This included clinical trial information
voluntarily submitted under section 402(j)(4)(A) of the PHS Act and/or
proposed Sec. 11.60, as well as clinical trial information necessary
to protect the public health and submitted under section 402(j)(4)(B)
of the PHS Act and/or proposed Sec. 11.62. Proposed Sec. 11.66
addressed several types of corrections (i.e. correction of errors,
correction of falsified data and other corrections). The discussion in
the NPRM preamble regarding Sec. 11.66 indicated that some errors and
other deficiencies are expected to be detected during quality review
procedures conducted by the Director (79 FR 69654). Section
402(j)(3)(D)(v)(III) of the PHS Act states that regulations shall
establish ``procedures for quality control . . . with respect to
completeness and content of clinical trial information under this
subsection, to help ensure that data elements are not false or
misleading and are non-promotional.'' The discussion of ``Quality
Control Procedures'' in Section III.C.12 of the NPRM outlined the
quality control process that would occur with clinical trial
information as part of submission. This included a two-step process by
which an automated system-based check would occur prior to submission
followed by a detailed, manual review after submission. This detailed
review would be based on quality review criteria for identifying
apparent errors, deficiencies, or inconsistencies that are not detected
by the automated checks. If any such problems are identified in the
detailed, manual review, the proposed rule stated, the Director would
send an electronic notification to the responsible party, indicating
that the submission contains apparent errors, deficiencies, and/or
inconsistencies listing such issues and requesting correction.
Consistent with proposed Sec. 11.66 on correction of errors, the NPRM
further outlined that responsible parties would be required to correct
the errors, deficiencies, and/or inconsistencies in clinical trial
information not later than 15 calendar days after being informed of
them by the Agency (or otherwise becoming aware of them), whichever is
later. The NPRM also recognized that because clinical trial information
will have to be posted not later than the 30 day posting deadlines
specified in Sec. Sec. 11.35 and 11.52, there may be some situations
in which submitted clinical trial information is posted before it has
been corrected. We noted that it would be necessary to include
information indicating that such information has not completed the
quality control process as well as implementing other mechanisms to
help users of ClinicalTrials.gov identify such clinical trial records
(79 FR 69586).
Although the statute did not establish timelines for correcting
errors, Sec. 11.66 proposed that corrections needed to be submitted
after the responsible party becomes aware that submitted clinical trial
information is incorrect or falsified or that corrections are needed
for other
[[Page 65110]]
reasons. Section 11.66(a) required responsible parties to correct
errors not later than 15 calendar days after the error is discovered.
Section 11.66(b) covered falsified data and proposed to require
notification to the Director of the falsification and submission of
corrected information not later than 15 calendar days after the
corrected information becomes available or notification not later than
15 calendar days after determining that the information cannot be
corrected or is correct. Section 11.66(c) addressed ``other corrections
of clinical trial information'' which were identified as ``various
other deficiencies'' including but not limited to ``inconsistencies in
submitted data, for example, a mismatch between the reported number of
subjects enrolled in a clinical trial and the sum of reported number of
subjects assigned to different arms . . .''(79 FR 69655) and stated
that a responsible party who becomes aware or is informed by NIH that
such corrections are needed must make them as soon as possible but not
later than 15 calendar days after becoming aware or being informed of
the problem.
Comments and Response
When must clinical trial information submitted to ClinicalTrials.gov be
updated?
Commenters addressed the update provisions in Sec. 11.64, with
some in support of the proposed approach, while others suggested
changes to the required updates and the proposed timelines. Among those
who suggested changes, commenters suggested that the specific timelines
for updates were too short. Some commenters suggested alternative
timelines for updates, including that the general timeline for updates
should be extended from not less than once every 12 months to once
every 18 months; the 30-day timeframe for rapid updates should be
extended to 45 or 60 days; and that all the timelines for each rapid
update element should be consistent (i.e., the timeline for updating
the U.S. FDA Approval, Licensure, or Clearance data element should also
be 30 calendar days). Although commenters suggested extending the
timelines, the 12 month general timeline is established by section
402(j)(4)(C)(i)(I) of the PHS Act. Similarly, the 30 day timeline
following changes to Overall Recruitment Status and Completion Date is
established by section 402(j)(4)(C)(i)(III) and section
402(j)(4)(C)(i)(IV) of the PHS Act. While the statute would allow for
modifying the 30 day timeline for other data elements, sufficient
evidence of burden was not provided by the public comments indicating
that these deadlines would be difficult to meet. Moreover, we believe
it makes sense, in the interest of simplicity (as has also been sought
by commenters), to keep the timeline for updates consistent to the
extent possible. Finally, rapid updating of this information is
consistent with the stated purpose of ClinicalTrials.gov set forth in
section 402(j)(2)(A)(i) of the PHS Act to ``enhance patient enrollment
and provide a mechanism to track subsequent progress of clinical
trials.'' If such key changes were not reflected in the record in
ClinicalTrials.gov for as long as 12 months after the change, then the
Agency believes that the value of ClinicalTrials.gov as a source of
reliable, accurate information for the public and potential
participants in clinical trials would be compromised.
Commenters also raised issues regarding specific data element
update requirements. One disagreed with the requirement that actual
enrollment data be provided when the Overall Recruitment Status changes
(i.e., trial's recruitment status changes to ``terminated'' or
``active, not recruiting'') and suggested that the NIH continue to
allow submission of actual enrollment data at the time of overall study
completion (e.g., LPLV). The Agency believes that submission of actual
enrollment information at the time that recruitment is no longer
occurring (Overall Recruitment Status is ``terminated'' or ``active,
not recruiting'') would permit users of ClinicalTrials.gov to know more
quickly whether the clinical trial achieved its target enrollment.
However, we also recognize the potential burden and some of the
challenges with providing such information in a more rapid manner. In
the final rule, therefore, we modify the requirement to be consistent
with current practice at ClinicalTrials.gov by requiring actual
enrollment to instead be updated within 30 calendar days of reaching
the Primary Completion Date.
Another commenter opposed the requirement that the status of
individual sites be updated because of concerns about burden on large
international trials. The Agency believes that changes in recruitment
status should be communicated promptly so that potential human subjects
can know whether or not a clinical trial is currently recruiting
subjects. In addition, prompt updates to Overall Recruitment Status as
well as Individual Site Status support the purpose of
ClinicalTrials.gov to enhance patient enrollment by assisting potential
human subjects who search for clinical trials by location and wish to
retrieve information about only those trials that are open to
recruitment in specified locations. We clarify that when the Overall
Recruitment Status is other than ``recruiting,'' the Individual Site
Status no longer needs to be updated because a change in the Overall
Recruitment Status would apply to each individual site and the
Individual Site Status will no longer be displayed by
ClinicalTrials.gov on the publicly posted study record. We also note
that the update burden to responsible parties is reduced by tools
available in the PRS that allow for easily changing the Individual Site
Status (e.g., from ``recruiting'' to ``active, not recruiting'') for
many sites at once.
Another commenter raised a question about which IRB approval date
is relevant in a multi-site trial involving multiple IRBs in response
to the requirement to update the record not later than 30 calendar days
after an amended protocol is approved by an IRB that involves changes
that are communicated to participants. We clarify that the date of the
first IRB approval for the amendment should be used. We note that we
invited public comment on other thresholds (other than those changes
that are communicated to enrolled participants) that could be used to
determine which protocol changes are significant enough to warrant 30-
day updating of affected clinical trial information, but none was
received.
Comments were also raised in opposition to the proposal to require
voluntarily registered trials to comply with the update and correction
timelines due to the burden involved. It was suggested that the
requirement may have the unintended consequence of decreasing voluntary
submissions and, thereby, transparency. The Agency believes that in
order to maintain the value of ClinicalTrials.gov as a source of
accurate and up-to-date clinical trial information each record,
including voluntary submissions, must be updated in accordance with the
timelines outlined in the final rule. Other commenters requested that a
mechanism be included in the PRS to make clear to responsible parties
when they have fulfilled all obligations to update the study record,
and no further updates are required. Proposed Sec. 11.64(a)(3)
indicated that the responsible party must continue to submit updates
until complete ``clinical trial results information specified in Sec.
11.48 has been submitted for all primary and secondary outcomes and all
adverse events that were collected in accordance with the protocol.''
We agree with the commenters on the need for
[[Page 65111]]
being able to identify when the obligation to update and/or correct
clinical trial information has ended. As one component of this
determination, we have added to Sec. Sec. 11.10(a) and 11.28, the
Study Completion Date data element to identify ``the date the final
subject was examined or received an intervention for purposes of final
collection of data for the primary and secondary outcome measures and
adverse events (e.g., last subject's last visit) . . .'' Providing the
Study Completion Date as clinical trial information and including it as
a data element that must be updated within 30 calendar days of a change
is consistent with the stated purpose of ClinicalTrials.gov to ``. . .
provide a mechanism to track subsequent progress of clinical trials''
(see section 402(j)(2)(A) of the PHS Act). Further, it establishes the
date on which the final subject was examined (or received an
intervention) for purposes of final data collection, thereby
identifying the maximum date under Sec. 11.44(d) by which partial
results information must be submitted (i.e., no later than one year
after the Study Completion Date).
The NPRM indicated that the obligation to update ends after
submission of complete clinical trial results information. We clarify
that the obligation to submit updates ends after all required clinical
trial results information has been submitted as specified in sections
402(j)(3)(C) and 402(j)(3)(I) of the PHS Act or as specified in Sec.
11.48, as applicable, and after any corrections have been made or
addressed as required under Sec. 11.64(b). We note that one reason it
is important for the update requirements to continue through the
conclusion of the quality control process is to ensure that the
Responsible Party and Responsible Party Contact Information remains
accurate during that process. We also have clarified that for any
clinical trials that are not subject to the clinical trial results
information submission requirements, the obligation to update ends on
the date on which all required clinical trial registration information
has been submitted as specified in section 402(j)(2)(A)(ii) of the PHS
Act or Sec. 11.28, as applicable, and corrections have been made or
addressed in response to any electronic notice received under Sec.
11.64(b)(1).
What are the requirements for corrections of clinical trial
information?
Commenters addressing the proposed quality control procedures and/
or the corrections provisions proposed in Sec. 11.66 commented on the
amount of time a responsible party has to correct clinical trial
information, timing of posting of clinical trial information in
relationship to quality control procedures, and the falsified data
provisions. Each of these topics is discussed in turn.
Commenters submitting input on the corrections provisions in Sec.
11.66 of the NPRM expressed general support for the requirement to
correct errors and some commenters also supported the 15 day timeline
for addressing corrections. Other commenters expressed concern about
the timeline for correction of errors, as they found it too short and
suggested that it was insufficient, unrealistic, and burdensome.
Commenters suggested that a rush by responsible parties to meet the
deadline might result in the unanticipated submission of more errors.
Alternative timeframes were proposed by commenters, who suggested
extending the correction of error timeline to 30 days, 45 days, and 60
days. One commenter proposed allowing 15 days for the responsible party
to notify the NIH from the time an error is discovered followed by a 30
day timeline to make any corrections. As noted in the NPRM discussion
of quality control procedures (Section III.C.12), the Agency expects to
conduct a quality control review and also aims to receive submission of
corrected clinical trial information prior to the deadlines for posting
such information publicly as specified in Sec. Sec. 11.35 and 11.52
(i.e., not later than 30 calendar days after submission). We are,
therefore, maintaining the proposed timeline of 15 calendar days for
the responsible party to correct clinical trial registration
information after a notification is sent by the Director, but we are
extending the timeline for correction of clinical trial results
information to ``25 calendar days.'' These timelines are in place for
two reasons: (1) To allow, in some cases, corrected clinical trial
information to be submitted by the responsible party in a timeline that
would allow for quality control review and posting in accordance with
the timelines in Sec. Sec. 11.35 or 11.52; and, (2) to minimize the
amount of time that posted clinical trial information is available
without conclusion of the quality control review process. In our
experience in operating the registry component of ClinicalTrials.gov,
we have found that clinical trial registration information can be
reviewed quickly and that responsible parties can submit corrected
information, if necessary, in a matter of days. However, allowing for a
longer timeline for corrections of clinical trial results information
acknowledges the inherent difference in complexity of the information
as compared to clinical trial registration. To better distinguish
between corrections that may be needed based on quality control by the
Director and other corrections that are needed based on identification
by the responsible party, we are modifying the corrections provisions
in the final rule to address these separately. When a responsible party
becomes aware of errors, the timelines to correct or address such
errors are 15 calendar days for registration information and 25
calendar days for results information. We clarify in the discussion of
the final rule requirements for corrections, the steps that can be
taken when the Director notifies a responsible party of issues.
As initially discussed in the context of Sec. Sec. 11.35 and
11.52, a number of commenters expressed the importance of quality
control and suggested that both registration and results information
should be posted only when quality control review criteria have been
fulfilled. Commenters expressed concern about the potential to
misinform those using the publicly posted study record and suggested
only posting sections that have fulfilled quality control criteria.
Some commenters suggested that the harm of posting information that has
not passed quality control review is greater than posting the
information in a timely manner. While we understand these concerns,
section 402(j)(3)(G) of the PHS Act established for applicable clinical
trials that the Director of NIH is required to post results information
``publicly in the registry and results database not later than 30 days
after such submission.'' In addition, because there may be cases in
which clinical trial information is posted without conclusion of the
quality control review process, a shorter timeline for corrections will
minimize the amount of time such records are posted. In the event that
a study record is posted in accordance with the statutory posting
deadline, and the quality control review has not concluded, the
clinical trial record will contain information that will be visible to
the public explaining that the quality control review process for the
posted clinical trial information has not concluded.
Regarding the proposed statements on a study record, commenters
were concerned that users of ClinicalTrials.gov may not understand such
notices and may make decisions based on information that is inaccurate,
unclear, or incomplete. To address this concern, we will evaluate
whether there are ways in which the notices for each
[[Page 65112]]
record could specify the data element(s) identified by the Agency that
may contain errors, deficiencies, and/or inconsistencies, and aim to
employ other measures to ensure that the notice is clear and limited to
the relevant sections. We note that the quality control review process
will continue even after the information is posted with a notice
indicating the process has not concluded. The general quality control
review process and the specific criteria utilized by the Director to
evaluate submitted results will be available at https://prsinfo.clinicaltrials.gov (or successor site), prior to the effective
date, for responsible parties and the public to have a better
understanding of the types of issues reviewed.
Responsible parties must correct or address apparent errors,
deficiencies, and/or inconsistencies within 15 calendar days (clinical
trial registration information) or 25 calendar days (clinical trial
results information) of the date the Director provides electronic
notification to the responsible party. Quality control review
procedures will be followed for any subsequent submission of revised
clinical trial information. When the responsible party submits revised
clinical trial information, or provides explanatory information that
addresses the apparent errors, deficiencies, and/or inconsistencies,
any revised information will be posted after quality control review.
Further, when all apparent errors, deficiencies, and/or inconsistencies
have been addressed, the statement that the quality control review
process had not concluded will be removed from the posted record.
However, the clinical trial information that was initially posted will
appear in the archived history for that clinical trial record, and the
archived version will indicate that it had been posted with a notice.
The electronic notification sent to the responsible party indicating
that the quality control review process has concluded will inform
responsible parties of these facts. We hope this notification further
encourages those with posted records that contain such a statement to
correct the information or address the issues raised by the quality
control review process as soon as possible, to help ensure that users
of ClinicalTrials.gov may rely on the information in the trial records,
as intended.
Some commenters requested more information, such as additional
guidance regarding quality control processes, while others made
suggestions, such as NIH development of common standards for quality
control or development of a process that involves domain experts. To
assist responsible parties in avoiding such errors, deficiencies, and
inconsistencies prior to this final rule, we developed and continued to
refine documentation explaining how to meet the quality review
criteria; identified and compiled lists of frequent errors,
deficiencies, and inconsistencies in submitted results information;
and, provided system support to help responsible parties minimize such
errors, deficiencies, and inconsistencies. We also have provided
intensive user support for responsible parties who are new to the
online submission process, particularly for results information,
whether through data entry using Web-based forms or automated uploading
of data files. In particular, we provide one-on-one assistance to
support a responsible party in submitting their clinical trial results
information. We have developed and posted draft educational materials,
such as tips on improving results information submissions and ways to
avoid common errors, deficiencies, and inconsistencies observed in
submissions to date. All such documents are available at https://prsinfo.clinicaltrials.gov (or successor site). We will continue to
provide such support to responsible parties and, based on these
interactions, develop new or updated materials in order to facilitate
and streamline preparation of clinical trial information for submission
to ClinicalTrials.gov and to help ensure that the submissions meet the
quality review criteria.
Commenters also addressed the falsified data correction provision
proposed in Sec. 11.66(b) and suggested that it was vague and unclear
about when errors should be reported as falsified data and how
responsible parties are to determine when sufficient credible evidence
exists to warrant a falsification report. They noted that no guidelines
were provided for what events should trigger a presumption that data
may be false and what constitutes a suitable investigation, and no
distinctions were made about materiality, e.g., inaccuracies about the
recruitment status versus inaccuracies about the validity of safety
data. Commenters inquired about the sanctions that would go with each
determination (error versus falsification) and asserted that a more
clearly defined and formal process would need to be in place to ensure
a thorough investigation is conducted before inaccuracies are reported
as falsified data. In addition, commenters suggested that the
falsification provision could result in depriving responsible parties
of their right to due process under the Fifth Amendment because it
would require companies to report falsification without establishing
clear parameters for what constitutes falsification. One commenter
asserted that, given that there are criminal penalties for making false
statements to the Government, the offense must be sufficiently explicit
to inform those who are bound by the law of the specific conduct that
will subject them to criminal penalties. A commenter suggested that it
was inappropriate to incorporate into the NPRM a definition of
falsification from FDA's proposed Reporting Information Regarding
Falsification of Data regulation (Docket No. FDA-2008-N-0115, 75 FR
7412 (Feb. 19, 2010)). Commenters also suggested that the certification
and falsification provisions should undergo a separate rulemaking
process to determine what constitutes falsification and intent, and
such process should be used and carried out in conjunction with FDA and
other federal biomedical research stakeholders to propose a system for
addressing the important and complicated issues related to intentional
research falsification. Another commenter suggested that a disclaimer
should be included in clinical trial records to inform the public that
ClinicalTrials.gov is not responsible for the accuracy of the study
results. Based on consideration of these comments, the final rule
eliminates the distinctions between the types of errors (i.e. errors,
falsifications, other errors) and simplifies the regulatory approach
for correction of errors as described below and in Sec. 11.64(b). From
a database integrity standpoint, the distinction between an inadvertent
and a deliberate error is not material, and eliminating this
distinction is responsive to concerns raised by public comments.
However, we emphasize existing mechanisms that address scientific
misconduct (see Sec. 11.6 and Section IV.A.3 of this preamble).
Final Rule
Taking into consideration commenters' suggestions regarding both
updates (proposed Sec. 11.64) and corrections (proposed Sec. 11.66),
as well as the statutory requirements, the final rule combines these
sections into the new Sec. 11.64--When must clinical trial information
submitted to ClinicalTrials.gov be updated or corrected? While both the
updates and corrections provisions in these sections include specific
timelines by which clinical trial information must be updated or
corrected, we encourage responsible parties to update or correct
[[Page 65113]]
information as soon as possible to help the ensure that posted clinical
trial information is accurate and up-to-date for those that rely on the
information on ClinicalTrials.gov. Additionally, final Sec. 11.64(a)
clarifies that ``drug'' means ``drug product.''
Required updates are described in Sec. 11.64(a), which generally
retains the NPRM proposal for required updates but modifies the
requirement for the timing of updating actual enrollment information.
Consistent with the revisions discussed in preceding sections of this
preamble, Sec. 11.64(a) also adds a requirement to update Study
Completion Date and clarifies the requirements for data elements
related to expanded access. In addition, we clarify how a responsible
party indicates that there were no changes to clinical trial
information in the previous 12 month period. Modifications were also
made to clarify when a responsible party's obligation to update and
correct clinical trial information ends. In addition, consistent with
the discussion in section IV.F of this preamble, we made revisions to
address the differing requirements that apply to applicable clinical
trials (and, if voluntarily submitted, other clinical trials).
For clinical trials initiated before the effective date of the
final rule, Sec. 11.64(a)(1)(i)(A) establishes a general requirement
for responsible parties to update clinical trial registration
information specified in section 402(j)(2)(A)(ii) not less than once
every 12 months if there are changes to any of the data elements
previously submitted. Section 11.64(a)(1)(i)(B) and (a)(1)(i)(C) detail
the requirement to update the Overall Recruitment Status data element
not later than 30 calendar days after any change in overall recruitment
status and the Primary Completion Date data element not later than 30
calendar days after the clinical trial reaches its actual primary
completion date.
For clinical trials initiated on or after the effective date of the
final rule, Sec. 11.64(a)(1)(ii)(A) establishes a general requirement
for responsible parties to update clinical trial registration
information specified in Sec. 11.28 not less than once every 12 months
if there are changes to any of the data elements previously submitted.
Section 11.64(a)(1)(ii)(B) through (a)(1)(ii)(O) establish requirements
for a responsible party to update certain clinical trial registration
information more rapidly after a change in the status or conduct of a
clinical trial or pediatric postmarket surveillance of a device
product. The NIH recognizes that it would be impractical and
potentially burdensome to responsible parties to require rapid updates
to all clinical trial information data elements each time a change
occurs, but we believe that changes to certain data elements beyond
those required to be rapidly updated in section 402(j) of the PHS Act
are sufficiently time-sensitive to require updates more rapidly than
once every 12 months.
Section 11.64(a)(1)(ii) outlines the requirements for updating the
following 14 data elements:
(1) Study Start Date. The Study Start Date data element must be
updated from estimated to actual not later than 30 calendar days after
the first human subject is enrolled in the clinical trial. This
requirement applies to clinical trials for which an estimated study
start date is provided at the time of registration, rather than an
actual study start date, i.e., clinical trial registration information
was submitted prior to enrollment of the first human subject. The
update ensures that potential human subjects know in a timely fashion
that recruitment has begun. It also ensures that the record reflects
the actual start date, as opposed to an estimated start date, and it
provides a mechanism to demonstrate whether a clinical trial has been
registered not later than 21 calendar days after enrollment of the
first subject.
(2) Intervention Name(s). The Intervention Name(s) data element
must be updated to a non-proprietary name not later than 30 calendar
days after a non-proprietary name is established for an intervention
studied in a clinical trial. Intervention Name is frequently used as a
search term to identify and retrieve clinical trials of interest. If it
is not updated for as long as a year, users of ClinicalTrials.gov will
not be able to accurately retrieve trials of interest during that time
or to easily compare information among multiple trials of the same
intervention.
(3) Availability of Expanded Access. Clinical trial information
submitted under the Availability of Expanded Access data element in
Sec. 11.28(a)(2)(ii)(H) must be updated by the responsible party who
is both the manufacturer of the drug and the sponsor of the applicable
clinical trial not later than 30 calendar days after expanded access
becomes available. Similarly, the data element must be updated not
later than 30 calendar days after the date on which the responsible
party receives an NCT number for the expanded access record. This data
element informs patients whether access to an investigational drug
product (including a biological product) to treat serious or life-
threatening diseases or conditions is available outside of the
applicable clinical trial. Expanded access may not be available at the
time clinical trial registration information is submitted, and expanded
access may no longer be available on a date other than the primary
completion date of the applicable clinical trial. Therefore, there are
specific update requirements:
First, when expanded access for a particular investigational drug
product (including a biological product) becomes available after
registration information has been submitted for applicable clinical
trial(s) of that investigational product, if the responsible party for
the applicable clinical trial(s) is both the manufacturer of the
investigational product and the sponsor of the applicable clinical
trial, the responsible party must update the Availability of Expanded
Access data element in Sec. 11.28(a)(2)(ii)(H) not later than 30
calendar days after expanded access becomes available.
Second, not later than 30 calendar days after expanded access
becomes available, if the responsible party is both the manufacturer of
the investigational drug product and the sponsor of the applicable
clinical trial, the responsible party must create an expanded access
record by submitting the data elements required under Sec. 11.28(c),
unless an expanded access record for the investigational drug product
has already been created. The responsible party is required to enter
the NCT number of the expanded access record in the relevant clinical
trial record(s) not later than 30 calendar days after the date on which
the responsible party receives such NCT number. We note that we have
removed the NPRM proposal to also require a responsible party to update
the Availability of Expanded Access data element not later than 30
calendar days after termination of the expanded access program. The
provision of the NCT number of the expanded access record as well as
the requirement to update the Expanded Access Record data element as
described in Sec. 11.64(a)(1)(ii)(E) will allow for ClinicalTrials.gov
to ensure that information on the availability of expanded access is
accurately displayed on the relevant posted record(s), while reducing
the update burden on a responsible party.
We note that, as discussed below, Sec. 11.64(a)(3) establishes
when a responsible party's obligation to submit updates for clinical
trial information ends. Even if an investigational product has not been
approved or licensed at the time the updating requirement ends, we
strongly encourage responsible parties to continue to update the
Expanded Access Record until the product is approved or licensed or
expanded
[[Page 65114]]
access is no longer available. Updating this information will provide
patients with accurate and up-to-date information about the
availability of investigational products, which we believe will
facilitate access to such products. Second, updating expanded access
records may reduce the burdens on responsible parties who are both the
manufacturer and the sponsor of the applicable clinical trial, because
patients who are interested in expanded access will be able to rely on
the information in ClinicalTrials.gov, rather than having to contact
the responsible party in order to obtain this information.
(4) Expanded Access Record. The Expanded Access Status data element
in Sec. 11.28(c)(2)(iv) must be updated not later than 30 calendar
days after a change in the status of the availability of expanded
access, to indicate whether access to the investigational drug product
is currently available. This data element plays a role in providing
information about expanded access that is similar to the role of
Overall Recruitment Status in applicable clinical trials, indicating
whether expanded access is currently available to patients. Expanded
Access Type in Sec. 11.28(c)(1)(x) must be updated not later than 30
calendar days after a change in the type of expanded access that is
available to patients. The timely update of these data elements is
important to have reflected in the data bank and is consistent with
statutory requirements.
(5) Overall Recruitment Status. This data element must be updated
not later than 30 calendar days after a change in the overall
recruitment status of the clinical trial. Changes in recruitment status
should be communicated promptly so that potential human subjects can
know whether or not a clinical trial is currently recruiting subjects.
In addition, if Overall Recruitment Status is updated to ``suspended,''
``terminated,'' or ``withdrawn,'' the responsible party must at the
same time provide information for the Why Study Stopped data element.
Suspension, termination, and withdrawal of a clinical trial are
significant changes that should be communicated promptly to prospective
human subjects, along with the reason for the change. The responsible
party will be allowed to enter this information as free-text so that he
or she has flexibility to explain the reason(s) why a clinical trial
stopped prematurely.
(6) Individual Site Status. This data element must be updated not
later than 30 calendar days after a change in status for any individual
site. It also supports the purpose of ClinicalTrials.gov to enhance
patient enrollment by assisting potential human subjects who search for
clinical trials by location and wish to retrieve information about only
those trials that are open to recruitment in specified locations.
(7) Human Subjects Protection Review Board Status. This data
element must be updated not later than 30 calendar days after a change
in Human Subjects Protection Review Board Status. Because such
information is intended to demonstrate to potential human subjects
whether a registered applicable clinical trial or other clinical trial
has undergone necessary human subjects protection review board review,
has received necessary approvals for human subjects research, or was
exempt from such review, it must be updated in a timely fashion.
(8) Primary Completion Date. This data element must be updated not
later than 30 calendar days after a clinical trial reaches its actual
primary completion date. In addition, at the time the date is changed
to ``actual,'' the responsible party must also update the Enrollment
data element to actual and specify the actual number of participants
enrolled.
(9) Study Completion Date. This data element must be updated not
later than 30 calendar days after a clinical trial reaches its actual
study completion date.
(10) Responsible Party, by Official Title. This data element must
be updated not later than 30 calendar days after a change in either the
name of the responsible party or in the responsible party's official
title. This update is necessary to enable NIH and other users of the
data bank to accurately identify the responsible party for the clinical
trial.
(11) Responsible Party Contact Information. Consistent with updates
required to the Responsible Party data element, the Responsible Party
Contact Information must be updated not later than 30 calendar days
after a change in the responsible party or the responsible party's
contact information. Given that the responsible party must make updates
to clinical trial information and, in general, must submit clinical
trial results information, it is essential for the Agency to know of
changes to the responsible party and to responsible party contact
information in a timely manner. Up-to-date information about the
responsible party ensures that the Agency has contact information for
the appropriate person responsible for submitting clinical trial
information about the applicable clinical trial or clinical trial.
(12) Device Product Not Approved or Cleared by U.S. FDA. This data
element must be updated not later than 15 calendar days after a change
in the approval or clearance status of one or more device products
studied in the applicable clinical trial. A change in the approval or
clearance status of a device product can trigger a requirement for the
Agency to post previously-submitted clinical trial registration
information within 30 calendar days of the change in status as further
discussed in Section IV.B.5 of this preamble. The 15 day deadline is a
procedural necessity to provide the Agency timely notice that it must
post publicly clinical trial registration information within 30
calendar days of the change in status, as required by law.
(13) Record Verification Date. This data element must be updated
any time the responsible party reviews the complete set of submitted
clinical trial information for accuracy, even if no other updated
information is submitted at that time. The record verification date is
intended to demonstrate when the information in ClinicalTrials.gov for
a particular clinical trial was last checked for accuracy. As noted in
Sec. 11.28, the responsible party will be required to update the
Record Verification Date if he or she examines the complete set of
submitted clinical trial information (e.g., as part of a monthly or
annual review), even if he or she determines that no additional or
updated information needs to be submitted. Similarly, the responsible
party will be required to update the Record Verification Date data
element if he or she updates a data element and reviews the rest of the
record for accuracy. However, the responsible party is not required to
update the Record Verification date if he or she submits updates to one
or more data elements without reviewing the accuracy of the rest of the
record. We clarify that the Record Verification Date must be updated
not less than once every 12 months, even if no other updated
information is submitted at that time. This approach does not require a
responsible party to review records more frequently or regularly than
will be needed in order to update submitted information as otherwise
required by Sec. 11.64(a), but it does require that the Record
Verification Date be updated if the complete record were reviewed for
accuracy during such an update and not less than once every 12 months.
Doing so indicates to users of ClinicalTrials.gov the currency of the
information and provides an additional assurance that it is up-to-date.
(14) Subsection 11.64(a)(1)(ii)(O) details that relevant clinical
trial
[[Page 65115]]
registration information be updated not later than 30 calendar days
after a protocol amendment is approved by a human subjects protection
review board, if the protocol is amended in such a manner that changes
are communicated to participants in the applicable clinical trial or
other clinical trial.
In addition, Sec. 11.64(a)(1)(iii) requires that responsible
parties update clinical trial registration information at the time they
submit clinical trial results information to ClinicalTrials.gov (unless
there are no changes to the clinical trial registration information).
If the clinical trial was initiated before the effective date of the
final rule, updates to clinical trial registration information must be
submitted as described in Sec. 11.64(a)(1)(i). If the clinical trial
was initiated on or after the effective date of the final rule, updates
must be submitted in accordance with Sec. 11.64(a)(1)(ii). As
discussed further in Section IV.F, this approach is consistent with the
Agency's interpretation of the differing requirements that apply to
applicable clinical trials initiated before the effective date of the
final rule and those initiated on or after the effective date of the
final rule. This requirement is intended to help ensure the consistency
and accuracy of information in the registry and results portions of the
data bank. Updated registration information will be used to pre-
populate certain data elements in the clinical trial record so that
responsible parties do not have to enter them again. Because the
submission and subsequent posting of clinical trial results information
is often a reason for users to retrieve the record for a particular
clinical trial, the additional update requirement will also ensure that
users have access to complete registration and results information that
is up-to-date.
For clinical trials that have a primary completion date on or after
the effective date of the final rule, Sec. 11.64(a)(2)(i) establishes
a general requirement for responsible parties to update clinical trial
results information not less than once every 12 months if there are
changes to any of the data elements previously submitted. The final
rule also clarifies that the protocol and statistical analysis plan
specified in Sec. 11.48(a)(5) and certain agreements specified in
Sec. 11.48(a)(6)(ii) are excluded from this general requirement as any
changes to this content will be submitted as partial results
information in Sec. 11.44(d)(3). Section 11.64(a)(2)(ii) requires for
applicable device clinical trials of unapproved or uncleared device
products that the following data elements, as the data elements are
defined in Sec. 11.10(b), be updated not later than 30 calendar days
after the relevant changes have occurred: Intervention Name(s), Primary
Completion Date, Study Completion Date, and Overall Recruitment Status.
The Record Verification Date must be updated any time the responsible
party reviews the complete set of submitted clinical trial information
for accuracy and not less than every 12 months. As described in Section
IV.C.4 of this preamble for Sec. 11.48(a)(7), we interpret the statute
to provide the Secretary the authority to require, through rulemaking,
for applicable device clinical trials of unapproved or uncleared device
products this additional descriptive information that is similar to the
type of information required to be submitted under section
402(j)(2)(A)(ii) of the PHS Act.
Section 11.64(a)(3) specifies that updates to clinical trial
information must be submitted until the date on which all required
clinical trial results information has been submitted as specified in
sections 402(j)(3)(C) and 402(j)(3)(I) of the PHS Act or Sec. 11.48
(as applicable), and all corrections have been made or addressed in
response to any electronic notice received under Sec. 11.64(b)(1).
Until that point in time, submitted clinical trial information will
continue to be subject to the corrections provisions in Sec. 11.64(b),
and responsible parties will be required to submit corrected
information when the responsible party becomes aware of any errors in
the clinical trial information. We have clarified that if no clinical
trial results information is required to be submitted, a responsible
party's obligation to submit updates ends on the date on which all
required clinical trial registration information has been submitted as
specified in section 402(j)(2)(A)(ii) of the Public Health Service Act
or Sec. 11.28, as applicable, and corrections have been made in
response to any electronic notice received under Sec. 11.64(b)(1).
We note that the updating requirements under Sec. 11.64(a) are
prompted by changes in the clinical trial and not by changes in the
format in which data must be submitted to ClinicalTrials.gov. For
example, if the Agency were to make administrative changes to the
format in which clinical trial information is submitted to
ClinicalTrials.gov after the responsible party had submitted clinical
trial information as required, the Agency's revisions to
ClinicalTrials.gov would not themselves give rise to a requirement that
the responsible party update the previously submitted applicable
clinical trial information. For example, if the Agency added additional
options to a drop-down menu for a particular data element, even if one
of the additional options is more appropriate with respect to an
applicable clinical trial, the responsible party would not be required
to update its previously-submitted clinical trial information, although
the responsible party it could choose to do so on an optional basis.
However, if a responsible party makes a required update to previously
submitted clinical trial information, for example, to reflect a change
in the conduct or progress of a clinical trial, the responsible party
is required to submit the updated information in the format required by
ClinicalTrials.gov at the time the update is submitted. For example, if
the set of options in a drop-down menu had changed since the
information had previously been submitted, the responsible party is
required to select from the new set of options. We also note that if
such options were modified, we would provide prior notice and seek
public comment as described in Section IV.A.4, as needed.
Updates to clinical trial registration information and clinical
trial results information will be posted in accordance with Sec. Sec.
11.35 and 11.52, respectively. Previously posted clinical trial
information will remain publicly available through the
ClinicalTrials.gov archive. The availability of updates is codified in
Sec. 11.64(a)(4).
With regard to the requirements for corrections of clinical trial
information, the final rule eliminates the distinction between the
three types of corrections described in the NPRM: Errors, falsified
data, and other corrections. We clarify, however, that the elimination
of ``falsification'' as a type of error does not reflect a lack of
concern about data integrity or tolerance by the Agency for
falsification of information, and we emphasize the existing mechanisms
that address scientific misconduct and falsifying information submitted
to the Government in Sec. 11.6. Instead, Sec. 11.64(b) of the final
rule requires a responsible party to correct or address (1) apparent
errors, deficiencies, and/or inconsistencies identified by the Director
during quality control review of submitted clinical trial information;
and, (2) errors in previously submitted information identified by the
responsible party. We also reiterate the procedures for quality control
review that were originally described in the NPRM in Section III.C.12
and that are directly related to the corrections provisions of this
final rule. Overall, we consider corrections of information to be
different from updates to
[[Page 65116]]
information, as described in Sec. 11.64(a). While updates are
modifications to clinical trial information that reflect changes in the
status or conduct of a clinical trial or the associated analysis,
corrections are used to revise submitted clinical trial information
that contains errors or appears to be invalid, incorrect, inconsistent,
or incomplete. Because problems in clinical trial information that is
(or will soon be) posted publicly need to be addressed in a timely
manner in order to ensure that accurate information is available to the
public, the final rule requires responsible parties to correct or
address all such problems not later than 15 calendar days for clinical
trial registration information and 25 calendar days for clinical trial
results information after electronic notification is sent by the
Director or are otherwise identified by the responsible party. A
responsible party must then either correct and resubmit the clinical
trial information to ClinicalTrials.gov or address each identified
issue, such as replying by electronic notification to the Director
explaining why the information is correct as submitted or why such
information cannot be corrected.
Section 11.64(b)(1) specifies the requirements for correcting
apparent errors, deficiencies, and/or inconsistencies identified based
on quality control review procedures established by the Director
(materials explaining how to meet the quality review criteria are
available at https://prsinfo.clinicaltrials.gov or successor site). Our
quality control review process is intended to help ensure that clinical
trial information posted on ClinicalTrials.gov has facial validity and
is free from obvious errors. Examples of errors, deficiencies, and/or
inconsistencies that may be identified during the quality control
review process include, but are not limited to, inadvertent,
typographical errors, such as transpositions of numbers or characters;
inadvertent omissions of data, such as omission of one component of set
of participant exclusion criteria; inconsistencies in submitted data,
for example, a mismatch between the reported number of subjects
enrolled in a clinical trial and the sum of reported number of subjects
assigned to different arms; and, incomplete entries that are
insufficient to convey their intended meaning, such as a description of
an outcome measure that does not describe the measurement scale being
used. They also include submitted values that are demonstrably wrong,
such as a mean age of participants of 624 years.
At the time of submission of clinical trial registration
information, clinical trial results information, and any related
updates or changes, the Agency will conduct quality control review
procedures that are similar to the procedures in place before the final
rule and will not affect the statutory deadlines for the submission and
updating of clinical trial information (as specified in Sec. Sec.
11.24, 11.44, and 11.64(a)) or publicly posting submitted clinical
trial information (as specified in Sec. Sec. 11.35 and 11.52). In
general, we aim to complete the quality control review process and to
receive submissions of corrected clinical trial information prior to
the statutory deadlines for posting submitted clinical trial
information publicly. We recognize that in some situations, the quality
control review process may not be concluded prior to the statutory
posting deadlines, and the Agency will post submitted information that
may need to be corrected. Clinical trial information posted without
having concluded the quality control review process, including any
necessary corrections by the responsible party, will include a
statement indicating that the quality control review process has not
concluded. In addition, as also mentioned in Section IV.B.5 of this
preamble, if the quality control review process has not concluded but
the clinical trial registration information is posted to the
ClinicalTrials.gov Web site based on the statutory posting deadline, an
NCT number will not be assigned until the quality control review
process has concluded. We believe additional precautions must be taken
with such clinical trial registration information because it is used by
the public, including by patients and healthcare providers who are
considering enrollment in a clinical trial. This approach is generally
consistent with the practice that has been in effect since
ClinicalTrials.gov was launched in 2000. This approach helps ensure
that the existence of an NCT number for a specific clinical trial
remains an indicator both that a publicly posted clinical trial has
been registered and that the clinical trial information has gone
through the quality control review process. Use of NCT numbers is
required in certain submissions to FDA and in reports to NIH and other
HHS agencies from relevant grantees and contractors as evidence that
clinical trials have been publicly registered, as required by section
402(j) of the PHS Act, and by other stakeholders, including journal
editors, as evidence of public disclosure of certain protocol
information. Users searching ClinicalTrials.gov will be able to elect
to include or exclude posted study records containing clinical trial
information that has not concluded the quality control review process.
In addition, because the quality control review process cannot ensure
the veracity of the data submitted, all entries in ClinicalTrials.gov
will carry a disclaimer to that effect.
The quality control review process will continue even after
submitted information is posted, with a notice that the quality control
review process has not concluded. Specifically, responsible parties
must correct or address apparent errors, deficiencies, and/or
inconsistencies within 15 calendar days (clinical trial registration
information) or 25 calendar days (clinical trial results information)
of notification sent by the Director. For example, if quality control
review identifies two or more data elements within a clinical trial
record that are internally inconsistent, the responsible party will be
notified that submitted clinical trial information does not appear to
meet specified quality review criteria, including the identity of the
particular elements involved. When the responsible party submits
revised clinical trial information or provides explanatory information
that addresses the apparent errors, deficiencies, and/or
inconsistencies, any revised information will be posted after the
quality control review. Further, when all apparent errors,
deficiencies, and/or inconsistencies have been addressed, the statement
that the quality control review process for that clinical trial record
has not concluded will be removed from the posted record. However, the
information that was initially posted will appear in the archived
history for that clinical trial entry, and the archived version would
indicate that it had been posted with a notice. The electronic
notification sent to the responsible party would inform responsible
parties of these facts.
We further explain that the quality control review process consists
of two sequential components as follows: (1) An automated system-based
check followed by (2) a manual review. In the first component, the
ClinicalTrials.gov system alerts responsible parties to machine-
detectable errors in the data entered (e.g., certain types of missing
information that is required, certain types of impossible values,
certain types of internally inconsistent data). The number of automated
checks the system performs has increased over time as we have gained
experience with the types of errors that occur and devised additional
automated rules for detection. We will continue to refine the
[[Page 65117]]
automated checks in order to assist submitters in detecting and
minimizing errors, deficiencies, and inconsistencies in the information
they are submitting. Following resolution of any errors identified by
the automated system prior to submission, ClinicalTrials.gov staff then
manually reviews data submissions to identify, based on detailed
quality control review criteria, additional apparent errors,
deficiencies, and/or inconsistencies not detected by the automated
checks. As noted previously, if problems are identified during the
manual review, an electronic notification will be sent to the
responsible party, indicating that the submission contains apparent
errors, deficiencies, and/or inconsistencies with a listing of the
specific issues that were identified with a request for correction
within 15 calendar days (clinical trial registration information) or 25
calendar days (clinical trial results information).
In the proposed rule, we detailed the steps taken to satisfy the
pilot quality control project under section 402(j)(5)(C)(i) of the PHS
Act that directed HHS to develop a process to help ensure that clinical
trial results information submitted to ClinicalTrials.gov is non-
promotional and is not false or misleading. The quality control study
consisted of two parts as follows: (1) Review of the results of more
than 4,500 clinical trials submitted under section 402(j)(3)(C) of the
PHS Act after September 27, 2008; and (2) an initial validation study
of the ClinicalTrials.gov results data bank with trial results reported
in the published literature, conducted under contract by researchers at
the Oregon Health Science University [Ref. 13].
Since publication of the NPRM, we have completed a third part of
the QC pilot study: A validation study of the ClinicalTrials.gov
results data bank with trial results reported in FDA review documents
that are publicly available on the Drugs@FDA Web site, conducted under
contract by researchers at The Dartmouth Institute for Health Policy
and Clinical Practice [Ref. 111a]. The study determined that primary
outcome descriptions for sampled trials with results available in both
sources were generally consistent. However, other information could not
be directly compared (e.g., adverse events are reported per trial at
ClinicalTrials.gov, but are sometimes aggregated across multiple trials
on Drugs@FDA to summarize the overall adverse event profile of a
particular product).
Given the limitations of, and differences in, the databases
identified in this study and the findings from the other parts of the
quality control study, we have determined that comparisons with
external sources of information could not be used to validate results
information submissions. Our experience reviewing submissions to date
leads us to conclude that the most appropriate approach for
implementing quality control procedures at ClinicalTrials.gov is to
have all submissions undergo the two-stage quality control review
process developed during the pilot study. This quality control review
process focuses on the content within a study record and includes
automated validation rules followed by a detailed, manual review of
submitted information.
The quality control review process is conducted to help identify
``apparent errors, deficiencies, and/or inconsistencies'' in the
submitted information. That process, however, cannot ensure that the
submitted information is truthful and non-misleading. Therefore,
compliance with the quality control review process, including the
requirements set forth in Sec. 11.64, does not constitute a legal
defense to enforcement pursuant to section 301(jj) of the FD&C Act (21
U.S.C. 331(jj)), section 303(f)(3) of the FD&C Act (21 U.S.C.
333(f)(3)), or any other Federal law. A provision has been added to
Sec. 11.64 of the final rule to clarify this point.
Section 11.64(b)(2) specifies the requirements for correcting
errors identified by a responsible party. It is anticipated that
responsible parties may become aware of needed corrections through
their own reviews of submitted data or from other parties. We,
therefore, define procedures similar to those in Sec. 11.64(b)(1) for
correcting or addressing such errors, including specifying the general
timeline for corrections as not later than 15 calendar days (clinical
trial registration information) or 25 calendar days (clinical trial
results information) after the responsible party becomes aware of any
such errors. In addition, for errors that are determined by the
responsible party and the Director to be uncorrectable, information
will be posted on the record regarding the uncorrectable information.
As specified in Sec. 11.64(b)(2)(ii), a responsible party's obligation
to submit correction of errors will end on the date on which complete
clinical trial results information has been submitted as specified in
section 402(j)(3)(C) and 402(j)(3)(I) of the PHS Act or Sec. 11.48, as
applicable, and corrections have been made, or addressed, in response
to any electronic notice received under Sec. 11.64(b)(1). We also have
clarified that for any clinical trials that are not subject to the
clinical trial results information submission requirements, the
obligation to correct errors ends on the date on which complete
clinical trial registration information has been submitted as specified
in section 402(j)(2)(A)(ii) of the PHS Act or Sec. 11.28, as
applicable, and corrections have been made in response to any
electronic notice received under Sec. 11.64(b)(1).
E. Subpart E--Potential Legal Consequences of Non-Compliance
1. Sec. 11.66--What are potential legal consequences of not complying
with the requirements of this part?
Overview of Proposal
Other than the requirement that a responsible party not submit
false or misleading information and the associated notice of potential
liabilities for doing so (see Sec. 11.6), the proposed codified text
did not describe the potential legal consequences of failing to comply
with the requirements of the rule. Although we did include in the
preamble to the proposed rule a general discussion of the statutory
procedures and penalties related to non-compliance (79 FR 69570), we
did not otherwise discuss in detail the legal ramifications of failure
to comply with the requirements of section 402(j) of the PHS Act,
including these regulations.
Comments and Response
As discussed in Section III.A above, we received a number of
comments about enforcement of the rule. Within the context of the FDAAA
Title VIII statutory enforcement provisions, commenters proposed that
NIH and FDA take certain approaches to enforcing the section 402(j)
requirements. Commenters proposed specific penalty structures, such as
only penalizing the responsible party and not the institution and
making all intentional violations criminal with mandatory prison
sentences. They also proposed incentives, such as providing easier
submission mechanisms and citable credit for shared data sets. As
previously stated, the specifics of how and under what circumstances
the agencies will seek to enforce section 402(j), including the
requirements of this final rule, are beyond the scope of this
rulemaking. We expect that the clarification of responsibilities and
obligations in this final rule will lead to a high level of voluntary
compliance with these requirements. However, we believe that it also is
important that responsible parties be more fully aware of the
procedures and penalties to which non-compliance could subject them.
Therefore, although the
[[Page 65118]]
procedures and penalties for non-compliance would be applicable
regardless of whether they are included in the codified text, we have
decided to add new Sec. 11.66, which describes the potential legal
consequences set forth in the FDAAA Title VIII enforcement provisions.
Final Rule
The final rule includes new Subpart E--Potential Legal Consequences
of Non-compliance and Sec. 11.66--What are potential legal
consequences of not complying with the requirements of this part? This
new section describes potential civil or criminal actions, civil
monetary penalty actions, and grant funding actions that may be taken
because of responsible parties' failure to comply with Part 11. Not all
potential legal consequences are included. For example, as discussed in
relation to Sec. 11.6, other federal laws also govern the veracity of
information submitted to the Federal Government, such as 18 U.S.C. 1001
(making it a crime to make certain false statements to the executive,
legislative, or judicial branch of the U.S. government). Accordingly,
new Sec. 11.66 should not be understood as describing the exclusive
means of enforcement that the Government might undertake with respect
to compliance with FDAAA Title VIII, including these regulations.
New Sec. 11.66(a) describes certain non-compliant activities that
can lead to civil or criminal judicial actions against the responsible
parties. FDAAA Title VIII amended the FD&C Act by adding a new
subsection 301(jj) (21 U.S.C. 331(jj)) to the prohibited acts
provisions. New Sec. 11.66(a)(1) describes that, under 301(jj)(1) of
the FD&C Act, failure to submit the certification required by section
402(j)(5)(B) of the PHS Act, or knowingly submitting a false
certification under that section, is a prohibited act. Section
402(j)(5)(B) requires submissions of new drug applications under
section 505 of the FD&C Act, premarket approval applications under
section 515 or 520(m) of the FD&C Act, biologics license applications
under section 351 of the PHS Act, or reports under section 510(k) of
the FD&C Act to be accompanied by a certification that all applicable
requirements of section 402(j) of the PHS Act have been met. The
applicable requirements of section 402(j) now include the requirements
in Part 11.
New Sec. 11.66(a)(2) describes that failure to submit clinical
trial information required under section 402(j) of the PHS Act is a
prohibited act under section 301(jj)(2) of the FD&C Act. The clinical
trial information required to be submitted under Part 11 is clinical
trial information required under section 402(j).
New Sec. 11.66(a)(3) describes that submission of clinical trial
information under section 402(j) that is false or misleading is a
prohibited act under section 301(jj)(3) of the FD&C Act. Section 11.6
specifically provides that information submitted by a responsible party
under this part ``shall not be false or misleading in any particular.''
This language in Sec. 11.6 reflects the precise language of section
402(j)(5)(D) of the PHS Act, which is then incorporated by reference in
section 301(jj)(3) of the FD&C Act's prohibited act section. Violating
Sec. 11.6 would thus be a prohibited act under section 301(jj)(3).
Judicial remedies for violations of section 301 of the FD&C Act
include injunctions and criminal penalties. Under section 302 of the
FD&C Act (21 U.S.C. 332), U.S. district courts have jurisdiction to
restrain violations of section 301. Under section 303 of the FD&C Act
persons who violate section 301 can be imprisoned or fined. Pursuant to
18 U.S.C. 3571, current generally applicable fines are (1) for
individuals, up to $100,000 for a misdemeanor, up to $250,000 for a
felony violation and (2) for organizations, up to $200,000 for a
misdemeanor, up to $500,000 for a felony violation. Such remedies could
be accomplished through judicial proceedings initiated by FDA and
brought to court by the Department of Justice.
New section 11.66(b) describes generally that any person who
violates section 301(jj) of the FD&C Act is subject to civil monetary
penalties under section 303(f)(3) of the FD&C Act (21 U.S.C.
333(f)(3)). Under FDAAA Title VIII's addition of 303(f)(3) to the FD&C
Act, a person who commits any of the prohibited acts described in
section 301(jj)(1),(2), or (3) would be subject to a civil monetary
penalty of ``not more than $10,000 for all violations adjudicated in a
single proceeding'' (21 U.S.C. 333(f)(3)(A)). Under 402(j)(5)(C)(ii),
if the Secretary determines that any clinical trial information was not
submitted as required, or was false or misleading, the Secretary shall
notify the responsible party and give them an opportunity to remedy the
non-compliance within 30 days. As part of the civil monetary penalties
provision, if the violation is not corrected within 30 days following
such notification, the person is subject to an additional civil
monetary penalty of ``not more than $10,000 for each day of the
violation'' until the violation is corrected (21 U.S.C. 333(f)(3)(B)).
With respect to the dollar amounts for the civil monetary penalties,
separate laws provide for periodically adjusting for inflation the
maximum civil monetary penalty amounts (the Federal Civil Penalties
Inflation Adjustment Act of 1990 (28 U.S.C. 2461 note 2(a)), as amended
by the Federal Civil Penalties Inflation Adjustment Act Improvements
Act of 2015 (section 701 of Public Law 114-74)). FDA's procedures for
administrative imposition of civil monetary penalties are in 21 CFR
part 17.
New Sec. 11.66(c) describes the FDAAA Title VIII provisions
related to grant funding. Under section 402(j)(5)(A) of the PHS Act, if
an applicable clinical trial is funded in whole or part by HHS, any
required grant or progress report forms must include a certification
that the responsible party has made all required registration and
results submissions. If it is not verified that the required
registration and results clinical trial information has been submitted
for each applicable clinical trial for which a grantee is the
responsible party, any remaining funding for a grant or funding for a
future grant to such grantee will not be released. If the head of an
HHS agency verifies that a grantee has not submitted such clinical
trial information, the agency head will provide notice to the grantee
of the non-compliance and allow the grantee 30 days to correct the non-
compliance and submit the required clinical trial information. As with
other matters, the head of the agency may delegate this authority to
other agency officials. Registration and results information
submissions required under Part 11 are required submissions for
purposes of these grant funding provisions.
Although not included in Sec. 11.66, there is a statutory
provision that directs NIH to include notices in the registry and
results data bank containing certain non-compliance information. Under
section 402(j)(5)(E), these notices, including specified statements,
alert the public to: Instances of failure to submit required
information; submission of false or misleading information; penalties
imposed, if any; whether the information has been corrected in the data
bank; and, failure to register the primary and secondary outcomes.
F. Effective Date, Compliance Date, and Applicability of Requirements
in This Part
Overview of Proposal
Section 402(j) of the PHS Act does not establish time periods for
the effective date or compliance date of the rule, or the length of
time between them. In the
[[Page 65119]]
NPRM, the effective date was 45 calendar days after the date on which
the final rule is published (79 FR 69592). As of that date, the
ClinicalTrials.gov system would be modified to allow responsible
parties to comply with the rule. We further proposed that the
compliance date would be 90 calendar days after the effective date (79
FR 69592), meaning that a responsible party would have until the
compliance date of the rule to come into compliance with the
requirements of the rule.
For applicable clinical trials, the NPRM also described in Section
III.D how clinical trial records at the time of the effective date
would be handled. For registration information, for information
submitted on or after the effective date, the information would need to
comply with the rule. For a trial ongoing as of the effective date,
with registration information submitted before the effective date, the
NPRM stated that the information would have to comply with Sec. 11.28
of the rule by the compliance date. Under this proposal, responsible
parties would have been required to revise and/or add registration
information to comply with the rule. For an applicable clinical trial
that reached its completion date prior to the effective date, the
responsible party would not have been required to comply with the rule,
but would have been expected to have provided registration information
as required by section 402(j)(2)(A)(ii) of the PHS Act. The responsible
party would also have been required to update any information
necessary, consistent with section 402(j)(4)(C) of the PHS Act.
With respect to results information, section 402(j)(3)(D)(iv)(II)
requires the Secretary to determine in rulemaking whether certain
clinical trial information (i.e., technical and non-technical
summaries, full protocols, and other categories, as appropriate)
``should be required to be submitted for an applicable clinical trial
for which the clinical trial information described in subparagraph (C)
[basic results] is submitted to the registry and results data bank
before the effective date of the regulations . . .'' The NPRM provided
that the responsible parties for applicable clinical trials for which
results information was submitted under section 402(j)(3)(C) of the PHS
Act before the effective date would not be required to provide the
results information specified in proposed Sec. 11.48 of the rule. For
an applicable clinical trial that reached its completion date prior to
the effective date of the final rule, the proposal would have required
the responsible party to submit all of the results information
specified in proposed Sec. 11.48 if the responsible party had not
submitted results information under section 402(j)(3)(C) of the PHS Act
prior to the effective date of the rule. For an applicable clinical
trial with a completion date before the effective date and for which
partial results were submitted prior to the effective date, but the
remaining partial results were neither due nor submitted until on or
after the effective date, the proposal would have required the
responsible party to submit clinical trial results information under
proposed Sec. 11.48 for all outcome measures, including modifying the
primary outcome measure(s) submitted before the effective date to be in
accordance with the requirements specified in proposed Sec. 11.48 (79
FR 69593). For applicable clinical trials completed before the
effective date of products that are never approved, licensed, or
cleared, results information would not have been required to be
submitted. For applicable clinical trials completed before the
effective date of unapproved, unlicensed, or cleared products that are
subsequently approved, licensed, or cleared after the effective date,
it was proposed that results information would be due by the earlier of
1 year after completion of the trial or 30 calendar days after FDA
approval, licensure, or clearance of the studied drug or device (79 FR
69594).
The NPRM addressed how voluntary submissions under Sec. 11.60 (for
applicable clinical trials for which registration clinical trial
information were not required to be submitted or clinical trials of
FDA-regulated drugs or devices that are not applicable clinical trials)
would be handled at the time of the effective date. It was proposed
that voluntary submissions made on or after the effective date must
comply with the final rule, regardless of trial completion date (79 FR
69594).
The NPRM also addressed how updates and corrections to submitted
clinical trial information (Sec. Sec. 11.64 and 11.66) would be
handled:
For clinical trial registration or clinical trial results
information due on or after the effective date, the responsible party
would be required to comply with proposed Sec. 11.64 for updating the
information.
For clinical trial information due prior to the effective
date, the responsible party would be required only to update the
information in accordance with section 402(j)(4)(C) of the PHS Act.
For an applicable clinical trial that reaches its
completion date prior to the effective date, but for which results
information are due after the effective date, the responsible party
would be required to update registration information according to
section 402(j)(2)(A)(ii) of the PHS Act, but update results information
(submitted after the effective date) according to proposed Sec. 11.64.
For an applicable clinical trial that is registered in
accordance with section 402(j)(2) of the PHS Act but is ongoing as of
the effective date, because the responsible party would be required to
submit registration information consistent with proposed Sec. 11.28 by
the compliance date, updates would also be required according to
proposed Sec. 11.64.
The NPRM also stated that if the responsible party is aware of
clinical trial information that contains errors, the responsible party
would be required to submit corrections according to Sec. 11.66,
regardless of when that information was originally submitted (79 FR
69594).
Comments and Response
Commenters expressed opinions on a variety of points related to the
proposed effective and compliance dates of the rule. Regarding the
timeline, commenters suggested an effective date later than the
proposed 45 calendar days after the rule's publication, such as 90
calendar days after the rule's publication. Similarly, commenters
suggested an compliance date later than the proposed 90 calendar days
after the effective date, such as 180 calendar days after the effective
date. Others supported a phased implementation of the rule's
requirements to permit increased institutional readiness and to allow
HHS to address practical compliance barriers that might arise during
the early stages of the rule's implementation, including the updating
of ClinicalTrials.gov to accommodate clinical trial information from
new types of trials.
First, we have extended the effective date from 45 calendar days to
provide at least 120 calendar days after filing for public inspection
of this rule by the Office of the Federal Register. However, but the
compliance date will remain 90 calendar days after the effective date.
This extended effective date will allow responsible parties subject to
the rule more time to review the new requirements and prepare, update,
and reconfigure their institutional operations and databases
appropriately. It will also allow ClinicalTrials.gov additional time to
ensure system readiness by the effective date (e.g., update the PRS
online forms to incorporate the new data elements, update the automated
validation rules,
[[Page 65120]]
and revise the user guide and other documentation to reflect the
requirements of the final rule). While the period of time between the
effective date and compliance date remains as proposed, responsible
parties can use the longer time between publication of the rule and the
effective date to prepare for any submissions needed to comply with the
final rule.
Commenters responded to the Agency's proposals on how clinical
trial records at the time of the effective date of the rule would be
handled. They disagreed with the approach to require results
information for all outcome measures to comply with the rule in
situations for which results information for primary outcome measures
were submitted prior to the effective date, but results information for
other measures are neither due nor submitted until on or after the
effective date. Commenters suggested that the NPRM proposal, which
would require updating the previously submitted information, might be
burdensome, and researchers may not have designed or budgeted for such
updates.
Others opposed the requirement to comply with the rule when a trial
was completed before the effective date and, regardless of its due
date, results information was not submitted prior to the effective
date. They highlighted burden and additional workload as reasons for
their opposition. One commenter opposed application of the rule to
ongoing trials, suggesting that it disrupts the investment-backed
expectations in place during early development of studied products.
Other commenters outlined alternatives to the proposal, including
that new registration provisions only apply to trials registered after
the effective date, and that new results provisions only apply to new
results posted after the effective date, and to clinical trials with
completion dates after the effective date. Another commenter suggested
the burden caused by the proposal when the First Subject First Visit or
Primary Completion Date is before the effective date--reporting on
these studies would require reworking to accommodate the new criteria.
This commenter noted a particular burden on small entities and
suggested that the rule only apply to studies with First Subject First
Visit or Primary Completion Dates after the effective date. As
mentioned above, we have simplified the requirements for information
submission during the transition, and this is discussed in more detail
below.
One commenter suggested that applying regulations retroactively
does not comport with typical legal standards of due process that favor
prospective, as opposed to retroactive, application. Another commenter
noted that if NIH does apply the rule retroactively to previously
registered trials, responsible parties may need more time to address
updates. We have considered the effects of the requirements in the
final rule and do not believe that there are any impermissible
retroactive effects that flow from the final rule. We believe that the
revised approach being adopted alleviates the concerns expressed by
commenters in this regard.
While we received no comments suggesting that the handling of
clinical trial records on and immediately after the effective date be
made explicit in the regulatory text, we did receive comments
indicating that the rules are confusing. To resolve that general
concern, we have restructured the requirements for which applicable
clinical trials must be registered, whether results information
submission is required for a particular applicable clinical trial, and
whether the applicable registration and results information submission
requirements are those specified in section 402(j) of the PHS Act or
are those specified in these regulations. In making these changes, our
aim is to be as clear as possible about the obligations of responsible
parties.
Final Rule
The final rule differs from the proposal the NPRM in two important
ways. First, we have extended the effective date from 45 calendar days
to at least 120 calendar days after filing for public inspection of
this rule by the Office of the Federal Register. However, the
compliance date will remain the same, at 90 calendar days after the
effective date. Second, the rule simplifies the process for determining
which applicable clinical trials and information are subject to the
rule's reporting requirements. Specifically, the registration
requirements that apply to an applicable clinical trial are determined
by the date on which the trial is initiated (i.e., the actual study
start date as defined in Sec. 11.10(b)(16)), and the results
information submission requirements that apply to an applicable
clinical trial are determined by the date on which the trial reaches
its actual primary completion date. We believe that this framework
provides a logical approach to registering and submitting results
information, in that it relies on what are, in the simplest terms, and
for purposes of section 402(j) of the PHS Act and these regulations,
the start date and the primary completion date of a trial.
Under this approach, the registration and results information
submission requirements that apply to any given applicable clinical
trial also depend on whether the trial is of an approved, licensed, or
cleared product, or an unapproved, unlicensed, or uncleared product. We
have reconsidered the approach described in the NPRM (79 FR 69593) with
respect to determining whether an applicable trial involves an
approved, licensed, or cleared product, or whether it involves an
unapproved, unlicensed, or uncleared product. For purposes of this
final rule, the marketing status of a product will be determined based
on its marketing status on the primary completion date. Thus, if a drug
product (including a biological product) or a device product is
approved, licensed, or cleared for any use as of the primary completion
date, we will consider that applicable clinical trial to be a trial of
an approved, licensed, or cleared product. Similarly, if a drug product
(including a biological product) or a device product is unapproved,
unlicensed, or uncleared for any use as of the primary completion date,
regardless of whether it is later approved, licensed, or cleared, we
will consider that applicable clinical trial to be a trial of an
unapproved, unlicensed, or uncleared product.
As a result of this interpretation, whether results information
submission is required for an applicable clinical trial of an
unapproved, unlicensed, or uncleared product depends on whether the
primary completion date for that trial falls before or after the
effective date of the regulations. If it falls before the effective
date, then no results information is required to be submitted for that
applicable clinical trial, regardless of whether the product studied in
that clinical trial is later approved, licensed, or cleared. If the
primary completion date is after the effective date of the final rule,
then results information submission is required as specified in the
final rule.
We recognize that there are responsible parties who submitted
results information pursuant to the provisions in sections 402(j)(3)(C)
and (E) for applicable clinical trials of products that were not
approved, licensed, or cleared at the time the trial was ongoing, but
which were approved after the primary completion date. Notwithstanding
the fact that, under the interpretation in the final rule, results
information for these trials was not required to be submitted, we do
not consider the results information for these trials to have been
submitted
[[Page 65121]]
pursuant to section 402(j)(4)(A). Although the previously submitted
information will remain in the PRS system and will be publicly
available, it is not subject to either the provisions of Sec. 11.60
regarding voluntary submissions or the requirements in Sec. 11.64 with
respect to updates and corrections of information. The Agency does,
however, encourage responsible parties to update such previously
submitted results information and would not consider such updates to be
subject to the voluntary submission requirements in Sec. 11.60.
The applicable registration and results information submission
requirements are summarized in the following table:
Applicability of Requirements in 42 CFR Part 11
--------------------------------------------------------------------------------------------------------------------------------------------------------
Registration information submission required? Results information submission required?
-----------------------------------------------------------------------------------------------------
Initiation date Primary completion Unapproved,
date Approved, licensed, or Unapproved, unlicensed, Approved, licensed, or unlicensed, or
cleared products or uncleared products cleared products uncleared products
--------------------------------------------------------------------------------------------------------------------------------------------------------
On or before September 27, After December 26, Yes, as specified in Yes, as specified in Yes, as specified in No.
2007. 2007 and before section 402(j)(2)(A)(ii) section 402(j)(2)(A)(ii) section 402(j)(3)(C) and
Effective Date of of the PHS Act. of the PHS Act. section 402(j)(3)(I) of
Final Rule. the PHS Act.
After September 27, 2007 and Before Effective Yes, as specified in Yes, as specified in Yes, as specified in No.
before the Effective Date of Date of Final Rule. section 402(j)(2)(A)(ii) section 402(j)(2)(A)(ii) section 402(j)(3)(C) and
the Final Rule. of the PHS Act. of the PHS Act. section 402(j)(3)(I) of
the PHS Act.
After September 27, 2007 and On or after Yes, as specified in Yes, as specified in Yes, as specified in 42 Yes, as specified
before Effective Date of Effective Date of section 402(j)(2)(A)(ii) section 402(j)(2)(A)(ii) CFR part 11. in 42 CFR part
Final Rule. Final Rule. of the PHS Act. of the PHS Act. 11.
On or after Effective Date of On or after Yes, as specified in 42 Yes, as specified in 42 Yes, as specified in 42 Yes, as specified
Final Rule. Effective Date of CFR part 11. CFR part 11. CFR part 11. in 42 CFR part
Final Rule. 11.
--------------------------------------------------------------------------------------------------------------------------------------------------------
The table above does not apply to voluntary submissions under Sec.
402(j)(4)(A) of the PHS Act and Sec. 11.60. The registration and
results information submission requirements for the voluntary
submission of clinical trial information are addressed in Sec. 11.60.
We recognize that there will be some situations that arise in the
months leading up to and following the effective date where a
responsible party's obligations may shift depending on a variety of
factors. For example, there may be a small number of applicable
clinical trials for which the study start date (i.e., the date of
initiation) changes after the trial is registered and that that change
may result in a shift in the registration and/or results information
submission requirements for that applicable clinical trial. For
example, if a responsible party initially registered an applicable
clinical trial two months before the effective date of the final rule
and entered an estimated study start date that fell one month before
the effective date of the final rule, the responsible party's
understanding at the time of registration would be that it would need
to submit registration information as specified in section
402(j)(2)(A)(ii) of the PHS Act. However, if the trial is not initiated
until after the effective date of the final rule, the responsible party
will be required to comply with the registration provisions as
specified in the final rule and to update the registration information
for that applicable clinical trial. In a situation such as this, we
would expect clinical trial registration information to be updated
promptly, but in any case no later than as required under Sec.
11.64(a) of the final rule. We note that in this scenario the
responsible party will have been on notice since the publication date
of the final rule both that the registration requirements will be
changing as of the effective date and what those changes will be.
Similarly, if a responsible party initially registered an
applicable clinical trial two months before the effective date of the
final rule and entered an estimated study start date that fell one
month after the effective date of the final rule, the responsible
party's understanding at the time of registration would be that it
would need to submit registration information as specified in the final
rule (although we note that, because of the work needed to update the
ClinicalTrials.gov data bank to accommodate the changes in the final
rule, it may not be possible to enter information required as specified
in the final rule prior to the effective date). However, if the
applicable clinical trial actually was initiated one week before the
effective date of the final rule, the trial would instead be subject to
the registration requirements as specified in section 402(j)(2)(A)(ii)
of the PHS Act and not the final rule.
Further, it is our understanding that, because of the complexities
of how clinical research activities are managed at larger institutions,
in some situations an applicable clinical trial might have been
initiated but the individual who is responsible for submitting
registration information regarding that trial might not have received
notice of that initiation. If this scenario were to occur shortly after
the effective date of the final rule, it is possible that the trial
would be registered under the assumption that the requirements in the
final rule apply and, therefore, more clinical trial information would
be submitted than would be required. In this situation, the responsible
party would not be required to update that additional registration
information (although the information itself would remain available in
the PRS system).
We also recognize that because a responsible party has 21 days
after
[[Page 65122]]
initiation in which to register an applicable clinical trial, it is
possible that a trial might be initiated before the effective date of
the final rule but the responsible party might not submit registration
information for it until after the effective date of the final rule. In
this situation, notwithstanding the fact that the registration
information for that applicable clinical trial was submitted after the
effective date of the final rule, the Responsible Party would only be
required to submit registration information as specified in section
402(j)(2)(A)(ii) of the PHS Act, not the final rule.
We appreciate that the possibility that situations such as these
may arise will be of concern to affected responsible parties, and we
are committed to assisting them in understanding their responsibilities
and determining which requirements apply to particular applicable
clinical trials. We would like to emphasize, however, that it has been
clear since the proposed rule was issued in 2014 (and, in our view,
since the enactment of FDAAA, with both its requirement that the
rulemaking address the issue of results information submission and the
provision that the Secretary may modify the registration requirements)
that changes to the registration and results information submission
requirements were both possible and highly probable.
While we believe that the NPRM provided a logical approach for
handling records in transition, we understand that the approach might
have been confusing to responsible parties. We believe that these
changes will address the concerns of many commenters, such as those who
did not believe primary outcome measures should have to be resubmitted
when secondary outcome measures were due and submitted after the
effective date. This change is simpler and clearer for those who were
compliant under section 402(j) of the PHS Act. In addition, with the
change to a later effective date, responsible parties who are subject
to the registration and/or results information submission requirements
in the final rule will have more time to plan accordingly.
V. Regulatory Impact Statement
The Agency has examined the impacts of this final rule under
Executive Order 12866, Regulatory Planning and Review, Executive Order
13563, Improving Regulation and Regulatory Review, the Regulatory
Flexibility Act (5 U.S.C. 601-612) (RFA), the Unfunded Mandates Reform
Act of 1995 (Pub. L. 104-4), and Executive Order 13132, Federalism.
Executive Order 12866, as amended by Executive Order 13563, directs
agencies to assess all costs and benefits of available regulatory
alternatives and, when regulation is necessary, to select regulatory
approaches that maximize net benefits (including potential economic,
environmental, public health and safety, and other advantages;
distributive impacts; and equity). A regulatory impact analysis must be
prepared for major rules with economically significant effects ($100
million or more in any single year). The Agency estimates that the
total cost of the requirements to regulated entities is approximately
$59.6 million annually. We anticipate the potential for significant
scientific and public health benefits, in the form of improvements in
clinical trial designs, human subjects' protections, and improved
evidence base to inform product development and clinical care. In
addition, enhanced access to information about clinical trials may
increase public trust in the research enterprise. We estimate that this
rule is not an economically significant regulatory action as defined by
Executive Order 12866. Because of the interest in this rule among
regulated entities and others involved in conducting or using the
results of clinical trials, we have, nevertheless, prepared an analysis
that, to the best of our ability, estimates the costs and benefits of
this rule. The RFA requires agencies to analyze regulatory options that
would minimize any significant impact of a rule on a substantial number
of small entities. The rule is estimated to impose costs of
approximately $17,907 per applicable clinical trial (see Table 1 and
Section V.G for additional information). Based on the RFA analysis (see
Section V.G), we estimated that most small entities would be expected
to be responsible for no more than one applicable clinical trial per
year and that the per applicable trial cost to them would in general
represent a small fraction of their revenues. This analysis forms the
basis of the Agency's certification that the final rule will not have a
significant economic impact on a substantial number of small entities.
Section 202 of the Unfunded Mandates Reform Act of 1995 requires,
among other things, that agencies prepare a written statement, which
includes an assessment of anticipated costs and benefits, before
proposing ``any rule that includes any Federal mandate that may result
in the expenditure by State, local, and tribal governments, in the
aggregate, or by the private sector, of $100,000,000 or more (adjusted
annually for inflation) in any one year'' (2 U.S.C. 1352(a)). The
current threshold, adjusted for inflation using the 2015 Implicit Price
Deflator for the Gross Domestic Product, is $146 million. The Agency
does not expect this rule to result in any 1-year expenditure that
would meet or exceed this amount. As explained above, however, the
Agency has conducted an analysis of the costs that could result from
this rule.
Executive Order 13132 (Federalism) establishes certain requirements
that an Agency must meet when it promulgates a proposed rule (and
subsequent final rule) that imposes substantial direct requirement
costs on State and local governments, preempts State law, or otherwise
has Federalism implications.
A. Comments and Response
Commenters responded to the economic analysis in the NPRM of the
estimates of the costs and benefits of the rule. While some commenters
found the analysis appropriate overall and considered a 40 hour
estimate for results information submission to be accurate, other
commenters suggested that the time estimates used to calculate
registration, results, and updates burden were lower than they should
be. Some argued that the burden of entering information into the
database is greater for smaller research institutions because, unlike
larger research organizations, they are less likely to have dedicated
and trained personnel to manage clinical trial information reporting.
Others suggested the rule will be equally burdensome to small and large
organizations. We recognize that some members of the regulated
community may spend more hours than others to develop, process, and
maintain clinical trial records. However, we believe our estimates of 8
hours for registration information, 40 hours for results information
and 16 hours for updates of information are a reasonable representation
of the overall average time required to complete all registration and
results requirements by all respondents.
Commenters also suggested that ClinicalTrials.gov harmonize its
clinical trial reporting requirements with existing international
regulations in order to decrease the burden on institutions. It was
suggested that reporting unique numbers of individuals with adverse
events by organ system differs from the EU reporting standards and
increases the burden of the rule. In consideration of the commenters'
concerns, the final rule no longer requires the reporting of numbers of
people with adverse events at the organ system level. We anticipate
[[Page 65123]]
that this change will decrease the burden of the rule.
One commenter suggested that the rule would also have an economic
impact on biopharmaceutical development because of competitive harms
associated with premature disclosure of confidential commercial
information. As discussed in Section III.B of this preamble and Sec.
11.44, this rule requires only summary level results information to be
submitted, and it allows for delayed submission with certification in
order to minimize any perceived competitive disadvantages for
unapproved, unlicensed, or uncleared products (see Sec. 11.44(b) and
(c)) and delayed posting of registration information for unapproved or
uncleared device products (see Sec. 11.35(b)(2)(i)). Submission of
clinical trial results information for applicable clinical trials of
approved, licensed, or cleared products and applicable clinical trials
of unapproved, unlicensed, or uncleared products, according to
deadlines established by the final rule, ensures consistent and timely
public access to comprehensive summary results for all applicable
clinical trials. Furthermore, we are not persuaded that economic harms
will result from the public posting of the required data elements.
Commenters also suggested that the cost estimates understated the
burden associated with bringing previously submitted registration
information into compliance with the final rule. One commenter
suggested that the cost of compliance will not go down over time, while
another suggested that in order to decrease this burden, the rule
should only apply to those trials that had their First Subject First
Visit or Primary Completion Date after the effective date of the rule.
In consideration of commenters' concerns, the final rule eliminates
virtually all additional burden associated with updating previously
submitted trial information by requiring only registration as specified
in the final rule for applicable clinical trials for which the date of
initiation is after the effective date of the final rule and by only
requiring results information submission as specified in the final rule
for applicable clinical trials that reach their primary completion date
after the effective date of the final rule. In light of these changes,
which are discussed in more detail in Section IV.F of this preamble,
there are very few applicable clinical trials registered or submitted
partial results prior to the effective date of the final rule that will
need to be updated as a consequence of the rule. As such, we expect the
burden associated with such situations to be minimal because they will
arise relatively infrequently. In addition, we anticipate that the
occurrence of such situations will decrease over the next three years
because, ultimately, there will be very few ongoing applicable clinical
trials that were initially registered prior to the effective date of
the final rule.
Another commenter suggested that the correction procedures proposed
in Sec. 11.66 could cause further economic burden because they thought
that no clear distinction in the definitions of errors and
falsifications was provided, which they said could lead to unnecessary
and costly preemptive actions by the responsible party. The final rule
no longer distinguishes between different types of errors (see Sec.
11.64), and, thus, the potential economic burden of differentiating the
type of error has been eliminated.
Commenters also suggested that the Agency should calculate actual
burden and include other costs such as reprograming of institutional
systems, increased medical review, and management oversight. They
suggested that we had not sufficiently considered the costs associated
with activities carried out by organizations that may invest
substantial resources to avoid the negative consequences of violating
the legal and regulatory requirements, e.g., loss of federal grant
support and/or monetary penalties. We agree that our cost estimate did
not attempt to isolate the cost and burden that an institution as a
whole might absorb in order to facilitate and monitor compliance among
clinical investigators subject to the rule who are employed by the
institution. Because overhead costs (i.e., costs not related to direct
labor or direct materials) varies among different industries and
occupations, we attempted to approximate those overhead costs by
doubling the average hourly wages in the personnel cost calculations.
We took this approach in part because the cost of this rule is likely
to vary significantly among institutions and organizations due to
differences in institution's sizes, frequency of clinical trials
performed per year and variation in the need to update or create
information technology tools or application used to support clinical
trial registration and results information submission and also because
of the lack of data on the cost of institutional compliance.
Nonetheless, in response to public comments, we have developed a
separate estimate of the costs that institutions may assume in order to
facilitate and monitor compliance among employees with responsibilities
under the rule. The estimate is described in Section E below.
Commenters suggested that the Agency should allow financial burden
of registration and results reporting to be covered as a direct cost in
grants, whether incurred by the investigator or shared with a central
administration unit. The Agency has previously clarified for NIH
awardees that ``[g]iven the nature of registration and result
information report requirement and that the project staff will
generally be in the best position to submit and maintain these data,
the costs of compliance with section 402(j) of the PHS Act will be
generally allowable as direct charges to NIH grants. While it is
expected that these costs will be covered by the funds provided with
the grant, administrative supplements could also be considered'' [Ref.
112].
B. The Final Rule
The final rule codifies in federal regulation the provisions for
the mandatory registration and submission of results information for
applicable clinical trials to ClinicalTrials.gov, as required by
section 402(j) of the PHS Act. This rule both clarifies the existing
statutory requirements for submission of registration and results
information, including adverse events information, and implements the
expansion of the registry and results data bank by rulemaking as
required by section 402(j)(3)(D) of the PHS Act.
C. Need for the Final Rule
The Agency is promulgating this rule to fulfill the requirements of
section 402(j) of PHS Act in a manner that will provide broad public
access to pertinent clinical trial registration and results
information. Section 402(j)(2)(A)(i) of the PHS Act requires the
Secretary to expand the clinical trials registry data bank with respect
to clinical trial information to ``enhance patient enrollment and
provide a mechanism to track subsequent progress'' of the clinical
trials. Sections 402(j)(3)(B) and 402(j)(3)(C) of the PHS Act instruct
the Secretary to expand the clinical registry data bank not later than
1 year after enactment of FDAAA to include the results information
specified in section 402(j)(3)(C) for certain applicable clinical
trials. Section 402(j) of the PHS Act also requires responsible parties
to submit to the expanded data bank specified registration information
(i.e., descriptive information, recruitment information, location
information, and administrative information) summarizing key aspects of
applicable clinical trials that are subject to the law and specified
results information
[[Page 65124]]
describing the outcomes of applicable clinical trials for which the
drugs or devices under study have been approved, cleared, or licensed
by FDA. Section 402(j) of the PHS Act further establishes deadlines by
which such information must be submitted and establishes penalties for
non-compliance. This final rule implements the statutory requirements
and clarifies the Agency's interpretation of them. It explains the
meaning of terms defined in the section 402(j) of the PHS Act (e.g.,
responsible party and applicable clinical trial) and of several data
elements that are required to be submitted to the data bank (e.g.,
study design, eligibility criteria). It also exercises the authority
given to the Secretary in section 402(j)(2)(iii) of the PHS Act to
modify by regulation the requirements for clinical trial registration
information. This final rule specifies several modifications to the
clinical trial registration information that the Agency believes meet
the statutory criteria of improving and not reducing the statutorily
specified clinical trial registration information.
In addition, this rule is necessary to implement provisions of
section 402(j) of the PHS Act that are specifically required to be
addressed by regulation. Section 402(j)(3)(I) of the PHS Act, requires
the Secretary to determine by regulation the ``best method'' for
including in the registry and results data bank appropriate results
information on serious adverse and other adverse events collected for
certain applicable clinical trials. Section 402(j)(3)(D) of the PHS Act
requires, among other things, the Secretary to further expand the
registry and results data bank through rulemaking to ``provide more
complete results information and to enhance patient access to and
understanding of the results of clinical trials.'' Section 402(j)(3)(D)
of the PHS Act specifies several topics that the rule is to address,
including whether to require the submission of results information for
applicable clinical trials of drugs and devices that have not been
approved, licensed, or cleared by FDA; whether technical or lay
summaries of a clinical trial can be included in the data bank without
being misleading or promotional; and whether to require responsible
parties to submit the protocol or ``such information on the protocol .
. . as may be necessary to help evaluate the results of the trial.''
This rule addresses each of these topics and others specified in
section 402(j) of the PHS Act.
D. Benefits of the Final Rule
As discussed in Section I of this preamble, the overarching aim of
the final rule is to provide public access to a standardized set of
information describing the conduct and results of certain clinical
trials of FDA-regulated drugs (including biological products) and
devices. Access to clinical trial information has significant
scientific, and public health benefits, which we describe in Section I.
These benefits accrue to potential and enrolled clinical trial
participants, clinical researchers, systematic reviewers, disease and
patient advocacy groups, regulators, drug and device manufacturers,
healthcare providers, patients and their family members. Public access
to clinical trial information can help patients find trials for which
they might be eligible, enhance the design of clinical trials and
prevent duplication of unsuccessful or unsafe trials, improve the
evidence base that informs clinical care, increase the efficiency of
drug and device development processes, improve clinical research
practice, and build public trust in clinical research.
Access to clinical trial information assists individuals in finding
trials in which they may be eligible to enroll. It can help people in
making more informed decisions about participating in a clinical trial
by providing them and their care providers with information about the
results of a broader set of clinical trials of various interventions
that have been studied for a disease or condition of interest. The
highly structured data and search engine allows members of the public
to search for trials for which they may be eligible [Ref. 19]. It also
enables third parties to use the information describing the clinical
trial to meet other specific needs [Ref. 35], such as reformatting the
data for constituents of various patient advocacy groups (e.g.,
patients with breast cancer) [Ref. 36], data mining for associations
among interventions and diseases studied worldwide, and for use in
semi-automated data collection for conducting critical appraisals and
systematic reviews to support evidence-based medicine. For example,
while ClinicalTrials.gov does not itself match potential participants
with relevant trials, the rule ensures the timely posting of
registration information about trials currently enrolling participants.
This information is used by third parties to provide matching services
that help patients find trials that might be appropriate for them.
Increased clinical trial transparency has the potential to drive
scientific progress by informing future research, identifying knowledge
gaps and opportunities, improving study designs, and preventing
replication of unsuccessful trials and initiation of unsafe trials.
Accessibility of clinical trial information may accelerate the drug
discovery and development process by reducing redundancies and
facilitating the identification and validation of new drug targets or
surrogate endpoints, and it allows for improved understanding of the
safety and efficacy of new therapies. The information provides a more
robust evidence base for new research, which reduces systematic bias
and leads to better science. Strengthening the evidence base also
maximizes returns on the contributions of clinical trial participants
as well as the time and financial investments of investigators, study
funders, and sponsors.
Access to clinical trial information enables IRBs [Ref. 25],
researchers, funding agencies, systematic reviewers [Ref. 26, 27],
bioethicists [Ref. 28], science and public policy makers [Ref. 29], and
others to see the landscape of trials on a given topic, by a particular
funder, by geography [Ref. 30], by population [Ref. 9], or other
relevant criteria. Providing these users with such a capability informs
their judgments about the potential value of new trials. It also helps
ensure that assessments of the risks and benefits of a potential
intervention for a particular use reflect the totality of evidence from
all prior trials. Such information also enhances scientific and
financial accountability of sponsors. Landscape analyses such as these
also provide feedback and insights for the clinical research community,
by informing the design and analysis of future trials [Ref. 11, 31,
32].
Access to clinical trial results information helps fill substantial
gaps in the database left by the non-publication (or very delayed
publication) of a substantial portion of clinical trials in the medical
literature [Ref. 42, 43]. Access to results from clinical trials of
unapproved, uncleared, or unlicensed products is expected to alleviate
the concerns regarding bias in the literature and selective
publication. The complete set of results for all primary and secondary
outcome measures supplements the more limited set of results data found
in the published literature [Ref. 13, 37]. The availability of results
information will help prevent the evidence base that is the foundation
of systematic reviews and clinical practice guidelines from being
skewed.
The availability of results information for trials of unapproved
products may inform the assessment of risks and benefits that potential
participants
[[Page 65125]]
might face in subsequent studies of those same or similar products; it
may also contribute to the overall assessments that are made of similar
marketed products [Ref. 46]. Trials of products that are unapproved,
unlicensed, and uncleared are unlikely to be published if the results
of these trials are insufficient to support applications for product
approvals (e.g., because the study resulted in negative findings or was
inadequately designed or executed).
Clinical trials are expensive to initiate and carry out, and they
are a significant national investment. Phase 2, 3, and 4 clinical
trials cost on average, $13 million, $20 million, and $20 million
respectively [Ref. 113], and it takes an average of $1.4 billion in
clinical trial costs to develop 1 new compound [Ref. 114]. In FY 2016,
NIH invested an estimated $3.3 billion in clinical trials and
supportive activities [Ref. 115]. Access to more complete information
about clinical trials helps conserve resources and, for federally
funding trials, optimize the public investment in research. It helps
avoid a suboptimal return on the financial resources invested by study
funders and sponsors [Ref. 47] and can reduce costs by minimizing
redundant trials.
Finally, another benefit of the rule is that it helps individual
investigators, the clinical trial enterprise, and society as a whole
fulfill an ethical obligation to trial participants. Individuals
participate in clinical trials with the understanding that the research
will contribute to the expansion of knowledge pertaining to human
health. When trial information is withheld from public scrutiny and
evaluation, the interpretation of the data and the public's trust in
the research may be compromised. The rule helps to further the goal of
ensuring that participation in research leads to accountability via the
public reporting of information. The importance of trust in clinical
research and public trust in the enterprise is promoted when we
establish a public record of the trials in which people participate.
E. Costs Associated With the Final Rule
The costs associated with the final rule consist of the time and
effort necessary for responsible parties to comply with the rule
requirements to register applicable clinical trials; submit specified
results information (including adverse event information); update and
correct submitted registration and results information, as needed;
submit certifications and/or extension requests to delay the deadline
for submitting results information; submit information describing
expanded access programs for drugs studied in an applicable clinical
trial, and request waivers to any of the requirements for results
information submission. We do not intend this rule to cause responsible
parties to collect any information that was not already intended to be
collected during the clinical trial, nor do we intend this rule to
cause responsible parties to analyze such information in ways that were
not intended under the protocol or the associated SAP. Rather, the rule
specifies those elements of the collected results information that must
be submitted to the data bank and the format in which that information
must be submitted.
The calculations below present our estimates of the time and cost
associated with meeting the information submission requirements of the
final rule, including the burden associated with assembling the
required information, formatting the information for submission,
submitting it to the data bank, and correcting or updating it over
time. The calculations break out the estimated annual costs associated
with: (1) Registering a trial; (2) submitting results information; (3)
submitting certifications, extension requests and appeals to delay the
results information submission deadline; (4) submitting clinical trial
information that is triggered by a voluntary submission; and, (5)
creating expanded access records for drugs studied in an applicable
clinical trial. The estimates include the costs associated with
updating submitted information and with correcting errors detected by
NIH. These are shown in the table below and, in the text below the
table in Sections 1-5, we described these costs in more detail. We also
estimate the costs of compliance to institutions that elect to devote
resources to help investigators in their institutions who are subject
to the rule to comply with its requirements. These additional resources
mainly involve the hiring or reassignment of personnel to support the
submission of registration and results information submission to
ClinicalTrials.gov. The approach we took to estimate these costs is
described below in Section 6. In the NPRM, we estimated cost of this
final rule to be $32 million. Our higher estimate of $59.6 million is
largely due to the more detailed consideration of costs that
organizations may incur to ensure compliance on the part of responsible
parties they employ.
1. Registration of Applicable Clinical Trials
To estimate the costs of trial registration, we first estimated the
number of applicable clinical trials that would be initiated in a given
year and be subject to the provisions of this final rule. Using the
approach described below, we estimate that a total of 7,400 applicable
clinical trials of drug products (including biological products) and
device products per year would be subject to the registration
requirement of this final rule. This estimate is based on information
from FDA indicating that it receives approximately 5,150 clinical trial
protocol submissions annually for applicable clinical trials (76 FR
256). This figure includes protocol submissions to CDER, CBER, and
CDRH; it does not include clinical trials that were not conducted under
an IND or IDE. To estimate the number of such clinical trials, we
examined the number of clinical trials registered with
ClinicalTrials.gov that appear to meet the criteria for an applicable
clinical trial but do not appear to have been conducted under an IND or
IDE, e.g., because they are exempt from the requirement to submit an
IND or IDE. We found approximately 1,700 and 2,000 such clinical trials
in 2012 and 2013, respectively. We increased this figure to 2,250 to
accommodate further growth in the number of such clinical trials that
would be registered following publication of the final rule. The sum of
these figures (i.e., 5,150 plus 2,250 equals 7,400) provides an
estimate of the number of applicable clinical trials that will be
subject to the registration requirement of this final rule each year.
To calculate the burden associated with registering 7,400 clinical
trials, we estimated the time required to submit complete clinical
trial registration information for an applicable clinical trial. We
estimate this time to be 8 hours, including time to extract information
from the study protocol, reformat it, and submit it to
ClinicalTrials.gov. This figure accounts for the estimated time needed
to submit the 5 additional data elements that will be required by this
final rule. Applying this time estimate to the estimated number of
applicable clinical trials yields a burden of 59,200 hours per year for
registering applicable clinical trials. Based on our previous
experience, we estimate that each registration record will be updated
an average of eight times during the course of the study (e.g., to
reflect changes in the conduct of the clinical trial, additions of
investigational sites, recruitment status updates). Although clinical
trials of long duration and with multiple sites will likely submit more
updates during the course of the trial, we have found that many
applicable clinical trials have a
[[Page 65126]]
relatively short duration and a limited number of study sites, which
lowers the average per clinical trial. The time required for subsequent
updates of clinical trial registration information is expected to be
significantly less than for the original registration as less
information must be provided) and is estimated to be 2 hours per
update, resulting in a total of 16 hours of additional time attributed
to updates per trial. Using these figures, we calculated the total
annual hour burden for updates to clinical trial registration
information for all applicable clinical trials to be 118,400 hours.
Combining this figure with the estimated time for initial registrations
(59,200 hours) yields an estimate of the total hour burden associated
with the submission and updating of clinical trial registration
information of 177,600 hours per year. These estimates include the time
involved in addressing any issues identified during quality control
review of submitted registration information.
To calculate the cost of registration, we examined May 2015 data
from the U.S. Bureau of Labor Statistics on the average wages of life,
physical, and social science workers in the pharmaceuticals and
medicine manufacturing and medical scientists (except epidemiologists)
also working in the pharmaceutical and medicine manufacturing
industries. During the time we have operated ClinicalTrials.gov, we
have found that this task is generally performed by junior-level
researchers or administrative staff. For purposes of this estimate, we
used an average hourly wage rate of $36.02, which is the average wage
of life, physical, and social science workers in the pharmaceuticals
and medicine manufacturing industries and is significantly higher than
the median wage of other administrative staff in those sectors who are
typically tasked with submitting registration information to
ClinicalTrials.gov. Because overhead costs vary among different
industries and organizations, we approximate overhead costs by doubling
the average hourly wages (to $72.04 per hour). Using this adjusted wage
figure, we calculated an estimated total annual cost of registration
under the final rule, including updates over the course of a clinical
trial, of $12,794,304 (Table 1). This figure represents an incremental
increase of $533,096 per year above the estimated cost of registration
prior to the rule.
2. Results Information Submission
To estimate the burden associated with submission of clinical trial
results information, we started with the premise that every clinical
trial required to register in a given year would be required
subsequently to submit results information. The statute requires
results information submission for all applicable clinical trials that
study drugs (including biological products) or devices that are
approved, cleared, or licensed by FDA. The rule requires, in addition,
the submission of clinical results information for applicable clinical
trials of drug products (including biological products) and device
products that are not approved, cleared, or licensed by FDA. We,
therefore, estimate the burden associated with results information
submission for a total of 7,400 applicable clinical trials of drug
products (including biological products) and device products per year,
recognizing that in most cases, such clinical trial results information
will not be submitted in the same year as the associated clinical trial
registration information but in accordance with the deadlines specified
in Sec. 11.44. We expect, however, that on average the number of
clinical trials for which clinical trial results information is
submitted in any given year will approximate the number of new trials
for which clinical trial registration information is submitted.
To estimate an average amount of time required to submit clinical
trial results information, we reviewed a variety of data sources,
including publicly available information from various organizations
about results information submission times [Ref. 116], comments made at
the April 2009 public meeting [Ref. 64], responses to the burden
estimates included in the current and previous OMB clearance documents
(77 FR 22579, Apr. 16, 2012; 73 FR 58972, Oct. 8, 2008), feedback from
respondents who tested preliminary versions of the data entry system
during the summer of 2008, and feedback from those submitting data to
the existing ClinicalTrials.gov system. These sources contain a wide-
range of estimates, from as little as 6 hours to as long as 60 hours.
We believe the differences in these estimates reflect a number of
factors, including the significant variation in the complexity of
applicable clinical trials, in terms of the study design, number of
outcome measures (primary and secondary), statistical analyses, and
adverse event information. The estimates also reflect differences in
the responsible party's familiarity with the clinical trial results
information and the ClinicalTrials.gov submission process and the time
they attribute to assembling the information for submission. Shorter
estimates may be indicative of situations in which the responsible
party already has assembled (and analyzed) the clinical trial results
information for purposes of preparing a journal article or other
summary report, while longer estimates may assume the clinical trial
results information needs to be calculated and compiled. We expect
that, in most situations, the responsible party would have ready access
to the necessary information because it is information that the
clinical trial is conducted to collect and analyze (i.e., the
information for submission would have been collected during the trial,
as specified in the protocol). Nevertheless, for purposes of this
analysis, we selected an average time of 40 hours for initial
submission of clinical trial results information, which corresponds to
the higher range of estimates contained in several industry surveys and
in other comments the Agency received. This figure represents an
increase of 15 hours over our 2015 estimate of 25 hours and reflects
the additional information that is required to be submitted under this
final rule. We expect the hour burden will decline as responsible
parties become more familiar with ClinicalTrials.gov and implement
procedures for streamlining data collection, analysis, and formatting.
This final rule requires submission of the full protocol and SAP
(if a separate document) at the time results are submitted and allows
redaction by the responsible party if confidential commercial
information or personally identifiable information is included. Because
protocol and SAP documents already exist, we do not expect that the
requirement to upload them will impose a significant burden that is not
already accounted for in the results submission burden. In addition, we
anticipate that the need for redaction will be very rare, so those
costs should also be minimal.
Prior to this final rule, we estimated that results information
would be submitted for 3,700 applicable clinical trials per year, which
is the estimated number of clinical trials that would have been
included in marketing applications for drug products, biological
products, and device products that were initially approved, licensed,
or cleared by the FDA and subject to the basic results reporting
provisions of section 402(j) of the PHS Act. Under the final rule,
results information is required to be submitted as specified in the
final rule for all applicable clinical trials that are subject to the
registration requirement and that reach their completion date after the
effective date of the final rule (i.e., an
[[Page 65127]]
estimated 7,400 clinical trials per year). Applying the 40 hour figure
to 7,400 applicable clinical trials per year produces a total estimated
burden of 296,000 hours per year for submitting clinical trial results
information. Our 2015 estimate was 92,500 hours.
We also estimated that, on average, each results record will be
updated 2 times after the initial submission to reflect changes in data
analysis or the submission of additional results from other pre-
specified outcome measures (e.g., submitting partial results). This
estimate is based on user data collected to date, which indicates that
each result record is updated, on average, 1.25 times after initial
submission. We estimated that each such update will take 10 hours, on
average. This figure is 2 hours over our 2015 estimate of 8 hours and
reflects ongoing experience with data submission to ClinicalTrials.gov.
Applying these estimates to 7,400 applicable clinical trials per year
produces an estimate of 148,000 hours per year for updates to clinical
trial results information (2 updates per trial), compared to 59,200
hours for the 3,700 applicable clinical trials estimated under the
existing information collection. Combining the figure for updates with
the estimate of the initial burden of submitting clinical trial results
information, produces a total estimated annual hour burden for results
information submission under the final rule of 444,000 hours, compared
with 151,700 hours under the existing information collection. These
estimates include the time involved in addressing any issues identified
during quality control review of submitted results information.
To calculate the economic cost of clinical trial results
information submission, we examined the average wages of workers in the
pharmaceuticals and medical equipment industries who typically are
involved in submitting clinical trial results information. Based on our
experience in operating the results database and our consultations with
data submitters, we believe that this task is performed generally by
clinical researchers who are more experienced than those involved in
registration. Based on May 2015 data from the U.S. Bureau of Labor
Statistics, we identified the average hourly wage rate of $55.02, which
corresponds to the mean hourly wage of a medical scientist (except
epidemiologists) working in the pharmaceutical and medicine
manufacturing industries. We doubled this wage rate (to $110.04) to
account for benefits and overhead. Using this adjusted wage rate, we
estimate a total annual cost of results information submission under
this final rule, including updates, of $48,857,760 (Table 1). This
represents an increase of $32,162,692 per year over our 2015 estimate
of $16,693,068.
3. Delayed Submission of Results via Certification or an Extension
Request
We also have estimated the average time and cost associated with
the submission of certifications and extension requests to delay
results information submission, consistent with Sec. 11.44(b), (c) and
(e). Responsible parties for applicable clinical trials may submit a
certification to delay results information submission for an applicable
clinical trial provided that initial approval, licensure, or clearance
or approval, licensure, or clearance of a new use for the studied
product is sought. We estimate that the number of clinical trials that
will qualify for delayed submission of results in a given year will not
exceed the estimated number of newly initiated applicable clinical
trials per year that are conducted under an IND or IDE. Such clinical
trials study drug products (including biological products) and device
products that are unapproved, unlicensed, or uncleared or that are
already approved, licensed, or cleared for one use but are seeking
approval, licensure, or clearance of a new use. While some responsible
parties might elect to submit clinical trial results information 1 year
after the primary completion date instead of certifying for delayed
submission, for purposes of this estimate, we assume that they all will
elect to submit a certification to delay results information
submission. (Note that the subsequent burden of submitting clinical
trial results information is captured by the calculations in Section 2
above.) Using the same FDA data we used to estimate the number of
applicable clinical trials subject to the registration requirements of
this final rule, we estimate that certifications will be submitted for
5,150 trials per year. We estimate that it will take no more than 30
minutes for a responsible party to determine that an applicable
clinical trial is eligible for a certification (and to verify the
eligibility with a sponsor or manufacturer, if necessary) and to submit
the necessary information to ClinicalTrials.gov. Using this figure
produces an estimated annual hour burden of 2,575 hours for
certifications. We estimate that the hourly wage of personnel who would
submit the certification is the same as that for submitting clinical
trial results information, or $55.02. Doubling this wage rate to
account for benefits and overhead produces an annual estimated cost of
$283,353 per year.
To estimate the number of good-cause extension requests, we
considered several factors, including the rate of submission of
requests between 2008 and 2015. A total of 192 requests were submitted
during those 8 years (i.e., 24 requests per year on average). Many of
these requests were not needed in order to delay results information
submission because the estimated primary completion date of the
applicable clinical trial had changed. An extension request is not
needed in such these situations because a responsible party need only
update the estimated primary completion date to reflect changes in the
progress of the trial. Other extension requests were submitted for
clinical trials that were not applicable clinical trials subject to
section 402(j) of the PHS Act. Under the rule, the approach outlined in
Sec. 11.22(b) and described in Section IV.B.2 of this preamble can be
used to determine that the clinical trial is not an applicable clinical
trial that is subject to this final rule. When these unnecessary
requests are excluded, we received about 20 requests per year to delay
results information submission for applicable clinical trials for which
the actual primary completion date had passed. We have not attempted to
estimate the number of responsible parties who may have thought they
had a good cause for delaying submission but, rather than seeking the
extension, chose instead to not submit results on time.
Under the final rule, we expect that the number of extension
requests will increase as responsible parties gain more clarity about
the deadlines for submitting clinical trial results information. We,
thus, estimate that approximately 200 requests will be submitted per
year, which represents a 10-fold increase over the annual rate of
submissions to date. The estimated 200 requests is equivalent to 3
percent of all applicable clinical trials for which clinical trial
results information is to be submitted in a given year (i.e., 200 out
of 7,400). It also represents about 10 percent of the applicable
clinical trials that do not certify for delayed results information
submission. We believe the 10-fold increase will also account for any
responsible parties who will now seek an extension rather than simply
not submitting results on time. While responsible parties may request
an extension request even after they have filed a certification, we do
not expect this to happen frequently. Moreover, as explained in Section
IV.C.3 of this preamble, we expect that extensions will be granted in
only a limited set of
[[Page 65128]]
circumstances where ``good cause'' has been demonstrated. In cases
where an extension request is denied, the responsible party will have
the opportunity to appeal the denial. If we estimate that 50 percent of
extension requests are denied and that 50 percent of denials result in
an appeal, we expect to receive 50 appeals per year.
We estimate that the time required for gathering the information
for a good-cause extension request or appeal and submitting it to
ClinicalTrials.gov will be no more than 2 hours. Using this figure, we
estimate that the annualized hourly burden for extension requests and
appeals will be 500 hours. We expect that requests will be submitted by
individuals familiar with the results information submission
requirements and, therefore, use an hourly wage of $55.02. Doubling
this wage rate (to $110.04) to account for benefits and overhead brings
the annualized cost of extension requests to $55,020. Combining the
estimated costs for certification and extension requests produces a
total cost of $338,373 per year (Table 1). Prior to the rule, we
estimated that 3,700 certifications would be submitted by responsible
parties seeking initial approval, licensure, or clearance or approval,
licensure, or clearance of a new use of a drug product (including
biological product) or device product studied in an applicable clinical
trial and that 200 extension requests would be submitted per year.
These figures yield an estimated annual cost of $245,114 meaning that
the incremental cost attributable to this rule is $93,259 per year.
We note that under Sec. 11.54, responsible parties may also seek a
waiver from any applicable requirement of the rule. Such waivers are
available only under extraordinary circumstances that must be
consistent with the protection of the public health or in the interest
of national security. We expect the need for such waivers to be
exceedingly rare. As such, we are subsuming the costs of waiver
requests in the extension request estimates.
4. Triggered Submission of Clinical Trial Information Following a
Voluntary Submission
Section 11.60 of the final rule implements section 402(j)(4)(A) of
the PHS Act and stipulates that if a responsible party voluntarily
registers or submits results information for a clinical trial of an
FDA-regulated drug product or device product that is not an applicable
clinical trial subject to the mandatory clinical trial information
submission requirements, that responsible party must, under specified
circumstances, also submit information for other applicable clinical
trials that are included in a marketing application or premarket
notification that is submitted to FDA and for which clinical trial
information has not already been submitted to ClinicalTrials.gov. The
types of trials for which the voluntary submission of clinical trial
information would invoke this requirement include, e.g., phase 1 trials
of drug products, small feasibility studies of device products (neither
of which is considered to be applicable clinical trial) or applicable
clinical trials that are not otherwise subject to section 402(j) of the
PHS Act because they were initiated prior to the date of enactment of
FDAAA and were no longer ongoing as of December 26, 2007. The voluntary
submission of clinical trial information for such trials will trigger a
requirement to submit clinical trial information for other applicable
clinical trials that are included in the marketing application for a
drug product or device product only if the entity submitting the
marketing application or premarket notification is the same as the
responsible party for those other trials and still has access to and
control over the necessary data.
In practice, we expect that the requirement under section
402(j)(4)(A) of the PHS Act to submit clinical trial information for
applicable clinical trials not otherwise registered in
ClinicalTrials.gov will be triggered infrequently. In most cases, when
clinical trial information is submitted voluntarily, we expect that the
applicable clinical trials required to be submitted in a marketing
application that includes the voluntarily-submitted clinical trial
would be registered in ClinicalTrials.gov consistent with section
402(j)(2)(C) of the PHS Act and Sec. 11.60. For example, the voluntary
submission of information for a phase 1 trial of an unapproved drug
product would trigger the submission of information for an applicable
clinical trial that was not previously submitted only if the
responsible party for the voluntarily-submitted trial is the same as
the entity submitting the marketing application, the applicable
clinical trial is required to be submitted in that marketing
application, and the marketing application is for the same use studied
in the voluntarily submitted trial. For purposes of this analysis, we
estimate that 1 percent of the clinical trials registered voluntarily
with ClinicalTrials.gov each year could trigger the submission of
clinical trial information for an applicable clinical trial for which
clinical trial information was not otherwise required to be submitted
to ClinicalTrials.gov. Of the 19,170 clinical trials that are
registered every year, on average, with ClinicalTrials.gov, we estimate
that 11,770 are voluntary or do not fall under the rule (i.e. non-
regulated) submissions (all but the 7,400 that are applicable clinical
trials). Using 1 percent estimate and this figure, we calculate that
voluntary registrations will trigger the required submission of
clinical trials information for an estimated 118 clinical trials per
year. Based on our experience to date with voluntary submissions, we
expect that for at least three-quarters of those triggered trials (88
total) registration information only will need to be submitted; for the
other quarter, results information will need to be submitted. For those
clinical trials for which only registration information is required, we
estimate that it will take a data submitter with an average hourly wage
rate of $36.02 (consistent with the figures used for registration of
applicable clinical trials) 8 hours to register the clinical trial.
Doubling the wage rate to account for benefits and overhead produces an
estimated cost of $50,716 per year. Submitted information will not
generally need to be updated because the clinical trial will, in
general, have reached its primary completion date by the time the
requirement to submit clinical trial information is triggered. For the
remaining quarter of the triggered clinical trials (30 total), we
estimate that the hourly burden would equal the 40 hours estimated for
results information submission for other applicable clinical trials
plus 5 hours to account for the additional data elements that are
specified in Sec. 11.60(b)(2)(i)(B) and (c)(2)(i)(B). Using these
figures and doubling the estimated average hourly rate of $55.02, we
estimate the annual cost of submission as $148,554. Combining this
figure with the $50,716 figure for triggered clinical trials that
submit only registration information produces a total annual estimated
cost of $199,270 for the submission of clinical trial information
triggered by the voluntary submission of information under Sec. 11.60
(Table 1). Because the submission of clinical trial information
triggered by the voluntary submission of information was not required
prior to the rule, the incremental cost attributable to this rule will
be the full estimated cost of $199,270 per year. We note that each year
a number of studies will likely be registered in ClinicalTrials.gov
that are not subject to section 402(j) of the PHS Act.
[[Page 65129]]
Investigators may choose to register such studies in order to assist in
the recruitment of subjects or to follow other policies, e.g.,
scientific journal publication requirements, or for other reasons.
Examples of such studies include studies of surgical or behavioral
interventions. It is also possible that investigators may choose to
register studies and report results information for clinical trials not
subject to section 402(j) of the PHS Act because the final rule may
bring about greater awareness of the registration or results
information submission process.
Because we are not able to distinguish the portion of voluntary
submissions of information to the database attributed to increased
awareness of the final rule, the cost to entities that submit clinical
trial information, but are not required to do so under section 402(j)
of the PHS Act, as implemented by this final rule, are not included in
this cost estimate. We do, however, account for them in the discussion
of the PRA clearance of the requirements under this rule because we
expect submissions to increase as a result of some combination of this
rule and the contemporaneous NIH policy document, both of which are
associated with the same OMB control number.
5. Expanded Access Records
As specified in Sec. 11.28(a), if an expanded access record is
available for an investigational drug product (including a biological
product) that is studied in an applicable drug clinical trial, the
responsible party for that applicable clinical trial must, if it is
both the manufacturer of the investigational product and the sponsor of
the applicable clinical trial, include the NCT number of the expanded
access record with the clinical trial information submitted at the time
of registration. If an expanded access record for the investigational
drug product (including a biological product) being studied in the
applicable clinical trial has not yet been submitted to
ClinicalTrials.gov, and if the responsible party is both the
manufacturer of the investigational product and the sponsor of the
applicable clinical trial, the responsible party must create an
expanded access record by submitting data elements in Sec. 11.28(c).
To determine the cost and burden associated with the creation of this
record, we relied on information from FDA. Each year, an estimated 135
investigational drug products (including biological products) that were
not previously available for expanded access use will be made available
for individual patient expanded access (including emergency use) by
responsible parties who are required to create an expanded access
record. FDA estimates that 10 treatment INDs or treatment protocols are
initiated annually and that expanded access use for intermediate size
patient populations is initiated 68 times annually. These are the three
types of expanded access for which information in Sec. 11.28(c) must
be submitted to ClinicalTrials.gov under this final rule for an
expanded access record. We estimate the time required to submit the
required information for an expanded access record to be 2 hours, which
is one-quarter of the estimated time to register an applicable clinical
trial. Compared to the number of data elements required under the rule
for applicable clinical trials, only about half as many data elements
are required for an expanded access record for expanded access use
under treatment INDs, treatment protocols and for intermediate-size
patient populations, and still fewer for expanded access records for
individual patient expanded access use. The rule also does not require
some of the more detailed data elements, such as Primary Outcome
Measure, Secondary Outcome Measure, Individual Site Status, and
Facility Location information. We also estimate an average of 2 updates
per expanded access record per year, each taking which 15 minutes. We
estimate the total hour burden associated with 213 expanded access
records (i.e., 135 investigational drug products available for single
patient access, 68 for intermediate size patient populations and 10
treatment INDs or treatment protocols) to be 533 hours per year (426
hours for initial information submission plus 107 hours for information
updates). We expect that expanded access records are submitted by staff
with the same qualifications as those registering applicable clinical
trials and, hence use an estimated hourly wage of $36.02. Doubling this
wage rate to $72.04 to account for benefits and overhead results in a
total estimated annual cost of $38,361 (Table 1). Because the
submission of expanded access records was not included prior to
rulemaking, the incremental cost attributable to this rule is the full
estimated cost of $38,361 per year.
6. Institutional Compliance Costs
Organizations such as academic institutions may decide to devote
more resources to ensure that applicable clinical trials being
conducted in their organizations are compliant with the final rule.
They may elect to do so in order to avoid the consequences of non-
compliance, which, for an organization receiving federal funding for
the clinical trial, could include suspension of grant funding were
there to be a finding of non-compliance. These additional resources
would primarily involve additional staff support to help facilitate and
monitor compliance on the part of responsible parties within the
organization.
Institutions of higher education that receive federal funding
generally cover compliance activities under indirect costs rates that
are negotiated for each institution. Although the final rule may cause
an increase in compliance costs, the increase is anticipated to be
incremental. Institutions can obtain up to 26 percent of their
administrative costs to pay for administrative support.
To estimate the costs that institutions may bear because of the
final rule, we estimated the current compliance costs (FDAAA pre-rule).
We first identified the number of industry and non-industry sponsors of
probable applicable clinical trials (pACTs) who submitted results to
ClinicalTrials.gov in 2015 and separated them into three categories
based on volume of pACTs submitted per year. The categories were low
volume, defined as 1 to 5 pACTs per year; medium volume, defined as 6
to 10 pACTs per year; and high volume, defined as 11 or more pACTs per
year. We identified 363 non-industry sponsors (312 low volume, 29
medium volume, 22 high volume) and 277 industry sponsors (238 low
volume, 17 medium volume, 22 high volume) who submitted pACT results
information in 2015. We then multiplied the current number of full time
employees (FTEs) per organization, a figure estimated to be 0.5 FTEs
[Ref. 117], by the total number of industry and non-industry sponsors
who submitted pACT results information in 2015. We then multiplied the
estimated total FTEs by the estimated annual salary costs, using U.S.
Bureau of Labor Statistics data on average wages from May 2015 of
medical scientists (except epidemiologists) in the pharmaceuticals and
medicine manufacturing ($36.02 per hour) and medical scientists (except
epidemiologist) in a college, university or professional school ($32.17
per hour). We doubled these wage figures (to $72.04 and $64.34) to
account for benefits and overhead. The final total product of the FDAAA
pre-rule institutional yearly cost of compliance for all sponsors was
estimated to be $45 million (Table 1).
We next estimated the cost of the final rule and used reported
number of compliance staff from a high volume sponsor [Ref. 118]. We
assumed that the required number of FTEs will depend
[[Page 65130]]
on the number of trials to be overseen and thus estimated that low
volume sponsors will need 0.5 FTEs. We assumed that, in most cases, low
volume sponsors will not need to hire additional FTEs because reporting
responsibilities will be fulfilled by the responsible parties
themselves (as detailed and calculated in Sections 1-3 above). We also
estimated that medium volume sponsors will need 2 FTEs and high volume
sponsors will require an estimated 3 FTEs. We calculated the product of
the total institutional cost with the adjusted increase in compliance
staff is estimated to be $70.3 million (Table 1). The difference
between the cost estimate of the final rule and the estimate of the
amount spent currently on compliance (FDAAA pre-rule) is $25.2 million.
We believe these estimates are likely to be overestimates because FTEs
involved in FDAAA final rule compliance activities at many institutions
will be engaged in other compliance activities that relate to other
federal and state laws and regulations governing clinical research
(e.g., FDA IND/IDE and IRB regulations, Common Rule) as well as
compliance activities due to non-governmental clinical trial-related
policies (e.g., journal editors require trial registration before the
first participant is enrolled as a condition for the publication
results after study completion) [Ref. 98]. We also assumed that the
FTEs will spend some time up front engaged in developing programs or
systems to facilitate institutional compliance efforts, and that they
will later shift their focus to compliance monitoring activities.
Therefore, the number of attributable FTEs is constant over time and
the cost of updating existing IT programs/systems is already included.
We also did not differentiate between industry and non-industry
organizations to reflect the fact that industry organizations have
well-established regulatory affairs operations, the functions of which
include compliance monitoring and oversight. We believe that many of
these operations are already engaged in oversight activities to support
compliance with the statutory requirements. Thus, the costs for
industry organizations are likely an overestimate.
We estimate the annualized cost to the Federal Government due to
the final rule data collection requirements is approximately $1.4
million for ClinicalTrials.gov activities. This figure includes the
increased cost associated with contractors required to develop software
and operate the database and senior scientists, analysts, and other
staff needed to carry out and oversee ClinicalTrials.gov operations as
well as other costs including database equipment and maintenance.
We estimate the total annual cost of the final rule to be $59.6
million. We expect that over time the cost of complying with the final
rule will decline notably as responsible parties become more familiar
with the registration and results information submission requirements
as well as the data submission and review processes. Many institutions
may have already developed systems and procedures to support
investigators in fulfilling their reporting responsibilities under the
statute. Also, a number of clinical trial data management software
tools currently allow users to output registration information for
automatic uploading of files in bulk to ClinicalTrials.gov. We expect
that by clarifying the requirements for submission of clinical trial in
this final rule, responsible parties will automate portions of the data
extraction and formatting processes for required results information,
significantly reducing the burden and associated cost of compliance
with this final rule.
Table 1--Estimated Annual Cost of Final Rule
----------------------------------------------------------------------------------------------------------------
Estimated Estimated Incremental
annual cost annual cost cost above
Provision Final rule section(s) prior to under the pre-rule data
rulemaking final rule collection
----------------------------------------------------------------------------------------------------------------
Registration of applicable clinical 11.28(a),(b), 11.64(a).... $12,261,208 $12,794,304 $533,096
trials, including updates.
Results information submission for 11.48, 11.64(a)........... 16,693,068 48,857,760 32,162,692
applicable clinical trials,
including updates.
Submission of certifications, 11.44(b), (c), (e)........ 245,114 338,373 93,259
extension requests, and appeals to
delay results information
submission.
Triggered registration and results 11.60..................... 0 199,270 199,270
information submission following
voluntary submissions.
Submission of expanded access 11.28(c).................. 0 38,361 38,361
records.
Institutional compliance costs...... .......................... 45,042,920 70,287,277 25,244,357
Cost to the Federal Government...... .......................... 4,826,307 6,190,784 1,364,477
---------------------------------------------------------------------------
Total........................... N/A....................... 79,068,617 138,706,129 59,635,512
----------------------------------------------------------------------------------------------------------------
F. Alternatives to the Final Rule
Section 402(j)(3)(D)(v)(VI) of the PHS Act requires the Secretary
to promulgate regulations to expand the registry and results data bank
and to address specific issues that are enumerated in the statute.
Section 402(j)(2)(A)(iii) of the PHS Act also authorizes the Secretary
to make additions or modifications to the statutorily enumerated
requirements for registration of applicable clinical trials. This final
rule implements and expands the basic provisions mandated by section
402(j) of the PHS Act that became effective prior to rulemaking on the
schedule established by the statute. In the NPRM, we described various
alternatives that we considered in exercising authority to add or
modify the statutory provisions and in addressing the topics that were
required to be addressed through rulemaking. In developing the final
rule, and informed by public comments, we considered alternatives
approaches that could be taken in the final rule. We discuss two here.
One important provision of the final rule requires results
information from applicable clinical trials of unapproved, unlicensed,
or uncleared products to be submitted. The Agency has concluded that
the public health benefits of this approach, as discussed in above in
Section D, justify the costs. In particular, trials of products that
are unapproved, unlicensed, or uncleared are unlikely to be published
if the
[[Page 65131]]
results of these trials would not help support applications for product
approval, licensure, or clearance. This rule's requirements that
responsible parties submit results information from applicable clinical
trials of unapproved, unlicensed, or uncleared products regardless of
whether approval, licensure, or clearance is sought, as well as the
public posting of this information, are expected to help address bias
in the literature and selective publication of results. The requirement
for results information submission will make information public that
otherwise likely would not have reached the public domain. The
availability of results information from such applicable clinical
trials will help to prevent the evidence base, which serves as a
foundation for future research, systematic reviews, and clinical
practice guidelines, from being skewed. The alternative position--not
requiring results information submission for applicable clinical trials
of unapproved, unlicensed, or uncleared products--would decrease the
costs of the rule as estimated in Section V.E.2, but it would likely be
costly to public health because of the absence of the benefits
described in Section V.D. Therefore, the Agency believes that the
benefits to public health justify the cost of compliance.
The final rule also requires submission of the final research
protocol and SAP as part of the results information (discussed in
Section III.D of the preamble). We expect the protocol to provide users
of ClinicalTrials.gov with more complete information about the trial.
One of the aims of section 402(j) of the PHS Act and of the rule is to
``provide more complete results information.'' We believe this goal
complements the goals of increased transparency and accountability. As
such, the submission of the protocol and SAP will provide more complete
results information and significantly enhance the understanding of the
trial and the context of the data fields provided. Because protocol and
SAP documents already exist, we do not expect that the requirement to
upload them will impose a significant burden that is not already
accounted for in the results submission burden. The alternative--not
requiring the submission of protocol--would have little to no effect in
reducing the burden of the rule, but it would decrease public health
benefits by decreasing the transparency of clinical trial results
information.
G. Regulatory Flexibility Act
The RFA (5 U.S.C. 601-612) requires agencies to analyze regulatory
options that would minimize any significant impact of a rule on small
entities. This final rule will affect a number of small entities that
conduct clinical trials of drug products and device products, but the
Agency estimates that the costs incurred by small entities would be
limited, especially in relation to the other costs associated with
conducting a clinical trial. As explained below, the Agency believes
that the final rule is not likely to have a significant economic impact
on a substantial number of small entities.
The companies that would be affected by this final rule are
classified in seven separate 2012 North American Industrial
Classification System (NAICS) categories by the Census Bureau. The
affected industries are NAICS 325412--Pharmaceutical Preparation; NAICS
325414--Biological Products (except diagnostic); NAICS 334510--
Electromedical and Electrotherapeutic Apparatus; NAICS 339112--Surgical
and Medical Instrument; NAICS 339113--Surgical Appliance and Supplies;
NAICS 339114--Dental Equipment and Supplies; NAICS 339115--Ophthalmic
Goods [Ref. 119]. The Small Business Administration (SBA) size
standards define small entities as those companies with a maximum
number of employees. The 2016 size standards for all these industries
are shown in the table below [Ref. 120]. The most recent data from the
U.S. Census of Manufacturers that offers the level of detail for
establishments at or near the employee size limits as defined by SBA is
from 2012 [Ref. 121]. In each of these establishment size categories,
large majorities (i.e., 90 percent or more) of the establishments meet
the criteria as small entities [Ref. 122]. Even taking into account
that many of these establishments are parts of multi-establishment
corporations, significant numbers of companies would still qualify as
small entities and have fewer than 100 employees across all of these
categories (i.e., ranging from 79 percent to 96 percent of all
establishments within a category). Although the Agency expects that
most companies sponsoring applicable clinical trials would be larger
than the average-sized company in their industry, the Agency concludes
that a substantial number of companies would still qualify as small
entities.
Table 2--Size Standards for Affected Companies
------------------------------------------------------------------------
Size
standards in
NAICS code and industry description number of
employees
------------------------------------------------------------------------
NAICS 339113--Surgical Appliance and Supplies........... 750
NAICS 339114--Dental Equipment and Supplies............. 750
NAICS 339112--Surgical and Medical Instrument........... 1,000
NAICS 339115--Ophthalmic Goods.......................... 1,000
NAICS 325412--Pharmaceutical Preparation................ 1,250
NAICS 325414--Biological Products (except diagnostic)... 1,250
NAICS 334510--Electromedical and Electrotherapeutic 1,250
Apparatus..............................................
------------------------------------------------------------------------
The cost analysis presented above indicates an estimated cost of
compliance with this final rule of $17,907 per applicable clinical
trial ($132,515,345 for 7,400 clinical trials per year). While some
larger firms could be the responsible party for multiple applicable
clinical trials in the same year, we expect most small firms would be
responsible for no more than one applicable clinical trial per year.
Using data from the 2012 Census of Manufacturers, we used the average
value of shipments for establishments in these industries to calculate
the cost percentage of the rule on small entities. Assuming that small
operations with one to four employees had one applicable clinical trial
that was required to submit registration or results information each
year, the costs of this final rule would representan estimated 3.4
percent of the annual value of shipments. For establishments with 50 to
99 employees, the costs of this final rule would represent an estimated
0.9 percent of the value of shipments, even
[[Page 65132]]
if they were responsible for 10 applicable clinical trials administered
annually. For establishments with 100 or more employees, the costs of
this final rule would represent an estimated 0.1 percent of the value
of shipments even with 10 applicable clinical trials administered
annually. Although the figure for establishments with one to four
employees in one industry was estimated to be 3.4 percent at most, the
remaining figures are well below the threshold of 3 to 5 percent of the
total revenue for small entities needed to consider that this final
rule would have a significant economic impact on a substantial number
of small entities. The Agency concludes and certifies that this final
rule would not have a significant economic impact on a substantial
number of small entities.
In practice, we expect the burden on small firms will be
significantly lower than this estimate. In general, the applicable
clinical trials initiated by small firms will be less complex than the
applicable clinical trials initiated by large firms, including, for
example, fewer trial locations (sites), shorter duration, and fewer
outcome measures. As a result, the amount of results information to be
submitted--and the time and cost associated with such submissions--will
be less than for larger entities and represent a smaller share of
shipments. In addition, these costs would affect only a fraction of
small firms in any given year. For example, by our estimates,
registration information would be required to be submitted (and results
information subsequently submitted) for approximately 500 applicable
device clinical trials in any given year. Information from the 2012
Economic Census of the United States indicates that there are
approximately 11,500 companies in the U.S. that are involved in the
manufacture of medical devices and that almost 11,000 of them have
fewer than 100 employees. Even if no company engaged in more than one
applicable clinical trial at the same time, then on average, less than
10 percent of all device manufacturers would initiate a trial subject
to the registration and results information submission requirements of
this final rule in any given year (700 applicable device clinical
trials per year divided by 11,500 firms equals 0.061 or 6.1 percent).
H. Unfunded Mandates Reform Act of 1995
Section 1352(a) of the Unfunded Mandates Reform Act of 1995
requires that the Agency prepare, among other things, a written
statement that includes an assessment of anticipated costs and benefits
before proposing ``any rule that includes any Federal mandate that may
result in the expenditure by State, local, and Tribal governments, in
the aggregate, or by the private sector, of $100,000,000 or more
(adjusted annually for inflation) in any 1 year'' (2 U.S.C. 1532(a)).
The current threshold, adjusted for inflation using the 2015 Implicit
Price Deflator for the Gross Domestic Product, is $146 million. We do
not expect the direct burden of this final rule, including the cost of
compiling, submitting, and updating clinical trial registration and
results information for applicable clinical trials, to result in any 1
year expenditure that would meet or exceed this amount. Nor do we
expect that State or local governments would bear a significant
fraction of this cost, as most of the entities affected by the final
regulation would be private entities. As a result, we conclude that
this rule has no consequential effect on State, local, or tribal
governments or on the private sector. We have determined that this
final rule would not constitute a significant rule under the Unfunded
Mandates Reform Act of 1995 because it would impose no mandates with
costs exceeding the current threshold.
I. Federalism
Executive Order 13132, Federalism, establishes certain requirements
that an Agency must meet when it promulgates a proposed rule (and
subsequent final rule) ``that imposes substantial direct compliance
costs on State and local governments,'' preempts State law, or
otherwise has federalism implications. The Agency has analyzed this
final rule in accordance with the principles set forth in Executive
Order 13132 and has determined that this final rule does not contain
policies that would impose any ``substantial direct compliance costs on
State or local governments[.]'' This final rule, does, however, have
federalism implications.
Section 801(d)(1) of FDAAA expressly provides a preemption
provision as follows: ``Upon the expansion of the registry and results
data bank under section 402(j)(3)(D) of the Public Health Service Act .
. . no State or political subdivision of a State may establish or
continue in effect any requirement for the registration of clinical
trials or for the inclusion of information relating to the results of
clinical trials in a database.'' We interpret this language to prohibit
a State or political subdivision of a State from establishing any
requirement for the inclusion of information in a database that is (1)
clinical trial registration information, as that term is defined in
Sec. 11.10, i.e., the actual registration data elements; (2) clinical
trial results information required to be submitted under section
402(j)(3) of the PHS Act and this part; or, (3) information that is
otherwise collected through any data element in ClinicalTrials.gov,
such as information relating to voluntary submissions and other
information whether or not required to be submitted under section
402(j) of the PHS Act and this part. We do not interpret section
801(d)(1) of FDAAA to preempt other types of reporting and/or data
collection that States may require related to public health, disease
surveillance, clinical care, or the practice of medicine such as
patient and disease registries or public health surveillance
registries.
VI. Paperwork Reduction Act of 1995
This final rule contains requirements that are subject to review by
OMB under the PRA (44 U.S.C. 3501-3520). Sections 11.28, 11.48, 11.60,
11.62, and 11.64 of this rule contain information collection
requirements that are subject to OMB approval. A revision of the 2015
PRA clearance for clinical trial registration and results information
submission (OMB 0925-0586) to meet the requirements of this final rule
will be submitted to OMB for review. It will also be updated to request
approval to collect clinical trial registration and results information
under a final policy that NIH is issuing in tandem with the final rule
that will apply to all NIH-funded clinical trials, including those not
subject to the rule [Ref. 65].
Section VII of the NPRM, the Agency provided an estimate of the
annualized burden hours associated with the information collection
requirements included in the proposed rule, and we invited comments on:
(1) Whether the proposed collection of information is necessary for the
proper performance of the functions of NIH, including whether the
information will have practical utility; (2) the accuracy of the
estimate of the burden of the proposed collection of information by
NIH, including the validity of the methodology and assumptions used;
(3) ways to enhance the quality, utility, and clarity of the
information to be collected; and (4) ways to minimize the burden of the
collection of information on respondents, including through the use of
automated collection techniques, when appropriate, and other forms of
information technology (79 FR 69663). The comments we received are
discussed in Section V.A of the final rule.
A description of the information collection requirements included
in this rule is provided in the Regulatory
[[Page 65133]]
Impact Statement (Section V of this preamble) and is summarized in this
section of the preamble with an estimate of the annualized burden
hours. Included in this estimate is the time for reviewing
instructions, searching existing data sources, gathering and
maintaining the data needed, and completing, reviewing, updating, and
correcting each collection of information.
Organizations and individuals desiring to submit comments on the
information collection and submission requirements should send their
comments by October 21, 2016 to (1) Ms. Mikia Currie, Project Clearance
Officer, National Institutes of Health, Rockledge Centre 1, 6705
Rockledge Drive, Room 3509, Bethesda, Maryland 20817, telephone 301-
594-7949 (not a toll-free number); and (2) the Office of Information
and Regulatory Affairs, OMB, [email protected], or by fax to
202-395-6974, and mark ``Attention: Desk Officer for the National
Institutes of Health, Department of Health and Human Services.'' After
we obtain OMB approval, we will publish the OMB control number in the
FR.
The estimate includes the annual hourly burden for submission,
updating, and correction of information both for applicable clinical
trials that are subject to this rule and for the larger number of
clinical trials for which information is submitted to
ClinicalTrials.gov on a voluntary basis in order to recruit subjects,
remain eligible to publish summary articles in scientific journals that
follow the guidelines of the ICMJE, to comply with NIH or other public,
company, or other organizational policies regarding public disclosure
of clinical trial information, or for other purposes.
The burden for trials that are subject to this rule follows the
estimates presented in Section V of this preamble. For registration, we
estimated 7,400 applicable clinical trials which included the number of
clinical trials that would be subject to mandatory registration under
the rule. This estimate reflects the number of protocols for applicable
clinical trials that are submitted to FDA under an IND or IDE (i.e.,
5,150), as well as applicable clinical trials that are not conducted
under an IND or IDE (i.e., 2,250). We also increased the estimated hour
burden of registration from 7 hours in the 2015 information collection,
to 8 hours to reflect the additional data elements that would be
required under this rule. For results information submission, we have
increased from 3,700 to 7,400 our estimate of the number of applicable
clinical trials that would be subject to mandatory results information
submission under this rule. The final rule requires the submission of
results information for all registered applicable clinical trials,
regardless of whether or not the drug product (including biological
product) or device product under study in the trial is approved,
licensed, or cleared. We have made corresponding increases in the
estimated number of applicable clinical trials for which a
certification to delay results information submission would be
submitted. We have also increased the estimated hour burden for
submitting results information from 25 hours to 40 hours to account for
the additional results information that would be required to be
submitted under this rule. In addition, we have added estimates of the
burden associated with the submission of registration and results
information that could be triggered by some voluntary submissions of
clinical trial information under Sec. 11.60. Finally, we have included
a separate estimate of the burden associated with the creation of an
expanded access record if an investigational drug product (including a
biological product) that is studied in an applicable clinical trial is
available under expanded access. See figures in Table 3.
As we noted in Section V, a number of trials studies will likely be
registered in ClinicalTrials.gov that are not subject to section 402(j)
of the PHS Act. Investigators may choose to register such studies in
order to assist in the recruitment of subjects or to comply with
medical journal policies that make registration in a publicly
accessible repository a condition of publication. In addition, starting
in 2017, clinical trial registration and results information will also
be collected from NIH-funded investigators whether or not they are
subject to the final rule, which will lead to an increase in the number
of non-regulated submissions.
In order to estimate the impact of the NIH policy, over and above
the impact of the rule, we began by determining that 526 NIH funded
trials that are likely not applicable clinical trials were first
registered in 2015. These represent the likely number of trials that
will have the additional burden of submitting results per year under
the NIH policy. In addition, we estimated that approximately 25 percent
of NIH-funded trials that are not applicable clinical trials have not
been registered in the past (despite encouragement from NIH and the
journal editors' policy). This leads to an estimate of an additional
131 trials registered and reporting results per year. The total number
of non-applicable clinical trials that will register and submit results
due to the NIH policy is estimated to be 657 per year. Investigators
subject to the NIH policy will be expected to submit the same
information within the same timeframes as parties subject to
402(j)(2)(C) of the PHS Act. We, thus, use the assumptions here that we
used to estimate the burden for applicable clinical trials, i.e.,
initial submission of registration information will take an average of
8 hours, updates of 2 hours apiece will take place 8 times during the
course of the study and, initial results submission will take on
average 40 hours with 2 expected updates requiring an average of 10
hours total. Adding the registration burden to the results information
burden yields an estimated total annual hour burden of 55,188 (Table
3).
In order to estimate the burden for clinical trials that are not
subject to section 402(j) of the PHS Act, including the requirements in
this final rule, and will not be subject to the NIH policy, we examined
registrations to ClinicalTrials.gov in calendar year 2015 and found
that a total of 19,170 clinical trials were registered that year. Since
we estimate that 7,400 of these are applicable clinical trials, the
remainder 11,770 trials, can be considered voluntary or to not fall
under the rule. Of these, 526 were NIH funded. This leaves an estimated
11,244 trials registered per year that do not fall under either the
rule or the NIH policy.
We expect that these clinical trials will submit the same clinical
trial registration information as is submitted for applicable clinical
trials that are subject to the rule. We expect that information
submitted for such clinical trials will be updated as frequently as
information for applicable clinical trials that are subject to the
rule. Therefore, for calculating the registration burden associated
with these clinical trials, we use the same assumptions as for
applicable clinical trials required to register under section
402(j)(2)(C) of the PHS Act, i.e., initial submission of registration
information will take an average of 8 hours, updates of 2 hours apiece
will take place 8 times during the course of the study. Applying these
figures yields an estimated annual burden of 269,856 hours, of which
89,952 derives from the initial registration and 179,904 derives from
updates (Table 3).
For clinical trials that are not subject to section 402(j) of the
PHS Act, including the requirements in this final rule, or the NIH
policy, we expect that often only clinical trial registration
information, and not both registration and results information, will be
[[Page 65134]]
submitted. To estimate the number results submissions will be
submitted, we looked at results submissions in 2015 and found that
1,580 were for clinical trials that were neither applicable clinical
trials nor funded by NIH. We estimate that this number will grow
slightly, secondary to various other funder policies (e.g., PCORI). We,
therefore, estimate that we will receive approximately 2,000 results
per year that are not due to either the rule or the NIH policy. We
estimate that the time required to submit clinical trial results
information for such clinical trials would be equivalent to that for
applicable clinical trials required to register under section
402(j)(2)(C) of the PHS Act. Using those figures, we estimate that the
total annual hour burden for submitting clinical trial results
information for clinical trials that are not otherwise required to
submit results information would be 80,000 hours, plus 40,000 hours for
updates (Table 3).
Table 3--Estimated Burden for Registration and Results Information Submission at ClinicalTrials.gov
----------------------------------------------------------------------------------------------------------------
Average time
Type of respondents Number of Frequency of response per response Annual hour
respondents (hours) burden
----------------------------------------------------------------------------------------------------------------
Regulated Submissions (Subject to this Rule)
----------------------------------------------------------------------------------------------------------------
Registration....................... 7,400 1 Initial.................. 8 59,200
.............. 8 Subsequent Updates....... 2 118,400
Results Information................ 7,400 1 Initial.................. 40 296,000
.............. 2 Subsequent Updates....... 10 148,000
Certifications to delay results 5,150 1.......................... 0.5 2,575
submission.
Extension requests and appeals..... 250 1.......................... 2 500
Registration triggered by voluntary 88 1.......................... 8 704
submission.
Results triggered by voluntary 30 1.......................... 45 1,350
submission.
Expanded access records............ 213 1 initial.................. 2 426
.............. 2 Subsequent Updates....... 0.25 107
----------------------------------------------------------------------------
Subtotal for Regulated 627,262
Submissions.
----------------------------------------------------------------------------------------------------------------
Non-regulated Submissions Related to the NIH Policy
----------------------------------------------------------------------------------------------------------------
Registration....................... 657 1 Initial.................. 8 5,256
.............. 8 Subsequent Updates....... 2 10,512
Results information................ 657 1 Initial.................. 40 26,280
.............. 2 Subsequent Updates....... 10 13,140
----------------------------------------------------------------------------
Subtotal for Non-regulated 55,188
Submissions Related to the NIH
Policy.
----------------------------------------------------------------------------------------------------------------
Non-regulated Submissions
----------------------------------------------------------------------------------------------------------------
Registration....................... 11,244 1 Initial.................. 8 89,952
.............. 8 Subsequent Updates....... 2 179,904
Results information................ 2,000 1 Initial.................. 40 80,000
.............. 2 Subsequent Updates....... 10 40,000
----------------------------------------------------------------------------
Subtotal for Non-regulated 389,856
Submissions.
----------------------------------------------------------------------------------------------------------------
Subtotal for Non-regulated 445,044
Submissions and Submissions
Related to the NIH Policy.
----------------------------------------------------------------------------------------------------------------
Total...................... 1,072,306
----------------------------------------------------------------------------------------------------------------
VII. Legal Authority
These regulations are issued under the authorities contained in 42
U.S.C. 282(i); 42 U.S.C. 282(j); 5 U.S.C. 301; 42 U.S.C. 286(a); 42
U.S.C. 241(a); 42 U.S.C. 216(b); and sections 801(c)-(d), Public Law
110-85, 121 Stat. 921-922 (42 U.S.C. 282 (note)).
VIII. References
1. International Committee of Medical Journal Editors.
Recommendations for the conduct, reporting, editing, and publication
of scholarly work in medical journals [Internet]. 2015 Dec [cited
2016 Sept 8]. Available from: http://www.icmje.org/icmje-recommendations.pdf.
2. ICMJE [Internet]. International Committee of Medical Journal
Editors; 2016. Clinical trial registration; 2011 [cited 2016 Aug 5];
[about 2 screens]. Available from: http://www.icmje.org/recommendations/browse/publishing-and-editorial-issues/clinical-trial-registration.html.
3. International Federation of Pharmaceutical Manufacturers and
Associations. Joint Position on the Disclosure of Sensitive
Information via Clinical Trial Registries [Internet]. 2005 Sept 5
[updated 2009 Nov 10; cited 2016 Aug 5]. Available from: http://www.efpia.eu/uploads/Modules/Documents/november_10_2009_updated_joint_position_on_the_disclosure_of_clinical_trial_information_via_clinical_trial_registries_and_databases.pdf.
4. Steinbrook R. Registration of clinical trials--voluntary or
mandatory? N Engl J Med. 2004 Oct 28;351(18):1820-2.
5. Evans T, G[uuml]lmezoglu M, Pang T. Registering clinical trials:
an essential role for WHO. Lancet. 2004 May 1;363(9419):1413-4.
6. Dickersin K, Davis BR, Dixon DO, George SL, Hawkinse BS, Lachin
J, Peduzzi P, Pocock S; Society for Clinical Trials. The Society for
Clinical Trials supports United States legislation mandating trials
[[Page 65135]]
registration. Clinical Trials. 2004;1(5):417-20.
7. Scherer RW, Langenberg P, von Elm E. Full publication of results
initially presented in abstracts. Cochrane Database of Systematic
Reviews. 2007 Apr 18;(2):MR000005.
8. Faubel S, Chawla LS, Chertow GM, Goldstein SL, Jaber BL, Liu KD;
Acute Kidney Injury Advisory Group of the American Society of
Nephrology. Ongoing clinical trials in AKI. CJASN. 2012 May
7;7(5):861-73.
9. Bourgeois FT, Murthy S, Pinto C, Olson KL, Ioannidis JP, Mandl
KD. Pediatric versus adult drug trials for conditions with high
pediatric disease burden. Pediatrics. 2012 Aug;130(2):285-92.
10. Li J, Lu Z. Systematic identification of pharmacogenomics
information from clinical trials. Journal Biomed Inform. 2012
Oct;45(5):870-8.
11. Califf RM, Zarin DA, Kramer JM, Sherman RE, Aberle LH, Tasneem
A. Characteristics of clinical trials registered in
ClinicalTrials.gov, 2007-2010. JAMA. 2012 May 2;307(17):1838-47.
12. Mayor S. Half of drug trials with results on ClinicalTrials.gov
are not published in journals. BMJ. 2013 Dec;347:f7219.
13. Hartung DM, Zarin DA, Guise JM, McDonagh M, Paynter R, Helfand
M. Reporting discrepancies between the ClinicalTrials.gov results
database and peer-reviewed publications. Ann Intern Med. 2014 Apr
1;160(7):477-83.
14. Gopal AD, Desai NR, Tse T, Ross JS. Reporting of noninferiority
trials in ClinicalTrials.gov and corresponding publications. JAMA.
2015 Mar 17;313(11):1163-5.
15. Cepeda MS, Lobanov V, Berlin JA. Use of ClinicalTrials.gov to
estimate condition-specific nocebo effects and other factors
affecting outcomes of analgesic trials. J Pain. 2013 Apr;14(4):405-
11.
16. Eguale T, Buckeridge DL, Verma A, Winslade NE., Benedetti A,
Hanley JA, Tamblyn R. Association of off-label drug use and adverse
drug events in an adult population. JAMA Intern Med. 2016
Jan;176(1):55-63;
17. Good CB, Gellad WF. Off-label drug use and adverse events,
turning up the heat on off-label prescribing. JAMA Intern Med. 2016
Jan;176(1):63-4.
18. McCray AT. Better access to information about clinical trials.
Ann Intern Med. 2000 Oct 17;133(8):609-14.
19. Ide NC, Loane RF, Demner-Fushman D. Essie: A concept-based
search engine for structured biomedical text. J Am Med Inform Assoc.
2007;14(3):253-63.
20. Zarin DA, Ide NC, Tse T, Harlan WR, West JC, Lindberg DA. Issues
in the registration of clinical trials. JAMA. 2007;297(19):2112-20.
21. Le Noury J, Nardo JM, Healy D, Jureidini J, Raven M, Tufanaru C,
Abi-Jaoude E. Restoring Study 329: efficacy and harms of paroxetine
and imipramine in treatment of major depression in adolescence. BMJ.
2015 Sep 16;351:h4320.
22. Fu R, Selph S, McDonagh M, Peterson K, Tiwari, A, Chou R,
Helfand M. Effectiveness and harms of recombinant human bone
morphogenetic protein-2 in spine fusion: a systematic review and
meta-analysis. Ann Intern Med. 2013 Jun 18;158(12):890-902.
23. Zarin DA, Tse T. Unambiguous identification of obesity trials. N
Engl J Med. 2013 Feb 7; 368(6):580-1.
24. Zarin DA, Tse T. Sharing individual participant data (IPD)
within the context of the trial reporting system (TRS). PLoS Med.
2016 Jan 19;13(1):e1001946.
25. Levin LA, Palmer JG. Institutional review boards should require
clinical trial registration. Arch Intern Med. 2007 Aug 13-
27;167(15):1576-80.
26. Zaccara G, Perucca P, Loiacono G, Giovannelli F, Verrotti A. The
adverse event profile of lacosamide: a systematic review and meta-
analysis of randomized controlled trials. Epilepsia. 2013
Jan;54(1):66-74.
27. Higgins JP, Green S. Cochrane Handbook for Systematic Reviews of
Interventions (version 5.1.0). 2011 Mar [cited 2016 Aug 23].
Available from: http://handbook.cochrane.org.
28. Presidential Commission for the Study of Bioethical Issues.
Moral Science: Protecting Participants in Human Subjects Research
[Internet]. [updated 2011 Dec; cited 2016 Aug 5]. Available from:
http://bioethics.gov/node/558.
29. Institute of Medicine (US) Forum on Drug Discovery, Development,
and Translation. Transforming Clinical Research in the United
States: Challenges and Opportunities: Workshop Summary. Washington
(DC): National Academies Press (US); 2010. Available from: http://www.ncbi.nlm.nih.gov/books/NBK50892/.
30. Dear RF, Barratt AL, McGeechan K, Askie L, Simes J, Tattersall
MH. Landscape of cancer clinical trials in Australia: using trial
registries to guide future research. Med J Aust. 2011;194(8):387-91.
31. Inrig JK, Califf RM, Tasneem A, Vegunta RK, Molina C, Stanifer
JW, Chiswell K, Patel UD. The landscape of clinical trials in
nephrology: a systematic review of Clinicaltrials.gov. Am J Kidney
Dis. 2014 May; 63(5):771-80.
32. Alexander K, Kong DF, Starr AZ, Kramer J, Chiswell K, Tasneem A,
Califf RM. Portfolio of clinical research in adult cardiovascular
disease as reflected in ClinicalTrials.gov. J Am Heart Assoc. 2013
Sep 26;2(5):e000009.
33. Turner EH, Matthews AM, Linardatos E, Tell RA, Rosenthal R.
Selective publication of antidepressant trials and its influence on
apparent efficacy. N Engl J Med. 2008 Jan 17;358(3):252-60.
34. Zarin DA, Tse T. Trust but verify: trial registration and
determining fidelity to the protocol. Ann Intern Med. 2013 Jul
2;159(1):65-7.
35. Tasneem A, Aberle L, Ananth H, Chakraborty S, Chiswell K,
McCourt B, Pietrobon R. The database for aggregate analysis of
ClinicalTrials.gov (AACT) and subsequent regrouping by clinical
specialty. PLoS One. 2012 Mar 16;7(3):e33677.
36. Breast Cancer Trials. About Breast Cancer Trials [Internet].
[cited 2016 Jul 25]. Available from: https://www.breastcancertrials.org/BCTIncludes/WhoWeAre/AboutUs.html.
37. Berlin JA, Morris S, Rockhold F, Askie L, Ghersi D,
Waldstreicher J. Bumps and bridges on the road to responsible
sharing of clinical trial data. Clinical Trials. 2014 Feb;11(1):7-
12.
38. Becker JE, Krumholz HM, Ben-Josef G, Ross JS. Reporting of
results in ClinicalTrials.gov and high-impact journals. JAMA. 2014
Mar 12;311(10):1063-5.
39. Mathieu S, Boutron I, Moher D, Altman DG, Ravaud P. Comparison
of registered and published primary outcomes in randomized
controlled trials. JAMA. 2009 Sep 2;302(9):977-84.
40. Zarin DA, Tse T, Williams RJ, Califf RM, Ide NC. The
ClinicalTrials.gov results database--update and key issues. N Engl J
Med. 2011;364(9):852-60.
41. Riveros C, Dechartres A, Perrodeau E, Haneef R, Boutron I,
Ravaud P. Timing and completeness of trial results posted at
ClinicalTrials.gov and published in journals. PLoS Med. 2013 Dec;
10(12):e1001566.
42. Ross JS, Tse T, Zarin DA, Xu H, Krumholz HM. Publication of NIH
funded trials registered in ClinicalTrials.gov: cross-sectional
analysis. BMJ. 2012 Jan 3;344:d7292.
43. Gordon D, Taddei-Peters W, Mascette A, Antman M, Kaufmann PG,
Lauer MS. Publication of trials funded by the National Heart, Lung,
and Blood Institute. N Engl J Med. 2013 Nov 14; 369(20):1926-34.
44. Wedzicha JA, Banerji D, Chapman KR, Vestbo J, Roche N, Ayers RT,
Thach C, Fogel R, Patalano F, Vogelmeier CF; FLAME Investigators.
Indacaterol-Glycopyrronium versus Salmeterol-Fluticasone for COPD. N
Engl J Med. 2016 Jun 9;374(23):2222-34.
45. Whittington CJ, Kendall T, Fonagy P, Cottrell D, Cotgrove A,
Boddington E. Selective serotonin reuptake inhibitors in childhood
depression: systematic review of published versus unpublished data.
Lancet. 2004 Apr 24;363(9418):1341-5.
46. Rogawski MA, Federoff HJ. Disclosure of clinical trial results
when product development is abandoned. Sci Transl Med. 2011 Sep
28;3(102):102cm29.
47. Institute of Medicine (US). Sharing clinical trial data:
maximizing benefits, minimizing risk. Washington (DC): National
Academies Press. 2015.
48. Earley A, Lau J, Uhlig K. Haphazard reporting of deaths in
clinical trials: a review of cases of ClinicalTrials.gov records and
matched publications-a cross-sectional study. BMJ Open. 2013 Jan
18;3(1). pii: e001963.
49. Chan A, Tetzlaff JM, Altman DG, Laupacis A, Gotzsche PC,
Krle[zcaron]a-Jeri[cacute] K, Hrobjartsson A, Mann H, Dickersin K,
Berlin J, Dore C, Parulekar W, Summerskill W, Goves T, Schulz K, Sox
H, Rockhold RV, Rennie D, Moher D. SPIRIT 2013 Statement: Defining
standard protocol items for clinical trials. Ann Intern Med.
2013;158:200-207.
[[Page 65136]]
50. Finfer S, Bellomo R. Why publish statistical analysis plans?
Crit Care Resusc. 2009 Mar;11(1):5-6.
51. Ioannidis JP. Effectiveness of antidepressants: an evidence myth
constructed from a thousand randomized trials? Philos Ethics Humanit
Med. 2008 May 27;3:14.
52. Vedula SS, Bero L, Scherer RW, Dickersin K. Outcome reporting in
industry-sponsored trials of gabapentin for off-label use. N Engl J
Med. 2009 Nov 12; 361(20):1963-71.
53. Chan AW, Laupacis A, Moher D. Registering results from clinical
trials. JAMA. 2010 Jun 2;303(21):2138-9; author reply 2139.
54. Dwan K, Altman DG, Clarke M, Gamble C, Higgins JP, Sterne JA,
Williamson PR, Kirkham JJ. Evidence for the selective reporting of
analyses and discrepancies in clinical trials: a systematic review
of cohort studies of clinical trials. PLoS Med. 2014 Jun
24;11(6):e1001666.
55. Miller JD. Registering clinical trial results: the next step.
JAMA. 2010 Feb 24; 303(8):773-4.
56. International Conference on Harmonisation of Technical
Requirements for Registration of Pharmaceuticals for Human Use. ICH
harmonised tripartite guideline e3: structure and content of study
reports; 1995 Nov 30. Available from: http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E3/E3_Guideline.pdf.
57. Hey SP, Kesselheim AS. An uninformative truth: the logic of
Amarin's off-label promotion. PLOS Medicine. 2016 Mar
15;13(3):e1001978.
58. Robertson CT. When Truth Cannot Be Presumed: The Regulation of
Drug Promotion Under An Expanding First Amendment. 94 B.U. L. REV.
545, 560-61 (2014).
59. Kapczynski A. Free speech and pharmaceutical regulation--fishy
business. JAMA Inter Med. 2016 Mar;176(3):295-6.
60. Avorn J, Sarpatwari A, Kesselheim AS. Forbidden and permitted
statements about medications--loosening the rules. N Engl J Med.
2015 Sep 3;373(10):967-73.
61. De Angelis C, Drazen JM, Frizelle FA, Haug C, Hoey J, Horton R,
Kotzin S, Laine C, Marusic A, Overbeke JPM, Schroeder TV, Sox HC,
Weyden VD. Clinical trial registration: a statement from the
International Committee of Medical Journal Editors. N Engl J Med.
2004 Sep 16;351(12):1250-1. http://www.ncbi.nlm.nih.gov/pubmed/15356289.
62. Taichman DB, Backus J, Baethge C, Bauchner H, de Leeuw PW,
Drazen JM, Fletcher J, Frizelle FA, Groves T, Haileamlak A, James A,
Laine C, Peiperl L, Pinborg A, Sahni P, Wu S. Sharing clinical trial
data-a proposal from the International Committee of Medical Journal
Editors. N Engl J Med. 2016 Jan 28;374(4):384-6.
63. U.S. Department of Health and Human Services, National
Institutes of Health, National Library of Medicine. Meetings:
Expansion of the Clinical Trails Registry and Results Databank.
[Internet]. 2009 Mar 23 [cited 2016 August 30]. Available from
https://www.regulations.gov/document?D=NIH-2009-0002-0001.
64. U.S. Department of Health and Human Services, National
Institutes of Health, National Library of Medicine. Memorandum to
file: notice of proposed rulemaking, FDAAA, Title VIII: clinical
trials registration and results submission regarding synopsis of
selected public comments [Internet]. 2012 Aug 23 [cited 2016 August
5]. Available from: http://www.regulations.gov/#!docketDetail;D=NIH-
2009-0002.
65. National Institutes of Health (US). Draft policy on
dissemination of NIH-funded clinical trial information. Washington
(DC): Federal Register/NIH Guide for Grants and Contracts; 2014 Nov
19 and 2015 February 13. No. NOT-OD-15-019; 2015 Feb 13;80(30):8096-
98.
66. National Institutes of Health (US). Compendium of Public
Comments on the Draft NIH Policy on Dissemination [Internet]. Cited
2016 August 31. Available from: http://osp.od.nih.gov/sites/default/files/resources/Clinical%20Trials%20Dissemination%20Policy%20Combined%20Comments_2.0.pdf].
67. European Union. Communication from the Commission. Guidance on
the information concerning pediatric clinical trials to be entered
into the EU Database on Clinical Trials (EudraCT) and on the
information to be made public by the European Medicines Agency
(EMEA), in accordance with Article 41 of Regulation (EC) No 1901/
2006. Official Journal of the European Union. C 28: 4; 2009 Feb 4
[cited 2016 Jul 25]. Available from: http://ec.europa.eu/health/files/eudralex/vol-10/2009_c28_01/2009_c28_01_en.pdf.
68. European Commission. Communication from the Commission regarding
the guideline on the data fields contained in the clinical trials
database provided for in Article 11 of Directive 2001/20/EC to be
included in the database on medicinal products provided for in
Article 57 of Regulation (EC) No 726/2004, Official Journal of the
European Union. C168: 2; 2008 Jul 7 [cited 2016 Jul 25]. Available
from: http://ec.europa.eu/health/files/eudralex/vol-10/2008_07/c_16820080703en00030004_en.pdf.
69. European Commission. List of fields to be made public from
EudraCT for Pediatric Clinical Trials in accordance with Article 41
of Regulation (EC) No 1901/2006 and its implementing guideline 2009/
C28/01; 2009 Feb 4 [cited 2016 Jul 25]. Available from: http://ec.europa.eu/health/files/eudralex/vol-10/2009_02_04_guidelines_paed_en.pdf.
70. EU Clinical Trials Register [Internet]. Canary Wharf, London;
[cited 2016 Aug 5]. Available from: https://www.clinicaltrialsregister.eu/.
71. European Medicines Agency [Internet]. European Medicines Agency;
c1995-2016. European Medicines Agency launches a new version of
EudraCT; 10 Nov 13 [cited 2016 Aug 8]; [about 2 screens]. Available
from: http://www.ema.europa.eu/ema/index.jsp?curl=pages%2Fnews_and_events%2Fnews%2F2013%2F10%2Fnews_detail_001918.jsp.
72. Risk Communication Advisory Committee, Food and Drug
Administration (US). Presentations, transcript, minutes; 2009 Nov.
Available from: http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/RiskCommunicationAdvisoryCommittee/ucm313608.htm.
73. World Health Organization (WHO). International Clinical Trial
Registry Platform Trial Registration Data Set (Version 1.2.1)
[Internet] [cited 2016 Aug 5]. Available from: http://www.who.int/ictrp/network/trds/en/.
74. WHO: World Health Organization [Internet]. World Health
Organization; 2016. WHO statement on public disclosure of clinical
trial results; [cited 2016 Aug 8]; [about 3 screens]. Available
from: http://www.who.int/ictrp/results/reporting/en/.
75. International Health Terminology Standards Development
Organization. SNOMED CT [Internet] [cited 2016 Aug 8]. Available
from: http://www.ihtsdo.org/snomed-ct.
76. Healthcare Information Technology Standards Panel (US). HITSP:
enabling healthcare interoperability [updated 30 April 2010; cited
2016 Aug 8]. Available from: http://www.hitsp.org.
77. Medical Subject Headings (MeSH[supreg]) Unified Medical Language
System (UMLS) Metathesaurus [Internet]. United States: National
Institutes of Health, National Library of Medicine (US). 1999--
[updated 2016 Jun 20; cited 2016 Aug 8]. Available from: https://www.nlm.nih.gov/mesh/.
78. Food and Drug Administration, [Internet]. U.S. Department of
Health and Human Services; 2002. Guidance for industry: information
program on clinical trials for serious or life-threatening diseases
and conditions [cited 2016 Aug 8]. Available from: http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126838.pdf.
79. Food and Drug Administration [Internet]. U.S. Department of
Health and Human Services; 2004. Guidance for industry: information
program on clinical trials for serious or life-threatening diseases
and conditions [cited 2016 Aug 8]. Available from: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM077229.pdf.
80. Office for Human Research Protections [Internet]. U.S.
Department of Health and Human Services. Unanticipated Problems
Involving Risks and Adverse Events Guidance [cited 2016 Aug 8].
Available from: http://www.hhs.gov/ohrp/regulations-and-policy/guidance/reviewing-unanticipated-problems/.
81. International Conference on Harmonisation of Technical
Requirements for Registration of
[[Page 65137]]
Pharmaceuticals for Human Use [Internet]. ICH Harmonised Tripartite
Guideline: Guideline for good clinical practice E6(R1) [1996 Jun 10;
cited 2016 Aug 8]. Available from: http://www.ich.org/products/guidelines/efficacy/article/efficacy-guidelines.html.
82. Food and Drug Administration. U.S. Department of Health and
Human Services; 2013. Investigational Device Exemptions (IDEs) for
early feasibility medical device clinical studies, including certain
First in Human (FIH) studies [cited 2016 Aug 8]. Available from:
http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM279103.pdf.
83. Food and Drug Administration. U.S. Department of Health and
Human Services; 2006. Guidance for sponsors, institutional review
boards, clinical investigators and FDA staff: guidance on informed
consent for in vitro diagnostic device studies using leftover human
specimens that are not individually identifiable [cited 2016 Aug 8].
Available from http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm071265.pdf.
84. Li T, Yu T, Hawkins BS, Dickersin K (2015) design, analysis, and
reporting of crossover trials for inclusion in a meta-analysis. PLoS
One. 2015;10(8): e0133023.
85. National Library of Medicine, National Institutes of Health.
Protocol Data Element Definitions. Washington (DC): U.S. Department
of Health and Human Services; 2015. Available from https://prsinfo.clinicaltrials.gov/definitions.html.
86. International Conference on Harmonisation of Technical
Requirements for Registration of Pharmaceuticals for Human Use
[Internet]. Choice of control group and related issues in clinical
trials (ICH E10) [2000 July 20; cited 2016 Aug 8]. Available from
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E10/Step4/E10_Guideline.pdf.
87. National Library of Medicine. National Institutes of Health.
Medical Literature Analysis and Retrieval System Online, Clinical
Trial Registry Numbers in MEDLINE[supreg]/PubMed[supreg] Records
[Internet]. U.S. Department of Health and Human Services. [updated
2008 Jan 17; cited 2016 Aug 8]. Available from: http://www.nlm.nih.gov/bsd/policy/clin_trials.html.
87a. National Library of Medicine. National Institutes of Health.
Grants and Funding [Internet]. 2013 Mar 13. [Cited 2016 Sep 5].
Available from: http://grants.nih.gov/grants/glossary.htm#ProgramDirector/PrincipalInvestigator(PD/PI)).
88. International Organization for Standardization [Internet].
Clinical investigation of medical devices for human subjects--good
clinical practice (ISO 14155:2011) [updated 2016 Jun 17; cited 2016
Aug 8]. Available from: http://www.iso.org/iso/catalogue_detail?csnumber=45557.
89. American Psychiatric Association. Diagnostic and Statistical
Manual of Mental Disorders. 5th rev. ed. Washington, DC: American
Psychiatric Association. 2013.
90. National Library of Medicine, National Institutes of Health.
Elaboration of Definitions. Washington (DC): U.S. Department of
Health and Human Services; 2009 Mar 9. Available from: https://prsinfo.clinicaltrials.gov/ElaborationsOnDefinitions.pdf.
91. Board of Regents Working Group. Final report to the NLM Board of
Regents from its Working Group on health data standards. National
Library of Medicine, National Institute of Health (US); 2009 Apr.
Available from: https://www.nlm.nih.gov/od/bor/past-working-groups.html.
92. Secretary's Advisory Committee on Human Research Protections,
Department of Health and Human Services (US). Meeting Presentations;
2011 Mar. Available from: http://wayback.archive-it.org/org-745/20150824190405/http://www.hhs.gov/ohrp/sachrp/mtgings/mtg03-11/20110308pfds.html.
93. Schulz KF, Altman DG, Moher D; CONSORT Group. CONSORT 2010
statement: updated guidelines for reporting parallel group
randomized trials. Ann Intern Med. 2010 Jun 1;152(11):726-32.
Available from: http://www.consort-statement.org/checklists/view/32-consort/78-interventions.
94. Fairman KA, Curtiss FR. What should be done about bias and
misconduct in clinical trials? J Manag Care Pharm. 2009
Mar;15(2):154-60.
95. Food and Drug Administration (US). Evaluation of sex-specific
data in medical device clinical studies--guidance for industry and
Food and Drug Administration staff. Washington (DC): U.S. Department
of Health and Human Services; 2014. Available from: http://www.fda.gov/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm283453.htm.
96. Institute of Medicine. Exploring the Biological Contributions to
Human Health: Does Sex Matter? Washington, DC: The National
Academies Press (US); 2001. Doi:10.17226/10028.
97. National Library of Medicine, National Institutes of Health.
Results data element definitions. Washington (DC): U.S. Department
of Health and Human Services; 2015. Available from https://prsinfo.clinicaltrials.gov/results_definitions.html.
98. About ICMJE [Internet]. International Committee of Medical
Journal Editors. Clinical Trials Registration [cited 2016 Aug 8].
Available from: http://www.icmje.org/about-icmje/faqs/clinical-trials-registration/.
98a. European Commission. European Clinical Trials Database, Results
Related Documentation [Internet]. 2016 Jul 15 [cited 2016 Sep 5].
Available from: https://eudract.ema.europa.eu/result.html.
99. MedDRA: Medical Dictionary for Regulatory Affairs [Internet].
International Conference on Harmonisation of Technical Requirements
for Registration of Pharmaceuticals for Human Use. c1990 [cited 2016
Aug 8]. Available from: http://www.meddra.org.
100. MedDRA [Internet]. International Conference on Harmonisation of
Technical Requirements for Registration of Pharmaceuticals for Human
Use. About MedDRA [cited 2016 Aug 8]. Available from: http://www.meddra.org/about-meddra/history.
101. NCIthesaurus [Internet]. National Cancer Institute (US).
Available from: https://ncit.nci.nih.gov/ncitbrowser/.
102. Rief W, Nestoriuc Y, von Lilienfeld-Toal A, Dogan I, Schreiber
F, Hofmann SG, Barsky AJ, Avorn J. Differences in adverse effect
reporting in placebo groups in SSRI and tricyclic antidepressant
trials: A systematic review and meta-analysis. Drug Saf.
2009;32(11):1041-56.
103. Ioannidis JP, Evans SJ, G[oslash]tzsche PC, O'Neill RT, Altman
DG, Schulz K, Moher D; CONSORT Group. Better reporting of harms in
randomized trials: an extension of the CONSORT statement. Ann Intern
Med. 2004 Nov 16;141(10):781-8.
104. Food and Drug Administration (US). Guidance on conducting a
clinical safety review of a new product application and preparing a
report on the review. Washington (DC): U.S. Department of Health and
Human Services; 2005. Available from: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm072974.pdf.
105. Sherman RB, Woodcock J, Norden J, Grandinetti C, Temple RJ. New
FDA regulation to improve safety reporting in clinical trials. N
Engl J Med. 2011 Jul 7; 365(1):3-5.
106. Hillman SL, Mandrekar SJ, Bot B, DeMatteo RP, Perez EA, Ballman
KV, Nelson H, Buckner JC, Sargent DJ. Evaluation of the value of
attribution in the interpretation of adverse event data: a North
Central Cancer Treatment Group and American College of Surgeons
Oncology Group investigation. J Clin Oncol. 2010 Jun 20;28(18):3002-
7.
107. Mukherjee SD, Coombes, ME, Levine M, Cosby J, Kowaleski B,
Arnold A. A qualitative study evaluating causality attribution for
serious adverse events during early phase oncology clinical trials.
Invest New Drugs. 2011 Oct;29(5):1013-20.
108. Rief W, Avorn J, Barsky AJ. Medication-attributed adverse
effects in placebo groups. Arch Intern Med. 2006 Jan 23;166(2):155-
60.
109. MedDRA [Internet]. International Conference on Harmonisation of
Technical Requirements for Registration of Pharmaceuticals for Human
Use. What's new? MedDRA Version 19.0. [updated 2016 Mar; cited 2016
Aug 8]. Available from: http://www.meddra.org/sites/default/files/guidance/file/whatsnew_19_0_english.pdf.
[[Page 65138]]
110. Mello MM, Clarridge BR, Studdert DM. Academic medical centers'
standards for clinical trial agreements with industry. N Engl J Med.
2005 May 26;352(21):2202-10.
111. ClinicalTrials.gov [Internet]. U.S. National Institutes of
Health. How to submit your results [updated 2014 Dec; cited 2016 Aug
8]. Available from: https://clinicaltrials.gov/ct2/manage-recs/how-report#ScientificInformation.
111a. Schwartz LM, Woloshin S, Zheng E, Tse T, Zarin DA.
ClinicalTrials.gov and Drugs@FDA: A Comparison of Results Reporting
for New Drug Approval Trials. Ann Intern Med. 2016 Jun 14.
112. Grants and Funding [Internet]. National Institutes of Health.
Frequently asked questions: FDAAA--further resources for NIH
grantees [updated 2011 April 25; cited 2016 August 8]. Available
from: http://grants.nih.gov/clinicaltrials_fdaaa/faq.htm#836.
113. Wong H, Jessup A. Examination of clinical trial costs and
barriers for drug development. Office of the Assistant Secretary for
Planning and Evaluation, Department of Health and Human Services
(US) [updated 2014; cited 2016 Aug 8]. Available from: https://aspe.hhs.gov/sites/default/files/pdf/77166/rpt_erg.pdf.
114. DiMasi JA, Grabowski HG, Hansen RW. Innovation in the
pharmaceutical industry: New estimates of R&D costs. J Health Econ.
2016 May;47:20-3.
115. National Institutes of Health (US). Estimates of funding for
various research, condition, and disease categories [updated 2016
Feb 10; cited 2016 July 27]. Available from: https://report.nih.gov/categorical_spending.aspx.
116. McCarthy K, Godlew BJ. ClinicalTrials.gov: a questionnaire of
industry experiences and perceptions. Drug Information Journal. May
2010 44: 233-241.
117. White, Sarah A. (Human Research Quality Improvement Program,
Partners' Healthcare, Boston Massachusetts). Conversation with:
Zarin, Deborah A (National Library of Medicine, National Institutes
of Health, Bethesda, MD). 2016 July 11.
118. O'Reilly EK, Hassell NJ, Snyder DC, Natoli S, Liu I, Rimmler J,
Amspacher V, Burnett BK, Parrish AB, Berglund JP, Stacy M.
ClinicalTrials.gov reporting: strategies for success at an academic
health center. Clin Transl Sci. 2015 Feb;8(1):48-51.
119. North American Industry Classification System, 2012 NAICS
Definitions [Internet]. U.S. Census Bureau [cited 2016 Aug 10].
Available from: http://www.census.gov/cgi-bin/sssd/naics/naicsrch?chart_code=31&search=2012%20NAICS%20Search.
120. Table of Small Business Size Standards Matched to North
American Industry Classification System Codes [Internet]. U.S. Small
Business Administration. 2016 Feb 26 [cited 2016 Aug 10]. Available
from: https://www.sba.gov/contracting/getting-started-contractor/make-sure-you-meet-sba-size-standards/table-small-business-size-standards.
121. U.S. Census Bureau Official Site [Internet]. Washington (DC):
Economic census; 2012 [cited 2016 Aug 10]. Available from: https://www.census.gov/econ/census/.
122. U.S. Census Bureau Official Site [Internet]. Washington (DC):
American FactFinder database; 2012 [cited 2016 Aug 10]. Available
from: http://factfinder.census.gov/faces/tableservices/jsf/pages/productview.xhtml?pid=ECN_2012_US_31SG2&prodType=table.
List of Subjects in 42 CFR Part 11
Biologics, Clinical trial, Data bank, Drugs, Human subjects
research, Medical devices, Medical research, Registry, Reporting and
recordkeeping requirements, Results information.
Regulatory Text
For the reasons stated in this preamble, the U.S. Department of
Health and Human Services amends Title 42, Chapter I of the Code of
Federal Regulations by adding Part 11 to subchapter A to read as
follows:
PART 11--CLINICAL TRIALS REGISTRATION AND RESULTS INFORMATION
SUBMISSION
Subpart A--General Provisions
Sec.
11.2 What is the purpose of this part?
11.4 To whom does this part apply?
11.6 What are the requirements for the submission of truthful
information?
11.8 In what format must clinical trial information be submitted?
11.10 What definitions apply to this part?
Subpart B--Registration
11.20 Who must submit clinical trial registration information?
11.22 Which applicable clinical trials must be registered?
11.24 When must clinical trial registration information be
submitted?
11.28 What constitutes clinical trial registration information?
11.35 By when will the NIH Director post clinical trial registration
information submitted under Sec. 11.28?
Subpart C--Results Information Submission
11.40 Who must submit clinical trial results information?
11.42 For which applicable clinical trials must clinical trial
results information be submitted?
11.44 When must clinical trial results information be submitted for
applicable clinical trials subject to Sec. 11.42?
11.48 What constitutes clinical trial results information?
11.52 By when will the NIH Director post submitted clinical trial
results information?
11.54 What are the procedures for requesting a waiver of the
requirements for clinical trial results information submission?
Subpart D--Additional Submission of Clinical Trial Information
11.60 What requirements apply to the voluntary submission of
clinical trial information for clinical trials of FDA-regulated drug
products (including biological products) and device products?
11.62 What requirements apply to applicable clinical trials for
which submission of clinical trial information has been determined
by the Director to be necessary to protect the public health?
11.64 When must clinical trial information submitted to
ClinicalTrials.gov be updated or corrected?
Subpart E--Potential Legal Consequences of Non-Compliance
11.66 What are potential legal consequences of not complying with
the requirements of this part?
Authority: 42 U.S.C. 282(i); 42 U.S.C. 282(j); 5 U.S.C. 301; 42
U.S.C. 286(a); 42 U.S.C. 241(a); 42 U.S.C. 216(b).
Subpart A--General Provisions
Sec. 11.2 What is the purpose of this part?
This part implements section 402(j) of the Public Health Service
Act (42 U.S.C. 282(j)) by providing requirements and procedures for the
submission of clinical trial information for certain applicable
clinical trials and other clinical trials to the Director of the
National Institutes of Health (NIH) to be made publicly available via
ClinicalTrials.gov, the Internet-accessible clinical trial registry and
results data bank established by the National Library of Medicine (NLM)
at https://clinicaltrials.gov.
Sec. 11.4 To whom does this part apply?
(a) This part applies to the responsible party for an applicable
clinical trial that is required to be registered under Sec. 11.22, a
clinical trial for which clinical trial registration information or
clinical trial results information is submitted voluntarily in
accordance with Sec. 11.60, or an applicable clinical trial that is
required by the Director to have clinical trial information submitted
to protect the public health under Sec. 11.62.
(b) The responsible party must communicate the identity and contact
information of the responsible party to the Director by submitting the
Responsible Party, by Official Title and Responsible Party Contact
Information data elements under Sec. 11.28(a)(2)(iii)(B) and
(a)(2)(iv)(F) as part of the clinical trial information submitted at
the time of registration. Changes must be communicated to the Director
by updating information in accordance with Sec. 11.64(a).
[[Page 65139]]
(c) Determination of responsible party. For purposes of this part,
each applicable clinical trial or other clinical trial must have one
responsible party. With respect to a clinical trial, the sponsor of the
clinical trial will be considered the responsible party unless and
until a principal investigator has been designated the responsible
party, in accordance with paragraph (c)(2) of this section. With
respect to a pediatric postmarket surveillance of a device product that
is not a clinical trial, the responsible party is the entity that the
U.S. Food and Drug Adminstration (FDA), under section 522 of the
Federal Food, Drug, and Cosmetic Act (21 U.S.C. 3601), orders to
conduct the pediatric postmarket surveillance of a device product.
(1) Determination of sponsor. For purposes of this part, each
applicable clinical trial or other clinical trial must have one
sponsor.
(i) When an applicable clinical trial or other clinical trial is
conducted under an investigational new drug application (IND) or
investigational device exemption (IDE), the IND or IDE holder will be
considered the sponsor.
(ii) When an applicable clinical trial or other clinical trial is
not conducted under an IND or IDE, the single person or entity who
initiates the trial, by preparing and/or planning the trial, and who
has authority and control over the trial, will be considered the
sponsor.
(2) Designation of a principal investigator as the responsible
party.
(i) The sponsor may designate a principal investigator as the
responsible party if such principal investigator meets all of the
following requirements:
(A) Is responsible for conducting the trial;
(B) Has access to and control over the data from the trial;
(C) Has the right to publish the results of the trial; and
(D) Has the ability to meet all of the requirements for submitting
and updating clinical trial information as specified in this part.
(ii) With regard to an applicable clinical trial or other clinical
trial, a designation by the sponsor under paragraph (c)(2)(i) of this
section shall consist of the sponsor obtaining from the principal
investigator an acknowledgment of the principal investigator's
responsibilities under this part as responsible party, and the
principal investigator acknowledging the designation as responsible
party to the Director in the format specified at https://prsinfo.clinicaltrials.gov.
(3) Withdrawal of the designation of a principal investigator as
the responsible party.
In the event that a principal investigator who has been designated
the responsible party no longer meets or is no longer able to meet all
the requirements for being so designated under paragraph (c)(2)(i) of
this section, the sponsor must withdraw the designation in the format
specified at https://prsinfo.clinicaltrials.gov, at which time the
sponsor will be considered the responsible party unless and until the
sponsor makes a new designation in accordance with paragraph (c)(2) of
this section.
Sec. 11.6 What are the requirements for the submission of truthful
information?
The clinical trial information submitted by a responsible party
under this part shall not be false or misleading in any particular. A
responsible party who submits false and/or misleading information is
subject to civil monetary penalties and/or other civil or criminal
remedies available under U.S. law.
Sec. 11.8 In what format must clinical trial information be
submitted?
Information submitted under this part must be submitted
electronically to ClinicalTrials.gov, in the format specified at
https://prsinfo.clinicaltrials.gov.
Sec. 11.10 What definitions apply to this part?
(a) The following definitions apply to terms used in this part:
Adverse event means any untoward or unfavorable medical occurrence
in a human subject, including any abnormal sign (for example, abnormal
physical exam or laboratory finding), symptom, or disease, temporally
associated with the subject's participation in the research, whether or
not considered related to the subject's participation in the research.
See also the definition of ``serious adverse event.''
Applicable clinical trial means an applicable device clinical trial
or an applicable drug clinical trial. Expanded access use under section
561 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 360bbb) is
not an applicable clinical trial.
Applicable device clinical trial means:
(1) A prospective clinical study of health outcomes comparing an
intervention with a device product subject to section 510(k), 515, or
520(m) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 360(k),
21 U.S.C. 360e, 21 U.S.C. 360j(m)) against a control in human subjects
(other than a small clinical trial to determine the feasibility of a
device product, or a clinical trial to test prototype device products
where the primary outcome measure relates to feasibility and not to
health outcomes);
(2) A pediatric postmarket surveillance of a device product as
required under section 522 of the Federal Food, Drug, and Cosmetic Act
(21 U.S.C. 3601); or
(3) A clinical trial of a combination product with a device primary
mode of action under 21 CFR part 3, provided that it meets all other
criteria of the definition under this part.
Applicable drug clinical trial means a controlled clinical
investigation, other than a phase 1 clinical investigation, of a drug
product subject to section 505 of the Federal Food, Drug, and Cosmetic
Act (21 U.S.C. 355) or a biological product subject to section 351 of
the Public Health Service Act (42 U.S.C. 262), where ``clinical
investigation'' has the meaning given in 21 CFR 312.3 and ``phase 1''
has the meaning given in 21 CFR 312.21. A clinical trial of a
combination product with a drug primary mode of action under 21 CFR
part 3 is also an applicable drug clinical trial, provided that it
meets all other criteria of the definition under this part.
Approved drug means a drug product that is approved for any use
under section 505 of the Federal Food, Drug, and Cosmetic Act (21
U.S.C. 355) or a biological product licensed for any use under section
351 of the Public Health Service Act (42 U.S.C. 262).
Approved or cleared device means a device product that is cleared
for any use under section 510(k) of the Federal Food, Drug, and
Cosmetic Act (21 U.S.C 360(k)) or approved for any use under sections
515 or 520(m) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C
360e, 360j(m)).
Arm means a pre-specified group or subgroup of human subject(s) in
a clinical trial assigned to receive specific intervention(s) (or no
intervention) according to a protocol.
Clinical study means research according to a protocol involving one
or more human subjects to evaluate biomedical or health-related
outcomes, including interventional studies and observational studies.
Clinical trial means a clinical investigation or a clinical study
in which human subject(s) are prospectively assigned, according to a
protocol, to one or more interventions (or no intervention) to evaluate
the effect(s) of the intervention(s) on biomedical or health-related
outcomes.
Clinical trial information means the data elements, including
clinical trial registration information and clinical trial results
information, that the responsible party is required to submit to
ClinicalTrials.gov, as specified in section 402(j) of the Public Health
[[Page 65140]]
Service Act (42 U.S.C. 282(j)) and this part.
Clinical trial registration information means the data elements
that the responsible party is required to submit to ClinicalTrials.gov,
as specified in section 402(j)(2)(A)(ii) of the Public Health Service
Act (42 U.S.C. 282(j)(2)(A)(ii)) or Sec. 11.28, as applicable.
Clinical trial results information means the data elements that the
responsible party is required to submit to ClinicalTrials.gov, as
specified in sections 402(j)(3)(C) and 402(j)(3)(I) of the Public
Health Service Act (42 U.S.C. 282(j)(3)(C) and (I)) or Sec. 11.48, as
applicable. If a responsible party submits clinical trial results
information voluntarily for a clinical trial, clinical trial results
information also means Sec. 11.60(b)(2)(i)(B) or Sec.
11.60(c)(2)(i)(B), as applicable.
Comparison group means a grouping of human subjects in a clinical
trial that is or may be used in analyzing the results data collected
during the clinical trial.
Completion date means, for a clinical trial, including an
applicable clinical trial, the date that the final subject was examined
or received an intervention for the purposes of final collection of
data for the primary outcome, whether the clinical trial concluded
according to the pre-specified protocol or was terminated. In the case
of clinical trials with more than one primary outcome measure with
different completion dates, this term refers to the date on which data
collection is completed for all of the primary outcomes. For a
pediatric postmarket surveillance of a device product that is not a
clinical trial, completion date means the date on which the final
report of the pediatric postmarket surveillance of the device product
is submitted to FDA. For purposes of this part, completion date is
referred to as ``primary completion date.''
Control or controlled means, with respect to a clinical trial, that
data collected on human subjects in the clinical trial will be compared
to concurrently collected data or to non-concurrently collected data
(e.g., historical controls, including a human subject's own baseline
data), as reflected in the pre-specified primary or secondary outcome
measures. For purposes of this part, all clinical trials with one or
more arms and pre-specified outcome measure(s) are controlled.
Device means a device as defined in section 201(h) of the Federal
Food, Drug, and Cosmetic Act (21 U.S.C. 321(h)).
Director means the NIH Director or any official of NIH to whom the
NIH Director delegates authorities granted in section 402(j) of the
Public Health Service Act (42 U.S.C. 282(j)).
Drug means a drug as defined in section 201(g) of the Federal Food,
Drug, and Cosmetic Act (21 U.S.C. 321(g)) or a biological product as
defined in section 351 of the Public Health Service Act (42 U.S.C.
262).
Enroll or enrolled means a human subject's, or their legally
authorized representative's, agreement to participate in a clinical
trial following completion of the informed consent process, as required
in 21 CFR part 50 and/or 45 CFR part 46, as applicable. For the
purposes of this part, potential subjects who are screened for the
purpose of determining eligibility for a trial, but do not participate
in the trial, are not considered enrolled, unless otherwise specified
by the protocol.
Human subjects protection review board means an institutional
review board (IRB) as defined in 21 CFR 50.3 or 45 CFR 46.102, as
applicable, that is responsible for assuring the protection of the
rights, safety, and well-being of human subjects involved in a clinical
trial and is adequately constituted to provide assurance of that
protection. An IRB may also be known as an ``independent ethics
committee.''
Interventional means, with respect to a clinical study or a
clinical investigation, that participants are assigned prospectively to
an intervention or interventions according to a protocol to evaluate
the effect of the intervention(s) on biomedical or other health-related
outcomes.
Investigational Device Exemption (IDE) has the meaning given in 21
CFR part 812.
Investigational New Drug Application (IND) has the meaning given in
21 CFR 312.3.
NCT number means the unique identification code assigned to each
record in ClinicalTrials.gov, including a record for an applicable
clinical trial, a clinical trial, or an expanded access program.
Ongoing means, with respect to a clinical trial of a drug product
(including a biological product) or a device product and to a date,
that one or more human subjects is enrolled in the clinical trial, and
the date is before the primary completion date of the clinical trial.
With respect to a pediatric postmarket surveillance of a device
product, ongoing means a date between the date on which FDA approves
the plan for conducting the surveillance and the date on which the
final report is submitted to FDA.
Outcome measure means a pre-specified measurement that will be used
to determine the effect of an experimental variable on the human
subject(s) in a clinical trial. See also the definitions of ``primary
outcome measure'' and ``secondary outcome measure.''
Pediatric postmarket surveillance of a device product means the
active, systematic, scientifically valid collection, analysis, and
interpretation of data or other information conducted under section 522
of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 360l) about a
marketed device product that is expected to have significant use in
patients who are 21 years of age or younger at the time of diagnosis or
treatment. A pediatric postmarket surveillance of a device product may
be, but is not always, a clinical trial.
Primary completion date means, for purposes of this part,
``completion date.'' See the definition of ``completion date.''
Primary outcome measure means the outcome measure(s) of greatest
importance specified in the protocol, usually the one(s) used in the
power calculation. Most clinical trials have one primary outcome
measure, but a clinical trial may have more than one. For purposes of
this part, ``primary outcome'' has the same meaning as primary outcome
measure.
Principal investigator means the individual who is responsible for
the overall scientific and technical direction of the study.
Protocol means the written description of the clinical trial,
including objective(s), design, and methods. It may also include
relevant scientific background and statistical considerations.
Responsible party means, with respect to a clinical trial, the
sponsor of the clinical trial, as defined in 21 CFR 50.3; or the
principal investigator of such clinical trial if so designated by a
sponsor, grantee, contractor, or awardee, so long as the principal
investigator is responsible for conducting the trial, has access to and
control over the data from the clinical trial, has the right to publish
the results of the trial, and has the ability to meet all of the
requirements under this part for the submission of clinical trial
information. For a pediatric postmarket surveillance of a device
product that is not a clinical trial, the responsible party is the
entity who FDA orders to conduct the pediatric postmarket surveillance
of the device product.
Secondary outcome measure means an outcome measure that is of
lesser importance than a primary outcome measure, but is part of a pre-
specified analysis plan for evaluating the effects
[[Page 65141]]
of the intervention or interventions under investigation in a clinical
trial and is not specified as an exploratory or other measure. A
clinical trial may have more than one secondary outcome measure. For
purposes of this part, ``secondary outcome'' has the same meaning as
secondary outcome measure.
Secretary means the Secretary of Health and Human Services or any
other official(s) to whom the Secretary delegates the authority
contained in section 402(j) of the Public Health Service Act (42 U.S.C.
282(j)).
Serious adverse event means an adverse event that results in any of
the following outcomes: Death, a life-threatening adverse event as
defined in 21 CFR 312.32, inpatient hospitalization or prolongation of
existing hospitalization, a persistent or significant incapacity or
substantial disruption of the ability to conduct normal life functions,
or a congenital anomaly/birth defect. Important medical events that may
not result in death, be life-threatening, or require hospitalization
may be considered serious when, based upon appropriate medical
judgment, they may jeopardize the human subject and may require medical
or surgical intervention to prevent one of the outcomes listed in this
definition. Examples of such medical events include allergic
bronchospasm requiring intensive treatment in an emergency room or at
home, blood dyscrasias or convulsions that do not result in inpatient
hospitalization, or the development of a substance use disorder.
Sponsor means either a ``sponsor'' or ``sponsor-investigator,'' as
each is defined in 21 CFR 50.3.
Study completion date means, for a clinical trial, the date the
final subject was examined or received an intervention for purposes of
final collection of data for the primary and secondary outcome measures
and adverse events (e.g., last subject's last visit), whether the
clinical trial concluded according to the pre-specified protocol or was
terminated.
U.S. FDA-regulated device product means, for purposes of this part,
a device product subject to section 510(k), 515, 520(m), or 522 of the
Federal Food, Drug, and Cosmetic Act (21 U.S.C. 360(k), 21 U.S.C. 360e,
21 U.S.C. 360j(m), 21 U.S.C. 360l).
U.S. FDA-regulated drug product means, for purposes of this part, a
drug product subject to section 505 of the Federal Food, Drug, and
Cosmetic Act or a biological product subject to section 351 of the
Public Health Service Act (21 U.S.C. 355, 42 U.S.C. 262) .
(b) The following definitions apply to data elements of clinical
trial information referenced in this part, unless otherwise specified:
(1) Brief Title means a short title of the clinical trial written
in language intended for the lay public, including any acronym or
abbreviation used publicly to identify the clinical trial.
(2) Official Title means the title of the clinical trial,
corresponding to the title of the protocol.
(3) Brief Summary means a short description of the clinical trial,
including a brief statement of the clinical trial's hypothesis, written
in language intended for the lay public.
(4) Primary Purpose means the main objective of the intervention(s)
being evaluated by the clinical trial.
(5) Study Design means a description of the manner in which the
clinical trial will be conducted, including the following information:
(i) Interventional Study Model. The strategy for assigning
interventions to human subjects.
(ii) Number of Arms. The number of arms in the clinical trial. For
a trial with multiple periods or phases that have different numbers of
arms, it means the maximum number of arms during all periods or phases.
(iii) Arm Information. A description of each arm of the clinical
trial that indicates its role in the clinical trial, provides an
informative title, and, if necessary, additional descriptive
information (including which interventions are administered in each
arm) to differentiate each arm from other arms in the clinical trial.
(iv) Allocation. The method by which human subjects are assigned to
arms in a clinical trial.
(v) Masking. The party or parties, if any, involved in the clinical
trial who are prevented from having knowledge of the interventions
assigned to individual human subjects.
(6) Study Phase means, for a clinical trial of a drug product
(including a biological product), the numerical phase of such clinical
trial, consistent with terminology in 21 CFR 312.21, such as phase 2 or
phase 3, and in 21 CFR 312.85 for phase 4 studies.
(7) Study Type means the nature of the investigation or
investigational use for which clinical trial information is being
submitted, e.g., interventional, observational.
(8) Pediatric Postmarket Surveillance of a Device Product means a
clinical trial or study that includes a U.S. FDA-regulated device
product as an intervention and is a pediatric postmarket surveillance
of a device product ordered under section 522 of the Federal Food,
Drug, and Cosmetic Act (21 U.S.C. 369l).
(9) Primary Disease or Condition Being Studied in the Trial, or the
Focus of the Study means the name(s) of the disease(s) or condition(s)
studied in the clinical trial, or the focus of the clinical trial. Use,
if available, appropriate descriptors from NLM's Medical Subject
Headings (MeSH)-controlled vocabulary thesaurus or terms from another
vocabulary, such as the Systematized Nomenclature of Medicine--Clinical
Terms (SNOMED CT), that has been mapped to MeSH within the Unified
Medical Language System (UMLS) Metathesaurus.
(10) Intervention Name(s) means a brief descriptive name used to
refer to the intervention(s) studied in each arm of the clinical trial.
A non-proprietary name of the intervention must be used, if available.
If a non-proprietary name is not available, a brief descriptive name or
identifier must be used.
(11) Other Intervention Name(s) means other current and former
name(s) or alias(es), if any, different from the Intervention Name(s),
that the sponsor has used publicly to identify the intervention(s),
including, but not limited to, past or present names such as brand
name(s), or serial numbers.
(12) Intervention Description means details that can be made public
about the intervention, other than the Intervention Name(s) and Other
Intervention Name(s), sufficient to distinguish the intervention from
other, similar interventions studied in the same or another clinical
trial. For example, interventions involving drugs may include dosage
form, dosage, frequency, and duration.
(13) Intervention Type means, for each intervention studied in the
clinical trial, the general type of intervention, e.g., drug,
biological/vaccine, or, device.
(14) Device Product Not Approved or Cleared by U.S. FDA means that
at least one device product studied in the clinical trial has not been
previously approved or cleared by FDA for one or more uses.
(15) Product Manufactured in and Exported from the U.S. means that
any drug product (including a biological product) or device product
studied in the clinical trial is manufactured in the United States or
one of its territories and exported for study in a clinical trial in
another country.
(16) Study Start Date means the estimated date on which the
clinical trial will be open for recruitment of human subjects, or the
actual date on which the first human subject was enrolled.
[[Page 65142]]
(17) Primary Completion Date means the estimated or actual primary
completion date. If an estimated primary completion date is used, the
responsible party must update the Primary Completion Date data element
once the clinical trial has reached the primary completion date to
reflect the actual primary completion date.
(18) Enrollment means the estimated total number of human subjects
to be enrolled (target number) or the actual total number of human
subjects that are enrolled in the clinical trial. Once the trial has
reached the primary completion date, the responsible party must update
the Enrollment data element to reflect the actual number of human
subjects enrolled in the clinical trial.
(19) Primary Outcome Measure Information means a description of
each primary outcome measure, to include the following information:
(i) Name of the specific primary outcome measure;
(ii) Description of the metric used to characterize the specific
primary outcome measure; and
(iii) Time point(s) at which the measurement is assessed for the
specific metric used.
(20) Secondary Outcome Measure Information means a description of
each secondary outcome measure, to include the following information:
(i) Name of the specific secondary outcome measure;
(ii) Description of the metric used to characterize the specific
secondary outcome measure; and
(iii) Time point(s) at which the measurement is assessed for the
specific metric used.
(21) Eligibility Criteria means a limited list of criteria for
selection of human subjects to participate in the clinical trial,
provided in terms of inclusion and exclusion criteria and suitable for
assisting potential human subjects in identifying clinical trials of
interest.
(22) Sex/Gender means the sex and, if applicable, gender of the
human subjects who may participate in the clinical trial.
(23) Age Limits means the minimum and maximum age of human subjects
who may participate in the clinical trial, provided in relevant units
of time.
(24) Accepts Healthy Volunteers means that human subjects who do
not have a disease or condition, or related conditions or symptoms,
under study in the clinical trial are permitted to participate in the
clinical trial.
(25) Overall Recruitment Status means the recruitment status for
the clinical trial as a whole, based on the status of the individual
sites. If at least one facility in a multi-site clinical trial has an
individual site status of ``recruiting,'' then the overall recruitment
status for the trial must be ``recruiting.''
(26) Why Study Stopped means, for a clinical trial that is
suspended or terminated or withdrawn prior to its planned completion as
anticipated by the protocol, a brief explanation of the reason(s) why
the clinical trial was stopped.
(27) Individual Site Status means the recruitment status of each
participating facility in a clinical trial.
(28) Availability of Expanded Access means, for an applicable drug
clinical trial of a drug product (including a biological product) that
is not an approved drug product (including a biological product), and
for which the responsible party is both the manufacturer of the drug
product (including a biological product) and the sponsor of the
applicable clinical trial:
(i) An indication of whether there is expanded access to the
investigational drug product (including a biological product) under
section 561 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C.
360bbb) for those individuals who do not qualify for enrollment in the
applicable clinical trial, under one or more of the following types of
expanded access programs: for individual patients, including for
emergency use, as specified in 21 CFR 312.310; for intermediate-size
patient populations, as specified in 21 CFR 312.315; or under a
treatment IND or treatment protocol, as specified in 21 CFR 312.320;
and
(ii) If expanded access is available under section 561 of the
Federal Food, Drug, and Cosmetic Act (21 U.S.C. 360bbb), the NCT number
of the expanded access record.
(29) Name of the Sponsor means the name of the entity or individual
who is the sponsor of the clinical trial, as defined in this part.
(30) Responsible Party, by Official Title means an:
(i) Indication of whether the responsible party is the sponsor of
the clinical trial, as that term is defined in 21 CFR 50.3; the
sponsor-investigator, as that term is defined in 21 CFR 50.3; or a
principal investigator designated pursuant to this part; and
(ii) Either:
(A) The official name of the entity, if the responsible party is an
entity; or
(B) The official title and primary organizational affiliation of
the individual, if the responsible party is an individual.
(31) Facility Information means, for each participating facility in
a clinical trial, the following information:
(i) Facility Name, meaning the full name of the organization where
the clinical trial is being conducted;
(ii) Facility Location, including city, state, country and zip code
for U.S. locations (including territories of the United States) and
city and country for locations in other countries; and
(iii) Either:
(A) For each facility participating in a clinical trial, Facility
Contact, including the name or title, telephone number, and email
address of a person to whom questions concerning the trial and
enrollment at that site can be addressed; or
(B) Central Contact Person, including the name or title, toll-free
telephone number, and email address of a person to whom questions
concerning enrollment at any location of the trial can be addressed.
(32) Unique Protocol Identification Number means any unique
identifier assigned to the protocol by the sponsor.
(33) Secondary ID means:
(i) Any identifier(s) other than the organization's unique protocol
identifier or NCT number that is assigned to the clinical trial,
including any unique clinical trial identifiers assigned by other
publicly available clinical trial registries. If the clinical trial is
funded in whole or in part by a U.S. Federal Government agency, the
complete grant or contract number must be submitted as a Secondary ID.
(ii) A description of the type of Secondary ID.
(34) U.S. Food and Drug Administration IND or IDE Number means an
indication of whether there is an IND or IDE for the clinical trial
and, if so, each of the following elements:
(i) Name or abbreviation of the FDA center with whom the IND or IDE
is filed;
(ii) IND or IDE number assigned by the FDA center; and
(iii) For an IND, the IND serial number, as defined in 21 CFR
312.23(e), if any, assigned to the clinical trial.
(35) Human Subjects Protection Review Board Status means
information to indicate whether a clinical trial has been reviewed and
approved by a human subjects protection review board or whether such
review is not required per applicable law (e.g., 21 CFR part 56, 45 CFR
part 46, or other applicable regulation). Human Subjects Protection
Review Board Status must be listed as ``approved'' if at least one
human subjects protection review board has approved the clinical trial.
[[Page 65143]]
(36) Record Verification Date means the date on which the
responsible party last verified the clinical trial information in the
entire ClinicalTrials.gov record for the clinical trial, even if no
additional or updated information was submitted at that time.
(37) Responsible Party Contact Information means administrative
information to identify and allow communication with the responsible
party by telephone, email, and regular mail or delivery service.
Responsible Party Contact Information includes the name, official
title, organizational affiliation, physical address, mailing address,
phone number, and email address of the individual who is the
responsible party or of a designated employee of the organization that
is the responsible party.
(38) Studies a U.S. FDA-regulated Device Product means that a
clinical trial studies a device product subject to section 510(k), 515,
or 520(m) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C.
360(k), 21 U.S.C. 360e, 21 U.S.C. 360j(m)).
(39) Studies a U.S. FDA-regulated Drug Product means a clinical
trial studies a drug product (including a biological product) subject
to section 505 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C.
355) or section 351 of the Public Health Service Act (42 U.S.C. 262).
(40) Post Prior to U.S. FDA Approval or Clearance means, for an
applicable device clinical trial of a device product that has not been
previously approved or cleared, the responsible party indicates to the
Director that it is authorizing the Director, in accordance with Sec.
11.35(b)(2)(ii), to publicly post its clinical trial registration
information, which would otherwise be subject to delayed posting, as
specified in Sec. 11.35(b)(2)(i), prior to the date of FDA approval or
clearance of its device product.
(41) Study Completion Date means the estimated or actual study
completion date. Once the clinical trial has reached the study
completion date, the responsible party must update the Study Completion
Date data element to reflect the actual study completion date in
accordance with Sec. 11.64(a)(1)(ii)(J) .
Subpart B--Registration
Sec. 11.20 Who must submit clinical trial registration information?
The responsible party for an applicable clinical trial specified in
Sec. 11.22 must submit clinical trial registration information for
that clinical trial.
Sec. 11.22 Which applicable clinical trials must be registered?
(a) General specification. (1) Any applicable clinical trial that
is initiated after September 27, 2007, must be registered.
(2) Any applicable clinical trial that is initiated on or before
September 27, 2007, and is ongoing on December 26, 2007, must be
registered.
(3) Determining the date of initiation for an applicable clinical
trial. An applicable clinical trial, other than a pediatric postmarket
surveillance of a device product that is not a clinical trial, is
considered to be initiated on the date on which the first human subject
is enrolled. A pediatric postmarket surveillance of a device product
that is not a clinical trial is considered to be initiated on the date
on which FDA approves the plan for conducting the surveillance.
(b) Determination of applicable clinical trial for a clinical trial
or study initiated on or after January 18, 2017. A clinical trial or
study that, at any point in time, meets the conditions listed in
paragraph (b)(1) or (2) of this section will be considered to meet the
definition of an applicable clinical trial.
(1) Applicable device clinical trial. A clinical trial or study
that meets the conditions listed in either paragraph (b)(1)(i) or (ii)
of this section is an applicable device clinical trial:
(i) The study is a pediatric postmarket surveillance of a device
product as required by FDA under section 522 of the Federal Food, Drug,
and Cosmetic Act (21 U.S.C. 3601).
(ii) The study is a clinical trial with one or more arms that meets
all of the following criteria:
(A) Study Type is interventional;
(B) Primary Purpose of the clinical trial is other than a
feasibility study;
(C) The clinical trial Studies a U.S. FDA-regulated Device Product;
and
(D) One or more of the following applies:
(1) At least one Facility Location is within the United States or
one of its territories,
(2) A device product under investigation is a Product Manufactured
in and Exported from the U.S. or one of its territories for study in
another country, or
(3) The clinical trial has a U.S. Food and Drug Administration IDE
Number.
(2) Applicable drug clinical trial. A clinical trial with one or
more arms that meets the following conditions is an applicable drug
clinical trial:
(i) Study Type is interventional;
(ii) Study Phase is other than phase 1;
(iii) The clinical trial Studies a U.S. FDA-regulated Drug Product;
and
(iv) One or more of the following applies:
(A) At least one Facility Location for the clinical trial is within
the United States or one of its territories,
(B) A drug product (including a biological product) under
investigation is a Product Manufactured in and Exported from the U.S.
or one of its territories for study in another country, or
(C) The clinical trial has a U.S. Food and Drug Administration IND
Number.
Sec. 11.24 When must clinical trial registration information be
submitted?
(a) General. Except as provided in paragraph (b) of this section,
the responsible party for an applicable clinical trial for which
submission of clinical trial registration information is required must
submit the clinical trial registration information specified in section
402(j)(2)(A)(ii) of the Public Health Service Act (42 U.S.C.
282(j)(2)(A)(ii)) or Sec. 11.28(a), as applicable, not later than
December 26, 2007, or 21 calendar days after the first human subject is
enrolled, whichever date is later.
(b) Exceptions:. (1) The responsible party for an applicable
clinical trial that is a clinical trial and for which the submission of
clinical trial registration information is required and that is not for
a serious or life-threatening disease or condition must submit clinical
trial registration information as specified in section 402(j)(2)(A)(ii)
of the Public Health Service Act (42 U.S.C. 282(j)(2)(A)(ii)) or Sec.
11.28(a), as applicable, not later than September 27, 2008, or 21
calendar days after the first human subject is enrolled, whichever date
is later.
(2) The responsible party for an applicable device clinical trial
that is a pediatric postmarket surveillance of a device product and is
not a clinical trial must submit clinical trial registration
information, as specified in section 402(j)(2)(A)(ii) of the Public
Health Service Act (42 U.S.C. 282(j)(2)(A)(ii)) or Sec. 11.28(b), not
later than December 26, 2007, or 21 calendar days after FDA approves
the postmarket surveillance plan, whichever date is later.
Sec. 11.28 What constitutes clinical trial registration information?
(a) For each applicable clinical trial that must be registered with
ClinicalTrials.gov, other than a pediatric postmarket surveillance of a
device product that is not a clinical trial, the responsible party must
submit the following information:
(1) For such applicable clinical trials that were initiated before
January 18,
[[Page 65144]]
2017, the responsible party must submit the information specified in
section 402(j)(2)(A)(ii) of the Public Health Service Act (42 U.S.C.
282(j)(2)(A)(ii)).
(2) For such applicable clinical trials that are initiated on or
after January 18, 2017, the responsible party must submit the data
elements listed below:
(i) Descriptive information:
(A) Brief Title;
(B) Official Title;
(C) Brief Summary;
(D) Primary Purpose;
(E) Study Design;
(F) Study Phase, for an applicable drug clinical trial;
(G) Study Type;
(H) Pediatric Postmarket Surveillance of a Device Product, for an
applicable device clinical trial that is a Pediatric Postmarket
Surveillance of a Device Product;
(I) Primary Disease or Condition Being Studied in the Trial, or the
Focus of the Study;
(J) Intervention Name(s), for each intervention studied;
(K) Other Intervention Name(s), for each intervention studied;
(L) Intervention Description, for each intervention studied;
(M) Intervention Type, for each intervention studied;
(N) Studies a U.S. FDA-regulated Device Product;
(O) Studies a U.S. FDA-regulated Drug Product;
(P) Device Product Not Approved or Cleared by U.S. FDA, if any
studied intervention is a device product;
(Q) Post Prior to U.S. FDA Approval or Clearance, for an applicable
device clinical trial that studies at least one device product not
previously approved or cleared by the U.S. FDA;
(R) Product Manufactured in and Exported from the U.S., if the
entry for U.S. Food and Drug Administration IND or IDE Number in Sec.
11.28(a)(2)(iv)(C) indicates that there is no IND or IDE for the
clinical trial, and the entry(ies) for Facility Information in Sec.
11.28(a)(2)(iii)(C) include no facility locations in the United States
or its territories;
(S) Study Start Date;
(T) Primary Completion Date;
(U) Study Completion Date;
(V) Enrollment;
(W) Primary Outcome Measure Information, for each primary outcome
measure; and
(X) Secondary Outcome Measure Information, for each secondary
outcome measure.
(ii) Recruitment information:
(A) Eligibility Criteria;
(B) Sex/Gender;
(C) Age Limits;
(D) Accepts Healthy Volunteers;
(E) Overall Recruitment Status;
(F) Why Study Stopped;
(G) Individual Site Status; and
(H) Availability of Expanded Access. If expanded access is
available for an investigational drug product (including a biological
product), an expanded access record must be submitted in accordance
with Sec. 11.28(c), unless an expanded access record was submitted
previously in accordance with that provision.
(iii) Location and contact information:
(A) Name of the Sponsor;
(B) Responsible Party, by Official Title; and
(C) Facility Information.
(iv) Administrative data:
(A) Unique Protocol Identification Number;
(B) Secondary ID;
(C) U.S. Food and Drug Administration IND or IDE Number;
(D) Human Subjects Protection Review Board Status;
(E) Record Verification Date; and
(F) Responsible Party Contact Information.
(b) Pediatric postmarket surveillance of a device product that is
not a clinical trial. For each pediatric postmarket surveillance of a
device product that is not a clinical trial, the responsible party must
submit the following information:
(1) For such applicable device clinical trials that were initiated
before January 18, 2017, the responsible party must submit the
information specified in section 402(j)(2)(A)(ii) of the Public Health
Service Act (42 U.S.C. 282(j)(2)(A)(ii)).
(2) For such applicable device clinical trials that are initiated
on or after January 18, 2017, the responsible party must submit the
data elements listed below:
(i) Descriptive information:
(A) Brief Title. A short title of the pediatric postmarket
surveillance of a device product in language intended for the lay
public. If an acronym or abbreviation is used to publicly identify the
surveillance, it must be provided.
(B) Official Title. The title of the pediatric postmarket
surveillance of a device product, corresponding to the title of the
protocol or the FDA-approved plan for conducting the surveillance
(C) Brief Summary. A short description of the pediatric postmarket
surveillance of a device product, including a brief statement of the
hypothesis or objective, written in language intended for the lay
public, and a general description of the surveillance design, including
relevant population information
(D) Study Type. The type of study being registered. In the case of
a pediatric postmarket surveillance of a device product that is not a
clinical trial, a study type of ``observational'' is required.
(E) Pediatric Postmarket Surveillance of a Device Product. For a
study that includes an FDA-regulated device product as an intervention
and is a pediatric postmarket surveillance of a device product
(F) Primary Disease or Condition Being Studied, or the Focus of the
Study. The name(s) of the disease(s) or condition(s) being studied in
the pediatric postmarket surveillance of a device product, or the focus
of the surveillance study. Use, if available, appropriate descriptors
fromNLM's MeSH-controlled vocabulary thesaurus or terms from another
vocabulary, such as the SNOMED CT, that has been mapped to MeSH within
the UMLS Metathesaurus.
(G) Intervention Name(s). A brief descriptive name used to refer to
each intervention studied in the pediatric postmarket surveillance of a
device product. A non-proprietary name of the intervention must be
used, if available. If a non-proprietary name is not available, a brief
descriptive name or identifier must be used.
(H) Other Intervention Name(s). Any other current and former
name(s) or alias(es), different from the Intervention Name(s), that the
sponsor has used publicly to identify the intervention(s), including,
but not limited to, past or present names such as brand name(s), or
serial numbers
(I) Intervention Description. Details that can be made public about
each intervention, other than the Intervention Name(s) and Other
Intervention Name(s), sufficient to distinguish the intervention from
other, similar interventions studied in the same or another clinical
trial or pediatric postmarket surveillance of a device product that is
not a clinical trial
(J) Intervention Type. For each intervention studied in the
pediatric postmarket surveillance of a device product, the general type
of intervention
(K) Study Start Date. The date on which FDA approves the pediatric
postmarket surveillance plan, as specified in 21 CFR 822.19(a).
(L) Primary Completion Date. The estimated or actual date on which
the final report of the pediatric postmarket surveillance of a device
product is expected to be submitted to FDA. Once the final report has
been submitted, this is the actual date on which the final report is
submitted to FDA.
(ii) Location and contact information:
[[Page 65145]]
(A) Name of the Sponsor.
(B) Responsible Party, by Official Title:
(1) If the responsible party is an entity, the official name of the
entity; or
(2) If the responsible party is an individual, the official title
and primary organizational affiliation of the individual.
(C) Contact Information. The name or official title, toll-free
telephone number, and email address of a person to whom questions
concerning the pediatric postmarket surveillance of a device product
can be addressed.
(iii) Administrative data:
(A) Unique Protocol Identification Number. The unique identifier
assigned to the pediatric postmarket surveillance of a device product
by the sponsor, if any.
(B) Secondary ID: (1) Identifier(s) other than the organization's
unique protocol identifier or NCT number that is assigned to the
pediatric postmarket surveillance of a device product, if any,
including any unique identifiers assigned by other publicly available
clinical study registries. If the pediatric postmarket surveillance of
a device product is funded in whole or in part by a U.S. Federal
Government agency, the complete grant or contract number must be
submitted as a Secondary ID.
(2) For each secondary ID listed, a description of the type of
secondary ID.
(C) Human Subjects Protection Review Board Status. Information to
indicate whether a pediatric postmarket surveillance of a device
product has been reviewed and approved by a human subjects protection
review board or whether such review is not required per applicable law
(e.g., 21 CFR part 56, 45 CFR part 46, or other applicable regulation).
Human Subjects Protection Review Board Status must be listed as
``approved'' if at least one human subjects protection review board has
approved the pediatric postmarket surveillance.
(D) Record Verification Date. The date on which the responsible
party last verified the clinical trial information in the entire
ClinicalTrials.gov record for the pediatric postmarket surveillance of
a device product, even if no additional or updated information was
submitted at that time
(E) Responsible Party Contact Information. Administrative
information sufficient to identify and allow communication with the
responsible party by telephone, email, and regular mail or delivery
service. Responsible Party Contact Information includes the name,
official title, organizational affiliation, physical address, mailing
address, phone number, and email address of the individual who is the
responsible party or of a designated employee of the organization that
is the responsible party.
(c) Expanded access record. If expanded access is available, as
specified in 21 CFR 312.315 (for an intermediate-size patient
population) or 21 CFR 312.320 (under a treatment IND or treatment
protocol), for an investigational drug product (including a biological
product) studied in an applicable drug clinical trial, and the data
elements set forth in paragraphs (c)(1) through (4) of this section
have not been submitted in an expanded access record for that
investigational product, the responsible party, if both the
manufacturer of the investigational product and the sponsor of the
applicable clinical trial, must submit the clinical trial information
specified in paragraphs (c)(1) through (4) of this section to
ClinicalTrials.gov in the form of an expanded access record. If
expanded access is available only as specified in 21 CFR 312.310 (for
individual patients, including for emergency use) for an
investigational drug product (including a biological product) studied
in an applicable drug clinical trial, and the data elements set forth
in paragraphs (c)(1)(i), (iii), (iv), (vi), (ix), (x), (c)(2)(iv),
(c)(3), (c)(4)(i), (iii),(iv), and (v) of this section have not been
submitted in an expanded access record for that investigational
product, the responsible party, if both the manufacturer of the
investigational product and the sponsor of the applicable clinical
trial, must submit the clinical trial information specified in those
paragraphs to ClinicalTrials.gov in the form of an expanded access
record.
(1) Descriptive information:
(i) Brief Title. A short title identifying the expanded access,
written in language intended for the lay public. If an acronym or
abbreviation is used publicly to identify the expanded access, it must
be provided.
(ii) Official Title. The title, if any, of the expanded access
program corresponding to the title that has been submitted to FDA for
that program
(iii) Brief Summary. A short description of the availability of
expanded access, including the procedure for requesting the
investigational drug product (including a biological product).
(iv) Study Type. The nature of the investigation or investigational
use for which clinical trial information is being submitted, i.e.,
``expanded access''.
(v) Primary Disease or Condition. The name(s) of the disease(s) or
condition(s) for which expanded access to the investigational drug
product (including a biological product) is available. Use, if
available, appropriate descriptors from NLM's MeSH-controlled
vocabulary thesaurus, or terms from another vocabulary, such as the
SNOMED CT, that has been mapped to MeSH within the UMLS Metathesaurus.
(vi) Intervention Name(s). A brief descriptive name used to refer
to the investigational drug product (including a biological product)
that is available through expanded access. A non-proprietary name of
the intervention must be used, if available. If a non-proprietary name
is not available, a brief descriptive name or identifier must be used.
(vii) Other Intervention Name(s). Any other current and former
name(s) or alias(es), different from the Intervention Name(s), that the
sponsor has used publicly to identify the intervention, including, but
not limited to, past or present names such as brand name(s), or serial
numbers.
(viii) Intervention Description. Details that can be made public
about each intervention, other than the Intervention Name(s) or Other
Intervention Name(s), sufficient to distinguish the intervention from
other, similar interventions that are available through expanded access
or in clinical trials.
(ix) Intervention Type. For each investigational drug product
(including a biological product) for which expanded access is
available, the general type of intervention, e.g., drug.
(x) Expanded Access Type. The type(s) of expanded access for which
the investigational drug product (including a biological product) is
available, as specified in Sec. 11.10(b)(28).
(2) Recruitment information:
(i) Eligibility Criteria. A limited list of criteria for
determining who is eligible to receive the investigational drug product
(including a biological product) through expanded access, provided in
terms of inclusion and exclusion criteria and suitable for assisting
potential patients in identifying investigational drug products
(including biological products) of interest for which expanded access
is available.
(ii) Sex/Gender. The sex and gender (if applicable) of the patients
for whom expanded access is available.
(iii) Age Limits. The minimum and maximum age of patients for whom
expanded access is available, provided in relevant units of time.
(iv) Expanded Access Status. The status of availability of the
investigational drug product (including a biological product) through
expanded access.
(3) Contact information:
[[Page 65146]]
(i) Name of the Sponsor.
(ii) Responsible Party, by Official Title. The official name of the
entity.
(iii) Contact Information. The name or official title, toll-free
telephone number, and email address of a person to whom questions
concerning expanded access can be addressed.
(4) Administrative data:
(i) Unique Protocol Identification Number. Any unique identifier
assigned by the sponsor to refer to the availability of its
investigational drug product (including a biological product) for
expanded access use or to identify the expanded access record.
(ii) Secondary ID: (A) Any identifier(s) other than the Unique
Protocol Identification Number or the NCT number that is assigned to
the expanded access record, including any unique identifiers assigned
by other publicly available clinical trial or expanded access
registries.
(B) For each Secondary ID listed, a description of the type of
Secondary ID.
(iii) U.S. Food and Drug Administration IND Number. An indication
of whether there is an IND and, if so, each of the following elements:
(A) Name or abbreviation of the FDA center with whom the IND is
filed (i.e., CDER or CBER), if applicable;
(B) IND number (assigned by the FDA center) under which the
investigational drug product (including a biological product) is being
made available for expanded access, if applicable; and
(C) IND serial number. as defined in 21 CFR 312.23(e), if any,
assigned to the expanded access.
(iv) Record Verification Date. The date on which the responsible
party last verified the information in the expanded access record, even
if no additional or updated information was submitted at that time.
(v) Responsible Party Contact Information. Administrative
information sufficient to identify and allow communication with the
responsible party entering the clinical trial information into the
expanded access record by telephone, email, and regular mail or
delivery service. Responsible Party Contact Information includes the
name, official title, organizational affiliation, physical address,
mailing address, phone number, and email address of the individual who
is the responsible party or of a designated employee of the
organization that is the responsible party.
Sec. 11.35 By when will the NIH Director post clinical trial
registration information submitted under Sec. 11.28?
(a) Applicable drug clinical trial. The Director will post publicly
on ClinicalTrials.gov the clinical trial registration information,
except for certain administrative data, for an applicable drug clinical
trial not later than 30 calendar days after the responsible party has
submitted such information, as specified in Sec. 11.24.
(b) Applicable device clinical trial. (1) For an applicable device
clinical trial of a device product that was previously approved or
cleared, the Director will post publicly on ClinicalTrials.gov the
clinical trial registration information, except for certain
administrative data, as soon as practicable, but not later than 30
calendar days after clinical trial results information is required to
be posted, as specified in Sec. 11.52.
(2) For an applicable device clinical trial of a device product
that has not been previously approved or cleared:
(i) The Director will post publicly on ClinicalTrials.gov the
clinical trial registration information, except for certain
administrative data, not earlier than the date of FDA approval or
clearance of the device product and not later than 30 calendar days
after the date of such approval or clearance, except as otherwise
provided in paragraph (b)(2)(ii) of this section.
(ii) If, prior to the date of approval or clearance of the device
product, the responsible party for an applicable clinical trial that is
initiated on or after January 18, 2017, indicates to the Director, by
submitting the Post Prior to U.S. FDA Approval or Clearance data
element under Sec. 11.28(a)(2)(i)(Q), that it is authorizing the
Director to publicly post its clinical trial registration information,
which would otherwise be subject to delayed posting as specified in
paragraph (b)(2)(i) of this section, prior to the date of FDA approval
or clearance of its device product, the Director will publicly post the
registration information, except for certain administrative data, as
soon as practicable.
Subpart C--Results Information Submission
Sec. 11.40 Who must submit clinical trial results information?
The responsible party for an applicable clinical trial specified in
Sec. 11.42 must submit clinical trial results information for that
clinical trial.
Sec. 11.42 For which applicable clinical trials must clinical trial
results information be submitted?
(a) Applicable clinical trials for which the studied product is
approved, licensed, or cleared by FDA. Unless a waiver of the
requirement to submit clinical trial results information is granted in
accordance with Sec. 11.54, clinical trial results information must be
submitted for any applicable clinical trial for which the studied
product is approved, licensed, or cleared by FDA for which submission
of clinical trial registration information is required in accordance
with the following:
(1) If the primary completion date is before January 18, 2017, the
responsible party must submit the clinical trial results information
specified in sections 402(j)(3)(C) and 402(j)(3)(I) of the Public
Health Service Act (42 U.S.C. 282(j)(3)(C) and 42 U.S.C. 282(j)(3)(I));
or
(2) If the primary completion date is on or after January 18, 2017,
the responsible party must submit the clinical trial results
information specified in Sec. 11.48.
(b) Applicable clinical trials for which the studied product is not
approved, licensed, or cleared by FDA. Unless a waiver of the
requirement to submit clinical trial results information is granted in
accordance with Sec. 11.54, clinical trial results information
specified in Sec. 11.48 must be submitted for any applicable clinical
trial with a primary completion date on or after January 18, 2017 for
which clinical trial registration information is required to be
submitted and for which the studied product is not approved, licensed,
or cleared by FDA.
Sec. 11.44 When must clinical trial results information be submitted
for applicable clinical trials subject to Sec. 11.42?
(a) Standard submission deadline. In general, for applicable
clinical trials subject to Sec. 11.42, clinical trial results
information specified in sections 402(j)(3)(C) and 402(j)(3)(I) of the
Public Health Service Act (42 U.S.C. 282(j)(3)(C) and 42 U.S.C.
282(j)(3)(I)) or in Sec. 11.48, as applicable, must be submitted no
later than 1 year after the primary completion date of the applicable
clinical trial.
(b) Delayed submission of results information with certification if
seeking approval, licensure, or clearance of a new use--(1) General
requirements. If, prior to the results information submission deadline
specified under paragraph (a) of this section, the responsible party
submits a certification that an applicable clinical trial involves an
FDA-regulated drug product (including a biological product) or
[[Page 65147]]
device product that previously has been approved, licensed, or cleared,
for which the manufacturer is the sponsor of the applicable clinical
trial and for which an application or premarket notification seeking
approval, licensure, or clearance of the use being studied (which is
not included in the labeling of the approved, licensed, or cleared drug
product (including a biological product) or device product) has been
filed or will be filed within 1 year with FDA, the deadline for
submitting clinical trial results information, as specified in sections
402(j)(3)(C) and 402(j)(3)(I) of the Public Health Service Act (42
U.S.C. 282(j)(3)(C) and 42 U.S.C. 282(j)(3)(I)) or Sec. 11.48, as
applicable, will be 30 calendar days after the earliest of the
following events:
(i) FDA approves, licenses, or clears the drug product (including a
biological product) or device product for the use studied in the
applicable clinical trial;
(ii) FDA issues a letter that ends the regulatory review cycle for
the application or submission but does not approve, license, or clear
the drug product (including a biological product) or device product for
the use studied in the applicable clinical trial; or
(iii) The application or premarket notification seeking approval,
licensure, or clearance of the new use is withdrawn without
resubmission for not less than 210 calendar days.
(2) Two-year limitation. Notwithstanding the deadlines specified in
paragraph (b)(1) of this section, the responsible party must submit
clinical trial results information specified in paragraph (b)(1) of
this section not later than the date that is 2 years after the date
that the certification was submitted, except to the extent that
paragraph (d) of this section applies.
(3) Additional requirements. If a responsible party who is both the
manufacturer of the drug product (including a biological product) or
device product studied in an applicable clinical trial and the sponsor
of the applicable clinical trial submits a certification in accordance
with paragraph (b)(1) of this section, that responsible party must
submit such a certification for each applicable clinical trial that
meets the following criteria:
(i) The applicable clinical trial is required to be submitted in an
application or premarket notification seeking approval, licensure, or
clearance of a new use; and
(ii) The applicable clinical trial studies the same drug product
(including a biological product) or device product for the same use as
studied in the applicable clinical trial for which the initial
certification was submitted.
(c) Delayed submission of results with certification if seeking
initial approval, licensure, or clearance.--(1) General requirements.
If, prior to the submission deadline specified under paragraph (a) of
this section, a responsible party submits a certification that an
applicable clinical trial studies an FDA-regulated drug product
(including a biological product) or device product that was not
approved, licensed, or cleared by FDA for any use before the primary
completion date of the trial, and that the sponsor intends to continue
with product development and is either seeking, or may at a future date
seek, FDA approval, licensure, or clearance of the drug product
(including a biological product) or device product under study, the
deadline for submitting clinical trial results information, as
specified in Sec. 11.48, will be 30 calendar days after the earlier of
the date on which:
(i) FDA approves, licenses, or clears the drug product (including a
biological product) or device product for any use that is studied in
the applicable clinical trial; or
(ii) The marketing application or premarket notification is
withdrawn without resubmission for not less than 210 calendar days.
(2) Two-year limitation. Notwithstanding the deadlines established
in paragraph (c)(1) of this section, the responsible party must submit
clinical trial results information specified in paragraph (c)(1) of
this section not later than 2 years after the date on which the
certification was submitted, except to the extent that paragraph (d) of
this section applies.
(d) Submitting partial results information. (1) If clinical trial
results information specified in sections 402(j)(3)(C) and 402(j)(3)(I)
of the Public Health Service Act (42 U.S.C. 282(j)(3)(C) and 42 U.S.C.
282(j)(3)(I)) or Sec. 11.48, as applicable, has not been collected for
a secondary outcome measure(s) or additional adverse event information
by the primary completion date, the responsible party must submit the
remaining required clinical trial results information for secondary
outcome measure(s) or additional adverse event information for that
clinical trial by the following deadlines:
(i) For secondary outcome measure(s), by the later of:
(A) One year after the date on which the final subject is examined
or receives an intervention for the purposes of final collection of
data for that secondary outcome measure, whether the clinical trial was
concluded according to the pre-specified protocol or was terminated; or
(B) If a certification to delay results information submission has
been submitted under paragraph (b) or (c) of this section, the date on
which results information for the primary outcome measures is due
pursuant to paragraph (b) or (c) of this section.
(ii) For additional adverse event information, by the later of:
(A) One year after the date of data collection for additional
adverse event information, whether the clinical trial was concluded
according to the pre-specified protocol or was terminated; or
(B) If a certification to delay results information submission has
been submitted under paragraph (b) or (c) of this section, the date on
which results information for the primary outcome measures is due
pursuant to paragraph (b) or (c) of this section.
(2) Except, if clinical trial results information was submitted for
the primary outcome measure(s) prior to the effective date of these
regulations but data collection for all of the secondary outcome
measure(s) or additional adverse event information is not completed
until on or after January 18, 2017, clinical trial results information
for all primary and secondary outcome measures and adverse event
information for the clinical trial must be submitted as specified in
sections 402(j)(3)(C) and 402(j)(3)(I) of the Public Health Service Act
(42 U.S.C. 282(j)(3)(C) and 42 U.S.C. 282(j)(3)(I)).
(3) For each submission of partial results information for a
clinical trial, as specified in paragraph (d)(1) of this section:
(i) If any amendments were made to the protocol and/or statistical
analysis plan as described in Sec. 11.48(a)(5) since the previous
submission of partial results information, the responsible party must
submit a copy of the revised protocol and/or statistical analysis plan;
and
(ii) If information about certain agreements as described in Sec.
11.48(a)(6)(ii) has changed since the previous submission of partial
results information, the responsible party must submit information to
reflect the new status of certain agreements between the principal
investigator and the sponsor.
(e) Extensions for good cause. (1) A responsible party may request
an extension of the deadline for submitting clinical trial results
information subject to paragraphs (e)(1)(i) and (ii) of this section or
section 402(j)(3)(E)(vi) of the Public Health Service Act (42 U.S.C.
282(j)(3)(E)(vi)), as applicable, and may request more than one
extension for the same applicable clinical trial.
[[Page 65148]]
(i) The responsible party must submit a request for an extension to
ClinicalTrials.gov prior to the date on which clinical trial results
information would otherwise be due in accordance with paragraph (a),
(b), (c), (d), (e), or (f) of this section.
(ii) A request for an extension must contain the following:
(A) Description of the reason(s) why clinical trial results
information cannot be provided according to the deadline, with
sufficient detail to allow for the evaluation of the request; and
(B) Estimate of the date on which the clinical trial results
information will be submitted.
(2) Decision and submission deadline. The Director will provide a
response electronically to the responsible party indicating whether the
requested extension demonstrates good cause and has been granted.
(i) If the extension request is granted, the responsible party must
submit clinical trial results information not later than the date of
the deadline specified in the electronic response.
(ii) If the extension request is denied, the responsible party must
either appeal in accordance with paragraph (e)(3) of this section or
submit clinical trial results information specified in Sec. 11.48 by
the later of the submission deadline specified in paragraph (a), (b),
(c), (d), (e), or (f) of this section, as applicable, or 30 calendar
days after the date on which the electronic notice of the denial is
sent to the responsible party.
(3) Appealing a denied extension request. (i) A responsible party
who seeks to appeal a denied extension request or the deadline
specified in a granted extension must submit an appeal to the Director
in the format specified at https://prsinfo.clinicaltrials.gov/ not
later than 30 calendar days after the date on which the electronic
notification of the granting or denial of the request is sent to the
responsible party.
(ii) An appeal must contain an explanation of the reason(s) why the
initial decision to deny the extension request or to grant the
extension request with a shorter deadline than requested should be
overturned or revised, with sufficient detail to allow for the
evaluation of the appeal.
(iii) The Director will provide an electronic notification to the
responsible party indicating whether the requested extension has been
granted upon appeal.
(iv) If the Director grants the extension request upon appeal, the
responsible party must submit clinical trial results information not
later than the deadline specified in the electronic notification
specified in paragraph (e)(3)(iii) of this section.
(v) If the Director denies the appeal of a denied extension
request, the responsible party must submit clinical trial results
information by the later of the deadline specified in paragraph (a),
(b), (c), (d), (e), or (f) of this section, or 30 calendar days after
the electronic notification of the denial of the appeal, specified in
paragraph (e)(3)(iii) of this section, is sent to the responsible
party.
(vi) If the Director denies an appeal of a denied deadline
specified in a granted extension request, the responsible party must
submit clinical trial results information by the later of the deadline
specified in the notification granting the extension request, specified
in paragraph (e)(2)(i) of this section, or 30 calendar days after the
electronic notification denying the appeal, specified in paragraph
(e)(3)(iii) of this section, is sent to the responsible party.
(f) Pediatric postmarket surveillance of a device product that is
not a clinical trial. For each pediatric postmarket surveillance of a
device product that is not a clinical trial as defined in this part,
the responsible party must submit clinical trial results information as
specified in Sec. 11.48(b) or section 402(j)(C)(3) of the Public
Health Service Act (42 U.S.C. 282(j)(C)(3)), as applicable, not later
than 30 calendar days after the date on which the final report of the
approved pediatric postmarket surveillance of a device product, as
specified in 21 CFR 822.38, is submitted to FDA.
Sec. 11.48 What constitutes clinical trial results information?
(a) For each applicable clinical trial, other than a pediatric
postmarket surveillance of a device product that is not a clinical
trial, for which clinical trial results information must be submitted
under Sec. 11.42, the responsible party must provide the following:
(1) Participant flow. Information for completing a table
documenting the progress of human subjects through a clinical trial, by
arm, including the number who started and completed the clinical trial.
This information must include the following elements:
(i) Participant Flow Arm Information. A brief description of each
arm used for describing the flow of human subjects through the clinical
trial, including a descriptive title used to identify each arm;
(ii) Pre-assignment Information. A description of significant
events in the clinical trial that occur after enrollment and prior to
assignment of human subjects to an arm, if any; and
(iii) Participant Data. The number of human subjects that started
and completed the clinical trial, by arm. If assignment is based on a
unit other than participants, also include a description of the unit of
assignment and the number of units that started and completed the
clinical trial, by arm.
(2) Demographic and baseline characteristics. Information for
completing a table of demographic and baseline measures and data
collected by arm or comparison group and for the entire population of
human subjects who participated in the clinical trial. This information
must include the following elements:
(i) Baseline Characteristics Arm/Group Information. A brief
description of each arm or comparison group used for describing the
demographic and baseline characteristics of the human subjects in the
clinical trial, including a descriptive title used to identify each arm
or comparison group.
(ii) Baseline Analysis Population Information--(A) Overall Number
of Baseline Participants. The total number of human subjects for whom
baseline characteristics were measured, by arm or comparison group and
overall.
(B) Overall Number of Units Analyzed. If the analysis is based on a
unit other than participants, a description of the unit of analysis and
the number of units for which baseline measures were measured and
analyzed, by arm or comparison group and overall.
(C) Analysis Population Description. If the Overall Number of
Baseline Participants (or units) differs from the number of human
subjects (or units) assigned to the arm or comparison group and
overall, a brief description of the reason(s) for the difference.
(iii) Baseline Measure Information. A description of each baseline
or demographic characteristic measured in the clinical trial, including
age, sex/gender, race, ethnicity (if collected under the protocol), and
any other measure(s) that were assessed at baseline and are used in the
analysis of the primary outcome measure(s) in accordance with Sec.
11.48(a)(3). The description of each measure must include the following
elements:
(A) Name and description of the measure, including any categories
that are used to submit Baseline Measure Data.
(B) Measure Type and Measure of Dispersion: For each baseline
measure submitted, an indication of the type of data to be submitted
and the associated measure of dispersion.
[[Page 65149]]
(C) Unit of Measure. For each baseline measure for which data are
collected, the unit of measure.
(iv) Baseline Measure Data. The value(s) for each submitted
baseline measure, by arm or comparison group and for the entire
population of human subjects for whom baseline characteristics were
measured.
(v) Number of baseline participants (and units), by arm or
comparison group and overall, if different from the Overall Number of
Baseline Participants or Overall Number of Units Analyzed in Sec.
11.48(a)(2)(ii)(A) and (B), respectively.
(3) Outcomes and statistical analyses. Information for completing a
table of data for each primary and secondary outcome measure by arm or
comparison group, including the result(s) of scientifically appropriate
statistical analyses that were performed on the outcome measure data,
if any. This information must include the following elements:
(i) Outcome Measure Arm/Group Information. A brief description of
each arm or comparison group used for submitting an outcome measure for
the clinical trial, including a descriptive title to identify each arm
or comparison group.
(ii) Analysis Population Information--(A) Number of Participants
Analyzed. The number of human subjects for whom an outcome was measured
and analyzed, by arm or comparison group.
(B) Number of Units Analyzed. If the analysis is based on a unit
other than participants, a description of the unit of analysis and the
number of units for which an outcome was measured and analyzed, by arm
or comparison group.
(C) Analysis Population Description. If the Number of Participants
Analyzed or Number of Units Analyzed differs from the number of human
subjects or units assigned to the arm or comparison group, a brief
description of the reason(s) for the difference.
(iii) Outcome Measure Information. A description of each outcome
measure, to include the following elements:
(A) Name of the specific outcome measure, including the titles of
any categories in which Outcome Measure Data in Sec. 11.48(a)(3)(iv)
are aggregated.
(B) Description of the metric used to characterize the specific
outcome measure.
(C) Time point(s) at which the measurement was assessed for the
specific metric.
(D) Outcome Measure Type. The type of outcome measure, whether
primary, secondary, other pre-specified, or post-hoc.
(E) Measure Type and Measure of Dispersion or Precision. For each
outcome measure for which data are collected, the type of data
submitted and the measure of dispersion or precision.
(F) Unit of Measure. For each outcome measure for which data are
collected, the unit of measure.
(iv) Outcome Measure Data. The measurement value(s) for each
outcome measure for which data are collected, by arm or comparison
group and by category (if specified).
(v) Statistical Analyses. Result(s) of scientifically appropriate
tests of the statistical significance of the primary and secondary
outcome measures, if any.
(A) A statistical analysis is required to be submitted if it is:
(1) Pre-specified in the protocol and/or statistical analysis plan
and was performed on the outcome measure data,
(2) Made public by the sponsor or responsible party prior to the
date on which clinical trial results information is submitted for the
primary outcome measures(s) studied in the clinical trial to which the
statistical analysis applies, or
(3) Conducted on a primary outcome measure in response to a request
made by FDA prior to the date on which clinical trial results
information is submitted for the primary outcome measure(s) studied in
the clinical trial to which the statistical analysis applies.
(B) Information for each statistical analysis specified in
paragraph (a)(3)(v)(A) of this section must include the following
elements:
(1) Statistical Analysis Overview: Identification of the arms or
comparison groups compared in the statistical analysis; the type of
statistical test conducted; and, for a non-inferiority or equivalence
test, a description of the analysis that includes, at minimum, the
power calculation and non-inferiority or equivalence margin.
(2) One of the following, as applicable:
(i) Statistical Test of Hypothesis: The p-value and the procedure
used for the statistical analysis; or
(ii) Method of Estimation: The estimation parameter, estimated
value, and confidence interval (if calculated).
(4) Adverse event information. (i) Information to describe the
methods for collecting adverse events during an applicable clinical
trial:
(A) Time Frame. The specific period of time over which adverse
event information was collected and for which information is submitted
in paragraph (a)(4)(iii) of this section.
(B) Adverse Event Reporting Description. If the adverse event
information collected in the clinical trial is collected based on a
different definition of adverse event and/or serious adverse event than
defined in this part, a brief description of how those definitions
differ.
(C) Collection Approach. The type of approach taken to collect
adverse event information, whether systematic or non-systematic.
(ii) Information for completing three tables summarizing
anticipated and unanticipated adverse events collected during an
applicable clinical trial:
(A) Table of all serious adverse events grouped by organ system,
with the number and frequency of each event by arm or comparison group;
(B) Table of all adverse events, other than serious adverse events,
that exceed a frequency of 5 percent within any arm of the clinical
trial, grouped by organ system, with the number and frequency of each
event by arm or comparison group; and
(C) Table of all-cause mortality, with the number and frequency of
deaths due to any cause by arm or comparison group.
(iii) Information for each table specified in paragraph (a)(4)(ii)
of this section must include the following elements, unless otherwise
specified:
(A) Adverse Event Arm/Group Information. A brief description of
each arm or comparison group used for submitting adverse event
information from the clinical trial, including a descriptive title used
to identify each arm or comparison group.
(B) Total Number Affected. The overall number of human subjects
affected, by arm or comparison group, by:
(1) Serious adverse event(s);
(2) Adverse event(s) other than serious adverse events that exceed
a frequency of 5 percent within any arm of the clinical trial; and
(3) Deaths due to any cause.
(C) Total Number at Risk. The overall number of human subjects
included in the assessment, by arm or comparison group, for:
(1) Serious adverse events;
(2) Adverse event(s) other than serious adverse events that exceed
a frequency of 5 percent within any arm of the clinical trial; or
(3) Deaths due to any cause.
(D) Adverse Event Information. For the two tables described in
paragraphs (a)(4)(ii)(A) and (B) of this section, a description of each
type of serious adverse event and other adverse event that is not a
serious adverse event and exceeds a frequency of 5 percent within any
arm of the clinical trial, consisting of the following attributes:
[[Page 65150]]
(1) Descriptive term for the adverse event; and
(2) Organ system associated with the adverse event.
(E) Adverse Event Data. For the two tables described in paragraphs
(a)(4)(ii)(A) and (B) of this section and for each adverse event listed
in accordance with paragraph (a)(4)(iii)(D) of this section:
(1) Number of human subjects affected by such adverse event.
(2) Number of human subjects at risk for such adverse event.
(5) Protocol and statistical analysis plan. A copy of the protocol
and the statistical analysis plan (if not included in the protocol),
including all amendments that have been approved by a human subjects
protection review board (if applicable) before the time of submission
under this subsection and that apply to all clinical trial Facility
Locations. The responsible party must include the Official Title (as
defined in Sec. 11.10(b)(2)), NCT number (as defined in Sec.
11.10(a)) (if available), and date of the protocol and the statistical
analysis plan on the cover page of each document. The responsible party
may redact names, addresses, and other personally identifiable
information, as well as any trade secret and/or confidential commercial
information (as those terms are defined in the Freedom of Information
Act (5 U.S.C. 552) and the Trade Secrets Act (18 U.S.C. 1905))
contained in the protocol or statistical analysis plan prior to
submission, unless such information is otherwise required to be
submitted under this part. The protocol and statistical analysis plan
must be submitted in a common electronic document format specified at
https://prsinfo.clinicaltrials.gov.
(6) Administrative information--(i) Results Point of Contact. Point
of contact for scientific information about the clinical trial results
information, including the following:
(A) Name or official title of the point of contact
(B) Name of the affiliated organization, and
(C) Telephone number and email address of the point of contact.
(ii) Certain Agreements. An indication of whether the principal
investigator is an employee of the sponsor and, if not, whether there
exists any agreement (other than an agreement solely to comply with
applicable provisions of law protecting the privacy of human subjects
participating in the clinical trial) between the sponsor or its agent
and the principal investigator that restricts in any manner the ability
of the principal investigator, after the primary completion date of the
clinical trial, to discuss the results of the clinical trial at a
scientific meeting or any other public or private forum or to publish
in a scientific or academic journal information concerning the results
of the clinical trial
(7) Additional clinical trial results information for applicable
device clinical trials of unapproved or uncleared device products. (i)
For an applicable device clinical trial of an unapproved or uncleared
device product and for which clinical trial registration information
has not been posted publicly on ClinicalTrials.gov by the Director in
accordance with Sec. 11.35(b)(2)(i), the responsible party must
provide the following data elements, as the data elements are defined
in Sec. 11.10(b): Brief Title; Official Title; Brief Summary; Primary
Purpose; Study Design; Study Type; Primary Disease or Condition Being
Studied in the Trial, or the Focus of the Study; Intervention Name(s);
Other Intervention Name(s); Intervention Description; Intervention
Type; Device Product Not Approved or Cleared by U.S. FDA, if any
studied intervention is a device product; Study Start Date; Primary
Completion Date; Study Completion Date, Enrollment; Primary Outcome
Measure Information; Secondary Outcome Measure Information; Eligibility
Criteria; Sex/Gender; Age Limits; Accepts Healthy Volunteers; Overall
Recruitment Status; Why Study Stopped; Name of the Sponsor; Responsible
Party, by Official Title; Facility Name and Facility Location, for each
participating facility in a clinical trial; Unique Protocol
Identification Number; Secondary ID; Human Subjects Protection Review
Board Status; and Record Verification Date.
(ii) The responsible party shall submit all the results information
specified in paragraph (a)(7)(i) and must submit an affirmation that
any information previously submitted to ClinicalTrials.gov for the data
elements listed in paragraph (a)(7)(i) of this section have been
updated in accordance with Sec. 11.64(a) and are to be included as
clinical trial results information.
(b) Pediatric postmarket surveillance of a device product that is
not a clinical trial. For each pediatric postmarket surveillance of a
device product that is not a clinical trial, the responsible party must
submit a copy of any final report that is submitted to FDA as specified
in 21 CFR 822.38. The responsible party may redact names, addresses,
and other personally identifiable information or commercial
confidential information contained in the final report prior to
submission to NIH, unless such information is otherwise required to be
submitted under this part. The final report must be in a common
electronic document format specified at https://prsinfo.clinicaltrials.gov.
Sec. 11.52 By when will the NIH Director post submitted clinical
trial results information?
Except for clinical trial results information submitted under
section 402(j)(4)(A) of the PHS Act and Sec. 11.60, the Director will
post publicly clinical trial results information on ClinicalTrials.gov
not later than 30 calendar days after the date of submission.
Sec. 11.54 What are the procedures for requesting and obtaining a
waiver of the requirements for clinical trial results information
submission?
(a) Waiver request. (1) A responsible party for an applicable
clinical trial with a primary completion date on or after January 18,
2017 may request a waiver from any applicable requirement(s) of this
subpart C by submitting a waiver request in the format specified at
https://prsinfo.clinicaltrials.gov/ to the Secretary or delegate prior
to the deadline specified in Sec. 11.44(a) for submitting clinical
trial results information.
(2) The waiver request must contain:
(i) The NCT number, Brief Title, and Name of the Sponsor of the
applicable clinical trial for which the waiver is requested;
(ii) The specific requirement(s) of this subpart C for which the
waiver is requested; and
(iii) A description of the extraordinary circumstances that the
responsible party believes justify the waiver and an explanation of why
granting the request would be consistent with the protection of public
health or in the interest of national security.
(3) The responsible party will not be required to comply with the
specified requirements of this subpart for which a waiver is granted.
(4) The responsible party must comply with any requirements of this
subpart for which a waiver is not granted or must submit an appeal as
set forth in paragraph (b) of this section. The deadline for submitting
any required clinical trial results information will be the later of
the original submission deadline or 30 calendar days after the
notification of the denial is sent to the responsible party.
(b) Appealing a denied waiver request. (1) A responsible party for
an applicable clinical trial with a primary completion date on or after
January 18,
[[Page 65151]]
2017 may appeal a denied waiver request by submitting an appeal to the
Secretary or delegate in the format specified at https://prsinfo.clinicaltrials.gov/ not later than 30 calendar days after the
date on which the electronic notification of the denial in paragraph
(a)(4) of this section denying the request is sent to the responsible
party.
(2) The responsible party is not required to comply with any
requirements of this subpart for which a waiver is granted upon appeal.
(3) The responsible party must submit clinical trial results
information to comply with any requirements of this subpart that are
not waived upon appeal by the later of the original submission deadline
or 30 calendar days after the notice of the denial upon appeal is sent
to the responsible party.
(c) If a waiver is granted under paragraph (a) or (b) of this
section:
(1) The Director will include a notation in the clinical trial
record that specified elements of the requirements of this part have
been waived.
(2) The Secretary will notify, in writing, the appropriate
committees of Congress and provide an explanation for why the waiver
was granted, not later than 30 calendar days after any waiver is
granted.
(d) A responsible party for an applicable clinical trial with a
primary completion date before January 18, 2017 may request a waiver
from any applicable requirement(s) for clinical trial results
information submission by submitting a waiver request, as specified in
section 402(j)(3)(H) of the Public Health Service Act (42 U.S.C.
282(j)(3)(H)).
Subpart D--Additional Submissions of Clinical Trial Information
Sec. 11.60 What requirements apply to the voluntary submission of
clinical trial information for clinical trials of FDA-regulated drug
products (including biological products) and device products?
(a) If a responsible party voluntarily submits clinical trial
information for a clinical trial described in paragraph (a)(1) of this
section, the responsible party must meet the conditions specified in
paragraph (a)(2) of this section.
(1) The requirements of paragraph (a) of this section apply to a
clinical trial that was initiated before January 18, 2017 and has a
primary completion date before January 18, 2017, and that is either:
(i) A clinical trial of an FDA-regulated drug product (including a
biological product) or device product that is not an applicable
clinical trial, or
(ii) An applicable clinical trial that is not otherwise required to
submit clinical trial registration information.
(2) If the responsible party for a clinical trial described in
paragraph (a)(1) of this section voluntarily submits clinical trial
registration information and/or clinical trial results information, the
responsible party must comply with the following requirements:
(i) The responsible party must submit the information in paragraphs
(b)(2)(i)(A), (B), or (C) of this section for the clinical trial being
submitted voluntarily.
(A) If the responsible party voluntarily registers a clinical
trial, the responsible party must submit clinical trial registration
information specified in section 402(j)(2)(A)(ii) of the Public Health
Service Act (42 U.S.C. 282(j)(2)(A)(ii)).
(B) If the responsible party voluntarily submits clinical trial
results information for a clinical trial for which the clinical trial
registration information specified in section 402(j)(2)(A)(ii) of the
Public Health Service Act (42 U.S.C. 282(j)(2)(A)(ii)) has not been
submitted, the responsible party must submit the clinical trial results
information specified in sections 402(j)(3)(C) and 402(j)(3)(I) of the
Public Health Service Act (42 U.S.C. 282(j)(3)(C) and 42 U.S.C.
282(j)(3)(I)).
(C) If the responsible party both voluntarily submits clinical
trial registration information and voluntarily submits clinical trial
results information, the responsible party must submit both clinical
trial registration information specified in section 402(j)(2)(A)(ii) of
the Public Health Service Act (42 U.S.C. 282(j)(2)(A)(ii)) and clinical
trial results information specified in sections 402(j)(3)(C) and
402(j)(3)(I) of the Public Health Service Act (42 U.S.C. 282(j)(3)(C)
and 42 U.S.C. 282(j)(3)(I)).
(ii) If, on or after September 27, 2007, a manufacturer submits an
application or premarket notification to FDA for approval, licensure,
or clearance of a drug product (including a biological product) or
device product under sections 505, 510(k), 515, or 520(m) of the
Federal Food, Drug, and Cosmetic Act (21 U.S.C 355, 360(k), 360e,
360j(m)) or section 351 of the Public Health Service Act (42 U.S.C.
262) for the use studied in the clinical trial submitted under
paragraph (a)(1) of this section, the responsible party specified in
paragraph (a)(1) of this section must also submit the information
specified in paragraph (a)(2)(iii) of this section by the deadline
specified in paragraph (a)(2)(iv)(B) of this section for any applicable
clinical trial that has not been submitted to ClinicalTrials.gov and
that meets the following criteria:
(A) The applicable clinical trial is required to be submitted to
FDA under sections 505, 510(k), 515, or 520(m) of the Federal Food,
Drug, and Cosmetic Act (21 U.S.C. 355, 360(k), 360e, 360j(m)) or
section 351 of the Public Health Service Act (42 U.S.C. 262) in an
application or premarket notification for approval, licensure, or
clearance to market the drug product (including a biological product)
or device product for the use studied in the clinical trial specified
in paragraph (a)(1) of this section; and
(B) The manufacturer of the drug product (including a biological
product) or device product studied in the applicable clinical trial is
also the responsible party for the clinical trial specified in
paragraph (a)(1) of this section.
(iii) Information to be submitted for clinical trials described in
paragraph (a)(2)(ii) of this section:
(A) If the clinical trial information voluntarily submitted for a
clinical trial described in paragraph (a)(1) of this section consists
only of the clinical trial registration information specified in
section 402(j)(2)(A)(ii) of the Public Health Service Act (42 U.S.C.
282(j)(2)(A)(ii)), the information to be submitted in accordance with
paragraph (a)(2)(ii) of this section must consist, at minimum, of the
clinical trial registration information specified in section
402(j)(2)(A)(ii) of the Public Health Service Act (42 U.S.C.
282(j)(2)(A)(ii)).
(B) If the clinical trial information voluntarily submitted for a
clinical trial described by paragraph (a)(1) of this section consists
of the clinical trial results information specified in sections
402(j)(3)(C) and 402(j)(3)(I) of the Public Health Service Act (42
U.S.C. 282(j)(3)(C) and 42 U.S.C. 282(j)(3)(I)), the information to be
submitted in accordance with paragraph (a)(2)(ii) of this section must
consist of the clinical trial results information specified in sections
402(j)(3)(C) and 402(j)(3)(I) of the Public Health Service Act (42
U.S.C. 282(j)(3)(C) and 42 U.S.C. 282(j)(3)(I)).
(C) If the clinical trial information voluntarily submitted for a
clinical trial described by paragraph (a)(1) of this section consists
of both the clinical trial registration information specified in
section 402(j)(2)(A)(ii) of the Public Health Service Act (42 U.S.C.
282(j)(2)(A)(ii)) and the clinical trial results information specified
in sections 402(j)(3)(C) and 402(j)(3)(I) of the Public Health Service
Act (42 U.S.C. 282(j)(3)(C) and 42 U.S.C. 282(j)(3)(I)), the
information to be submitted in
[[Page 65152]]
accordance with paragraph (a)(2)(ii) of this section must consist of
both the clinical trial registration information specified in section
402(j)(2)(A)(ii) of the Public Health Service Act (42 U.S.C.
282(j)(2)(A)(ii)) and the clinical trial results information specified
in sections 402(j)(3)(C) and 402(j)(3)(I) of the Public Health Service
Act (42 U.S.C. 282(j)(3)(C) and 42 U.S.C. 282(j)(3)(I)).
(iv) Submission deadlines:
(A) Secondary outcome measure(s) and adverse event information for
voluntarily submitted clinical trials, under paragraph (a) of this
section:
(1) If data collection for secondary outcome measure(s) for a
voluntarily submitted clinical trial under paragraph (a) of this
section is not completed by the primary completion date of the
voluntarily submitted clinical trial, clinical trial results
information for the secondary outcome measure(s) required in section
402(j)(3)(C) of the Public Health Service Act (42 U.S.C. 282(j)(3)(C))
must be submitted by the later of the date that the clinical trial
results information is voluntarily submitted for the primary outcome
measure(s) or 1 year after the date on which the final subject was
examined or received an intervention for the purposes of final
collection of data for the secondary outcome(s), whether the clinical
trial was concluded according to the pre-specified protocol or was
terminated.
(2) If data collection for adverse event information continues
after the primary completion date of the voluntarily submitted clinical
trial, any adverse event information collected after the primary
completion date and subject to the submission requirements in section
402(j)(3)(I) of the Public Health Service Act (42 U.S.C. 282(j)(3)(I))
must be submitted by the later of the date that the clinical trial
results information is voluntarily submitted for the primary outcome
measure(s) or 1 year after the date of final collection of data for
adverse event information, whether the clinical trial was concluded
according to the pre-specified protocol or was terminated.
(B) The clinical trial information specified in paragraph
(a)(2)(iii) of this section must be submitted not later than the later
of the date on which the application or premarket notification to FDA
for approval, licensure, or clearance to market a drug product
(including a biological product) or device product under section 351 of
the Public Health Service Act (42 U.S.C. 262) or section 505, 510(k),
515, or 520(m) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C.
355, 360(k), 360e, 360j(m)) for the use studied in the clinical trial
specified under paragraph (a)(1) of this section is submitted to FDA or
the date on which the clinical trial information specified in paragraph
(a)(2)(i) of this section for the clinical trial specified under
paragraph (a)(1) of this section is submitted to ClinicalTrials.gov.
(b) If a responsible party voluntarily submits clinical trial
information for a clinical trial described in paragraph (b)(1) of this
section, the responsible party must meet the conditions specified in
paragraph (b)(2) of this section.
(1) The requirements of paragraph (b) of this section apply to a
clinical trial that was initiated before January 18, 2017 and has a
primary completion date on or after January 18, 2017, and that is
either:
(i) A clinical trial of an FDA-regulated drug product (including a
biological product) or device product that is not an applicable
clinical trial; or
(ii) An applicable clinical trial that is not otherwise required to
submit clinical trial registration information.
(2) If the responsible party for a clinical trial described in
paragraph (b)(1) of this section voluntarily submits clinical trial
registration information and/or clinical trial results information, the
responsible party must comply with the following requirements:
(i) The responsible party must submit the information in paragraph
(b)(2)(i)(A), (B), or (C) of this section for the clinical trial being
submitted voluntarily.
(A) If the responsible party voluntarily registers a clinical
trial, the responsible party must submit clinical trial registration
information specified in section 402(j)(2)(A)(ii) of the Public Health
Service Act (42 U.S.C. 282(j)(2)(A)(ii)).
(B) If the responsible party voluntarily submits clinical trial
results information for a clinical trial for which the clinical trial
registration information specified in section 402(j)(2)(A)(ii) of the
Public Health Service Act (42 U.S.C. 282(j)(2)(A)(ii)) has not been
submitted, the responsible party must submit the data elements
specified in Sec. 11.48, as well as the data elements listed below, as
those data elements are defined in Sec. 11.10(b) and apply to the
clinical trial and the intervention(s) studied: Brief Title; Official
Title; Brief Summary; Primary Purpose; Study Design; Study Phase, for a
clinical trial of a drug product (including a biological product);
Study Type; Pediatric Postmarket Surveillance of a Device Product;
Primary Disease or Condition Being Studied in the Trial, or the Focus
of the Study; Intervention Name(s), for each intervention studied;
Other Intervention Name(s), for each intervention studied; Intervention
Description, for each intervention studied; Intervention Type, for each
intervention studied; Device Product Not Approved or Cleared by U.S.
FDA, if any studied intervention is a device product; Product
Manufactured in and Exported from the U.S.; Studies a U.S. FDA-
regulated Device Product; Studies a U.S. FDA-regulated Drug Product;
Study Start Date; Primary Completion Date; Study Completion Date;
Enrollment; Eligibility Criteria; Sex/Gender; Age Limits; Accepts
Healthy Volunteers; Overall Recruitment Status; Why Study Stopped;
Availability of Expanded Access, if any studied intervention is an
investigational drug product (including a biological product); Name of
the Sponsor; Responsible Party, by Official Title; Facility
Information, for each participating facility; Unique Protocol
Identification Number; Secondary ID; U.S. Food and Drug Administration
IND or IDE Number; Human Subjects Protection Review Board Status;
Record Verification Date; and Responsible Party Contact Information.
(C) If the responsible party both voluntarily submits clinical
trial registration information and voluntarily submits clinical trial
results information, the responsible party must submit both the
clinical trial registration information specified in section
402(j)(2)(A)(ii) of the Public Health Service Act (42 U.S.C.
282(j)(2)(A)(ii)) and the clinical trial results information specified
in Sec. 11.48.
(ii) If, on or after September 27, 2007, a manufacturer submits an
application or premarket notification to FDA for approval, licensure,
or clearance of a drug product (including a biological product) or
device product under section 505, 510(k), 515, or 520(m) of the Federal
Food, Drug, and Cosmetic Act (21 U.S.C. 355, 360(k), 360e, 360j(m)) or
section 351 of the Public Health Service Act (42 U.S.C. 262) for the
use studied in the clinical trial submitted under paragraph (b)(1) of
this section, the responsible party specified in paragraph (b)(1) of
this section must also submit the information specified in paragraph
(b)(2)(iii) of this section by the deadline specified in paragraph
(b)(2)(iv)(B) of this section for any applicable clinical trial that
has not been submitted to ClinicalTrials.gov and that meets the
following criteria:
(A) The applicable clinical trial is required to be submitted to
FDA under section 505, 510(k), 515, or 520(m) of the Federal Food,
Drug, and Cosmetic Act (21 U.S.C. 355, 360(k), 360e,
[[Page 65153]]
360j(m)) or section 351 of the Public Health Service Act (42 U.S.C.
262) in an application or premarket notification for approval,
licensure, or clearance to market the drug product (including a
biological product) or device product for the use studied in the
clinical trial specified in paragraph (b)(1) of this section; and
(B) The manufacturer of the drug product (including a biological
product) or device product studied in the applicable clinical trial is
also the responsible party for the clinical trial specified in
paragraph (b)(1) of this section.
(iii) Information to be submitted for clinical trials described in
paragraph (b)(2)(ii) of this section:
(A) If the clinical trial information voluntarily submitted for a
clinical trial described in paragraph (b)(1) of this section consists
only of the clinical trial registration information specified in
section 402(j)(2)(A)(ii) of the Public Health Service Act (42 U.S.C.
282(j)(2)(A)(ii)), the information to be submitted in accordance with
paragraph (b)(2)(ii) of this section must consist, at minimum, of the
clinical trial registration information specified in section
402(j)(2)(A)(ii) of the Public Health Service Act (42 U.S.C.
282(j)(2)(A)(ii)).
(B) If the clinical trial information voluntarily submitted for a
clinical trial described by paragraph (b)(1) of this section consists
of the clinical trial results information specified in Sec.
11.60(b)(2)(i)(B), the information to be submitted in accordance with
paragraph (b)(2)(ii) of this section must consist of the clinical trial
results information specified in Sec. 11.60(b)(2)(i)(B).
(C) If the clinical trial information voluntarily submitted for a
clinical trial described by paragraph (b)(1) of this section consists
of both the clinical trial registration information specified in
section 402(j)(2)(A)(ii) of the Public Health Service Act (42 U.S.C.
282(j)(2)(A)(ii)) and the clinical trial results information specified
in Sec. 11.48, the information to be submitted in accordance with
paragraph (b)(2)(ii) of this section must consist of both the clinical
trial registration information specified in section 402(j)(2)(A)(ii) of
the Public Health Service Act (42 U.S.C. 282(j)(2)(A)(ii)) and the
clinical trial results information specified in Sec. 11.48.
(iv) Submission deadlines:
(A) Secondary outcome measure(s) and adverse event information for
voluntarily submitted clinical trials, under paragraph (b) of this
section:
(1) If data collection for secondary outcome measure(s) for a
voluntarily submitted clinical trial under paragraph (b) of this
section is not completed by the primary completion date of the
voluntarily submitted clinical trial, clinical trial results
information for the secondary outcome measure(s) required in Sec.
11.48(a)(3) must be submitted by the later of the date that the
clinical trial results information is voluntarily submitted for the
primary outcome measure(s) or 1 year after the date on which the final
subject was examined or received an intervention for the purposes of
final collection of data for the secondary outcome(s), whether the
clinical trial was concluded according to the pre-specified protocol or
was terminated.
(2) If data collection for adverse event information continues
after the primary completion date of the voluntarily submitted clinical
trial, any adverse event information collected after the primary
completion date and subject to the submission requirements in Sec.
11.48(a)(4) must be submitted by the later of the date that the
clinical trial results information is voluntarily submitted for the
primary outcome measure(s) or 1 year after the date of final collection
of data for adverse event information, whether the clinical trial was
concluded according to the pre-specified protocol or was terminated.
(B) The clinical trial information specified in paragraph
(b)(2)(iii) of this section must be submitted not later than the later
of the date on which the application or premarket notification to FDA
for approval, licensure, or clearance to market a drug product
(including a biological product) or device product under section 351 of
the Public Health Service Act (42 U.S.C. 262) or section 505, 510(k),
515, or 520(m) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C.
355, 360(k), 360e, 360j(m)) for the use studied in the clinical trial
specified under paragraph (b)(1) of this section is submitted to FDA or
the date on which the clinical trial information specified in paragraph
(b)(2)(i) of this section for the clinical trial specified under
paragraph (b)(1) of this section is submitted to ClinicalTrials.gov.
(c) If a responsible party voluntarily submits clinical trial
information for a clinical trial described in paragraph (c)(1) of this
section, the responsible party must meet the conditions specified in
paragraph (c)(2) of this section.
(1) The requirements of paragraph (c) of this section apply to a
clinical trial that was initiated on or after January 18, 2017 and has
a primary completion date on or after January 18, 2017, and that is
either:
(i) A clinical trial of an FDA-regulated drug product (including a
biological product) or device product that is not an applicable
clinical trial; or
(ii) An applicable clinical trial that is not otherwise required to
submit clinical trial registration information.
(2) If the responsible party for a clinical trial described in
paragraph (c)(1) of this section voluntarily submits clinical trial
registration information and/or clinical trial results information, the
responsible party must comply with the following requirements:
(i) The responsible party must submit the information in paragraph
(c)(2)(i)(A), (B), or (C) of this section for the clinical trial being
submitted voluntarily.
(A) If the responsible party voluntarily registers a clinical
trial, the responsible party must submit the clinical trial
registration information specified in Sec. 11.28(a).
(B) If the responsible party voluntarily submits clinical trial
results information for a clinical trial for which the clinical trial
registration information specified in Sec. 11.28(a) has not been
submitted, the responsible party must submit the data elements
specified in paragraph (b)(2)(i)(B) of this section.
(C) If the responsible party both voluntarily submits clinical
trial registration information and voluntarily submits clinical trial
results information, the responsible party must submit both the
clinical trial registration information specified in Sec. 11.28(a) and
the clinical trial results information specified in Sec. 11.48.
(ii) If, on or after September 27, 2007, a manufacturer submits an
application or premarket notification to FDA for approval, licensure,
or clearance of a drug product (including a biological product) or
device product under section 505, 510(k), 515, or 520(m) of the Federal
Food, Drug, and Cosmetic Act (21 U.S.C. 355, 360(k), 360e, 360j(m)) or
section 351 of the Public Health Service Act (42 U.S.C. 262) for the
use studied in the clinical trial submitted under paragraph (c)(1) of
this section, the responsible party specified in paragraph (c)(1) of
this section must also submit the information specified in paragraph
(c)(2)(iii) of this section by the deadline specified in paragraph
(c)(2)(iv)(B) of this section for any applicable clinical trial that
has not been submitted to ClinicalTrials.gov and that meets the
following criteria:
(A) The applicable clinical trial is required to be submitted to
FDA under section 505, 510(k), 515, or 520(m) of the Federal Food,
Drug, and Cosmetic Act (21 U.S.C. 355, 360(k), 360e, 360j(m)) or
section 351 of the Public Health Service Act (42 U.S.C. 262) in an
[[Page 65154]]
application or premarket notification for approval, licensure, or
clearance to market the drug product (including a biological product)
or device product for the use studied in the clinical trial specified
in paragraph (c)(1) of this section; and
(B) The manufacturer of the drug product (including a biological
product) or device product studied in the applicable clinical trial is
also the responsible party for the clinical trial specified in
paragraph (c)(1) of this section.
(iii) Information to be submitted for clinical trials described in
paragraph (c)(2)(ii) of this section:
(A) If the clinical trial information voluntarily submitted for a
clinical trial described in paragraph (c)(1) of this section consists
only of the clinical trial registration information specified in Sec.
11.28(a), the information to be submitted in accordance with paragraph
(c)(2)(ii) of this section must consist, at minimum, of the clinical
trial registration information specified in Sec. 11.28(a).
(B) If the clinical trial information voluntarily submitted for a
clinical trial described by paragraph (c)(1) of this section consists
of the clinical trial results information specified in Sec.
11.60(c)(2)(i)(B), the information to be submitted in accordance with
paragraph (c)(2)(ii) of this section must consist of the clinical trial
results information specified in Sec. 11.60(c)(2)(i)(B).
(C) If the clinical trial information voluntarily submitted for a
clinical trial described by paragraph (c)(1) of this section consists
of both the clinical trial registration information specified in Sec.
11.28(a) and the clinical trial results information specified in Sec.
11.48, the information to be submitted in accordance with paragraph
(c)(2)(ii) of this section must consist of both the clinical trial
registration information specified in Sec. 11.28(a) and the clinical
trial results information specified in Sec. 11.48.
(iv) Submission deadlines:
(A) Secondary outcome measure(s) and adverse event information for
voluntarily-submitted clinical trials, under paragraph (c) of this
section:
(1) If data collection for secondary outcome measure(s) for a
voluntarily submitted clinical trial under paragraph (c) of this
section is not completed by the primary completion date of the
voluntarily submitted clinical trial, clinical trial results
information for the secondary outcome measure(s) required in Sec.
11.48(a)(3) must be submitted by the later of the date that the
clinical trial results information is voluntarily submitted for the
primary outcome measure(s) or 1 year after the date on which the final
subject was examined or received an intervention for the purposes of
final collection of data for the secondary outcome(s), whether the
clinical trial was concluded according to the pre-specified protocol or
was terminated.
(2) If data collection for adverse event information continues
after the primary completion date of the voluntarily submitted clinical
trial, any adverse event information collected after the primary
completion date and subject to the submission requirements in Sec.
11.48(a)(4) must be submitted by the later of the date that the
clinical trial results information is voluntarily submitted for the
primary outcome measure(s) or 1 year after the date of final collection
of data for adverse events information, whether the clinical trial was
concluded according to the pre-specified protocol or was terminated.
(B) The clinical trial information specified in paragraph
(c)(2)(iii) of this section must be submitted not later than the later
of the date on which the application or premarket notification to FDA
for approval, licensure, or clearance to market a drug product
(including a biological product) or device product under section 351 of
the Public Health Service Act (42 U.S.C. 262) or section 505, 510(k),
515, or 520(m) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C.
355, 360(k), 360e, 360j(m)) for the use studied in the clinical trial
specified under paragraph (c)(1) of this section is submitted to FDA or
the date on which the clinical trial information specified in paragraph
(c)(2)(i) of this section for the clinical trial specified under
paragraph (c)(1) of this section is submitted to ClinicalTrials.gov.
(v) All submissions of clinical trial information under paragraph
(c) of this section are subject to the applicable update and
corrections requirements specified in Sec. 11.64.
(d) Statement to accompany applicable clinical trials submitted
under paragraphs (a), (b), and (c) of this section. Each applicable
clinical trial for which clinical trial information is submitted under
paragraphs (a), (b), and (c) of this section and posted on
ClinicalTrials.gov will include the statement ``This clinical trial
information was submitted voluntarily under the applicable law and,
therefore, certain submission deadlines may not apply. (That is,
clinical trial information for this applicable clinical trial was
submitted under section 402(j)(4)(A) of the Public Health Service Act
and 42 CFR 11.60 and is not subject to the deadlines established by
sections 402(j)(2) and (3) of the Public Health Service Act or 42 CFR
11.24 and 11.44.)''
Sec. 11.62 What requirements apply to applicable clinical trials for
which submission of clinical trial information has been determined by
the Director to be necessary to protect the public health?
(a) A responsible party who receives notification that the Director
has determined that posting of clinical trial information for an
applicable clinical trial described in paragraph (b) of this section is
necessary to protect the public health must submit clinical trial
information as specified in paragraph (c) of this section.
(b) An applicable clinical trial subject to this section must be
either:
(1) An applicable clinical trial of an approved, licensed, or
cleared drug product (including a biological product) or device product
that has a primary completion date on or after September 27, 1997; or
(2) An applicable clinical trial that is subject to registration
under Sec. 11.22(a) and studies a drug product (including a biological
product) or device product that is unapproved, unlicensed, or
uncleared, regardless of whether approval, licensure, or clearance was,
is, or will be sought, and that is not otherwise subject to results
information submission in accordance with the regulation.
(c) Deadline for submission of clinical trial information:
(1) General. Except as provided in paragraphs (c)(2) and (c)(3) of
this section, a responsible party for an applicable clinical trial that
is subject to this section must submit the clinical trial registration
information specified in Sec. 11.28(a) and the clinical trial results
information specified in Sec. 11.48(a) not later than 30 calendar days
after the submission date specified in the notification described in
paragraph (a) of this section.
(2) Exception. If a responsible party submits a certification
consistent with Sec. 11.44(b) or (c) not later than 30 calendar days
after the submission date specified in the notification described in
paragraph (a) of this section, the responsible party must submit the
clinical trial results information specified in Sec. 11.48(a) not
later than the deadline specified in Sec. 11.44(b) or (c), as
applicable.
(3) If a responsible party submitted clinical trial registration
information describing the applicable clinical trial specified in the
notification described in paragraph (a) of this section prior to the
date on which the notification is sent to
[[Page 65155]]
the responsible party, the responsible party must update such clinical
trial information to reflect changes, if any, in the applicable
clinical trial not later than 30 calendar days after the submission
date specified in the notification described in paragraph (a) of this
section, irrespective of the deadline for updates specified in Sec.
11.64.
Sec. 11.64 When must clinical trial information submitted to
ClinicalTrials.gov be updated or corrected?
(a) Updates. (1) Clinical trial registration information:
(i) The responsible party for an applicable clinical trial for
which clinical trial registration information was required to be
submitted if the clinical trial was initiated before January 18, 2017,
must submit updates in accordance with the following:
(A) In general, changes to the clinical trial registration
information specified in section 402(j)(2)(A)(ii) of the Public Health
Service Act (42 U.S.C. 282(j)(2)(A)(ii)) that was required at the time
of submission must be updated not less than once every 12 months.
(B) Overall Recruitment Status must be updated not later than 30
calendar days after any change in overall recruitment status.
(C) Primary Completion Date must be updated not later than 30
calendar days after the clinical trial reaches its actual primary
completion date.
(ii) The responsible party for an applicable clinical trial, or for
another clinical trial for which registration information was
voluntarily submitted pursuant to Sec. 11.60(c), if the clinical trial
was initiated on or after January 18, 2017, must submit updates in
accordance with the following:
(A) In general, changes to clinical trial registration information
specified in Sec. 11.28 must be updated not less than once every 12
months.
(B) If the first human subject was not enrolled in the clinical
trial at the time of registration, the Study Start Date data element
must be updated not later than 30 calendar days after the first human
subject is enrolled.
(C) Intervention Name(s) must be updated to a non-proprietary name
not later than 30 calendar days after a non-proprietary name is
established for any intervention included in the Intervention Name(s)
data element.
(D) Availability of expanded access:
(1) If expanded access to an investigational drug product
(including a biological product) becomes available after an applicable
clinical trial of that product has been registered, the responsible
party, if both the manufacturer of the investigational drug product
(including a biological product) and the sponsor of the applicable
clinical trial, must, not later than 30 calendar days after expanded
access becomes available, update the Availability of Expanded Access
data element for that applicable clinical trial and, unless an expanded
access record has already been created as required by Sec.
11.28(a)(2)(ii)(H), submit the data elements in accordance with Sec.
11.28(c) to create an expanded access record.
(2) No later than 30 calendar days after the date on which the
responsible party receives an NCT number for an expanded access record
created as required by Sec. 11.28(a)(2)(ii)(H), the responsible party
must update the Availability of Expanded Access data element by
entering the NCT number in the clinical trial record for the applicable
clinical trial.
(E) Expanded access record:
(1) Expanded Access Status, under Sec. 11.28(c)(2)(iv), must be
updated not later than 30 calendar days after a change in the
availability of expanded access to an investigational drug product
(including a biological product) under section 561 of the Federal Food,
Drug, and Cosmetic Act (21 U.S.C. 360bbb).
(2) Expanded Access Type, under Sec. 11.28(c)(1)(x), must be
updated not later than 30 calendar days after a change in the type(s)
of expanded access available for an investigational drug product
(including a biological product) under section 561 of the Federal Food,
Drug, and Cosmetic Act (21 U.S.C. 360bbb).
(F) Overall Recruitment Status must be updated not later than 30
calendar days after any change in overall recruitment status. If, at
any time, Overall Recruitment Status is changed to ``suspended,''
``terminated,'' or ``withdrawn,'' the responsible party must also
submit the Why Study Stopped data element.
(G) Individual Site Status must be updated not later than 30
calendar days after a change in status for any individual site.
(H) Human Subjects Protection Review Board Status must be updated
not later than 30 calendar days after a change in status.
(I) Primary Completion Date must be updated not later than 30
calendar days after the clinical trial reaches its actual primary
completion date. At the time, the date is changed to ``actual,'' and
the Enrollment data element specifying the actual number of
participants enrolled must be submitted.
(J) Study Completion Date must be updated not later than 30
calendar days after the clinical trial reaches its actual study
completion date.
(K) Responsible Party, by Official Title must be updated not later
than 30 calendar days after a change in the responsible party or the
official title of the responsible party.
(L) Responsible Party Contact Information must be updated not later
than 30 calendar days after a change in the responsible party or the
contact information for the responsible party.
(M) Device Product Not Approved or Cleared by U.S. FDA must be
updated not later than 15 calendar days after a change in approval or
clearance status has occurred.
(N) Record Verification Date must be updated any time the
responsible party reviews the complete set of submitted clinical trial
information for accuracy and not less than every 12 months, even if no
other updated information is submitted at that time.
(O) If a protocol is amended in such a manner that changes are
communicated to human subjects in the clinical trial, updates to any
relevant clinical trial registration information data elements must be
submitted not later than 30 calendar days after the protocol amendment
is approved by a human subjects protection review board.
(iii) In addition to the update requirements established in
paragraphs (a)(1)(i) and (a)(1)(ii) of this section, clinical trial
registration information must be updated at the time that clinical
trial results information for that clinical trial is initially
submitted.
(A) If the clinical trial was initiated before January 18, 2017, a
responsible party must submit updates to the clinical trial
registration information described in Sec. 11.64(a)(1)(i).
(B) If the clinical trial was initiated on or after January 18,
2017, the responsible party must submit updates to the clinical trial
registration information in accordance with Sec. 11.64(a)(1)(ii).
(2) Clinical trial results information. The responsible party for
an applicable clinical trial, or for another clinical trial for which
results information was voluntarily submitted pursuant to Sec.
11.60(b) or (c), where the clinical trial has a Primary Completion Date
on or after January 18, 2017, must submit updates in accordance with
the following:
(i) In general, changes to required clinical trial results
information, other than the protocol and statistical analysis plan
specified in Sec. 11.48(a)(5) and certain agreements specified in
Sec. 11.48(a)(6)(ii),must be updated not less than once every 12
months.
[[Page 65156]]
(ii) For applicable device clinical trials of unapproved or
uncleared device products, the responsible party must update the
following data elements, as defined in Sec. 11.10(b), in accordance
with the following:
(A) Intervention Name(s) must be updated to a non-proprietary name
not later than 30 calendar days after a non-proprietary name is
established for any intervention included in the Intervention Name(s)
data element.
(B) Primary Completion Date must be updated not later than 30
calendar days after the clinical trial reaches its actual primary
completion date. At the time the date is changed to ``actual,'' the
Enrollment data element specifying the actual number of participants
enrolled must be submitted.
(C) Study Completion Date must be updated not later than 30
calendar days after the clinical trial reaches its actual study
completion date.
(D) Overall Recruitment Status must be updated not later than 30
calendar days after any change in overall recruitment status. If, at
any time, Overall Recruitment Status is changed to ``suspended,''
``terminated,'' or ``withdrawn,'' the responsible party must also
submit the Why Study Stopped data element.
(E) Record Verification Date must be updated any time the
responsible party reviews the complete set of submitted clinical trial
information for accuracy and not less than every 12 months, even if no
other updated information is submitted at that time.
(3) A responsible party's obligation to submit updates as specified
in this section ends on the date on which all required clinical trial
results information has been submitted as specified in sections
402(j)(3)(C) and 402(j)(3)(I) of the Public Health Service Act (42
U.S.C. 282(j)(3)(C)) and 42 U.S.C. 282(j)(3)(I)) or as specified in
Sec. 11.48, as applicable, and corrections have been made or addressed
in response to any electronic notice received under Sec. 11.64(b)(1).
If no clinical trial results information is required to be submitted, a
responsible party's obligation to submit updates to clinical trial
registration information ends on the date on which all required
clinical trial registration information has been submitted as specified
in section 402(j)(2)(A)(ii) of the Public Health Service Act (42 U.S.C.
282(j)(2)(A)(ii) or Sec. 11.28, as applicable, and corrections have
been made or addressed in response to any electronic notice received
under Sec. 11.64(b)(1).
(4) Public availability of updates. (i) Updates to clinical trial
registration information and clinical trial results information will be
posted in accordance with Sec. 11.35 and Sec. 11.52, respectively.
(ii) The Director will retain prior clinical trial registration
information and clinical trial results information and make it publicly
available in accordance with Sec. 11.35 and Sec. 11.52, respectively,
through ClinicalTrials.gov so that updates do not result in the removal
of any information from the original submission or any preceding
update.
(b) Corrections--(1) Quality control. After clinical trial
registration information has been submitted as specified in section
402(j)(2)(A)(ii) of the Public Health Service Act (42 U.S.C.
282(j)(2)(A)(ii)) or Sec. 11.28, as applicable, or clinical trial
results information has been submitted as specified in sections
402(j)(3)(C) and 402(j)(3)(I) of the Public Health Service Act (42
U.S.C. 282(j)(3)(C) and 42 U.S.C. 282(j)(3)(I)) or Sec. 11.48, as
applicable, including the updates specified in paragraph (a) of this
section, the Director may provide electronic notification to the
responsible party of apparent errors, deficiencies, and/or
inconsistencies in the submitted information identified during
procedures for quality control review established by the Director, as
specified at https://prsinfo.clinicaltrials.gov. The responsible party
must correct or address all apparent errors, deficiencies, and/or
inconsistencies identified in the notification not later than 15
calendar days for clinical trial registration information, or 25
calendar days for clinical trial results information, after the date of
the electronic notification sent to the responsible party.
(2) Other corrections. (i) A responsible party who becomes aware of
errors, other than those specified in paragraph (b)(1) of this section,
in any clinical trial information submitted under this part shall have
not more than 15 calendar days for clinical trial registration
information, or 25 calendar days for clinical trial results
information, to correct or address such errors.
(ii) A responsible party's obligation to correct or address errors
as specified in paragraph (b)(2) of this section ends on the date on
which all required clinical trial results information has been
submitted as specified in sections 402(j)(3)(C) and 402(j)(3)(I) of the
Public Health Service Act (42 U.S.C. 282(j)(3)(C) and 42 U.S.C.
282(j)(3)(I)) or Sec. 11.48, as applicable, and corrections have been
made or addressed in response to any electronic notice received under
Sec. 11.64(b)(1). If no clinical trial results information is required
to be submitted, a responsible party's obligation to correct or address
errors ends on the date on which all required clinical trial
registration information has been submitted as specified in section
402(j)(2)(A)(ii) of the Public Health Service Act (42 U.S.C.
282(j)(2)(A)(ii)) or Sec. 11.28, as applicable, and corrections have
been made or addressed in response to any electronic notice received
under Sec. 11.64(b)(1).
(3) Compliance with the quality control review process, including
the requirements of this section, does not constitute a legal defense
to enforcement pursuant to section 301(jj) of the Federal Food, Drug
and Cosmetic Act (21 U.S.C. 331(jj)), section 303(f)(3) of the Federal
Food, Drug and Cosmetic Act (21 U.S.C. 333(f)(3)), or any other Federal
law.
Subpart E--Potential Legal Consequences of Non-compliance
Sec. 11.66 What are potential legal consequences of not complying
with the requirements of this part?
(a) Civil or criminal judicial actions. Failure to comply with the
requirements of this part, issued under section 402(j) of the Public
Health Service Act (42 U.S.C. 282(j)), is a prohibited act under one or
more provisions of section 301(jj) of the Federal Food, Drug, and
Cosmetic Act (21 U.S.C. 331(jj)):
(1) Failure to submit the certification required by section
402(j)(5)(B) of the Public Health Service (42 U.S.C. 282(j)(5)(B)) that
all applicable requirements of section 402(j) have been met, or
knowingly submitting a false certification under section 402(j)(5)(B),
is a prohibited act under section 301(jj)(1) of the Federal Food, Drug,
and Cosmetic Act.
(2) Failure to submit clinical trial information required under
section 402(j) of the Public Health Service Act is a prohibited act
under section 301(jj)(2) of the Federal Food, Drug, and Cosmetic Act.
(3) Submission of clinical trial information under section 402(j)
that is false or misleading in any particular is a prohibited act under
section 301(jj)(3) of the Federal Food, Drug, and Cosmetic Act.
(b) Civil monetary penalty actions. Any person who violates section
301(jj) of the Federal Food, Drug, and Cosmetic Act is subject to civil
monetary penalties under section 303(f)(3) of the Federal Food, Drug,
and Cosmetic Act (21 U.S.C. 333(f)(3)).
(c) Grant funding actions. Under section 402(j)(5)(A) of the Public
Health Service Act (42 U.S.C. 282(j)(5)(A)), if an applicable clinical
trial is funded in whole or part by the Department of Health and Human
Services, any required grant or progress report forms
[[Page 65157]]
must include a certification that the responsible party has made all
required registration and results submissions. If it is not verified
that the required registration and results clinical trial information
for each applicable clinical trial for which a grantee is the
responsible party has been submitted, any remaining funding for a grant
or funding for a future grant to such grantee will not be released. If
the head of an HHS agency verifies that a grantee has not submitted
such required clinical trial information, the agency head will provide
notice to the grantee of the non-compliance and allow the grantee 30
days to correct the non-compliance and submit the required clinical
trial information.
Dated: September 8, 2016.
Francis S. Collins,
Director, National Institutes of Health.
Approved: Dated: September 9, 2016.
Sylvia Mathews Burwell,
Secretary.
[FR Doc. 2016-22129 Filed 9-16-16; 11:15 am]
BILLING CODE P