[Federal Register Volume 79, Number 135 (Tuesday, July 15, 2014)]
[Proposed Rules]
[Pages 41149-41152]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2014-16374]
=======================================================================
-----------------------------------------------------------------------
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 15
[Docket No. FDA-2014-N-0824]
Confidentiality of Interim Results in Cardiovascular Outcome
Safety Trials; Public Hearing; Request for Comments
AGENCY: Food and Drug Administration, HHS.
ACTION: Notification of public hearing; request for comments.
-----------------------------------------------------------------------
SUMMARY: The Food and Drug Administration (FDA) is announcing a public
hearing that will provide a forum to discuss confidentiality of interim
results for certain cardiovascular outcomes trials (CVOTs) submitted to
the Agency while the trials are still ongoing. The purpose of the
public hearing is to initiate constructive discussion among regulators,
researchers, health care providers, representatives from the
pharmaceutical industry and health care organizations, and the general
public, about appropriate handling of interim analysis results of these
ongoing CVOTs. FDA is also opening a public docket to receive comments
on this topic.
DATES: The public hearing will be held on August 11, 2014, from 8 a.m.
to 5 p.m. Individuals who wish to present at the public hearing must
register by July 28, 2014. Section IV provides attendance and
registration information. To ensure consideration, submit comments by
July 28, 2014. Electronic or written comments will be accepted after
the public hearing until October 10, 2014.
ADDRESSES: The public hearing will be held at the FDA White Oak Campus,
10903 New Hampshire Ave., Bldg. 31 Conference Center, the Great Room
(rm. 1503), Silver Spring, MD 20993-0002. Entrance for the public
hearing participants (non-FDA employees) is through Building 1 where
routine security check procedures will be performed. For parking and
security information, please refer to http://www.fda.gov/AboutFDA/WorkingatFDA/BuildingsandFacilities/WhiteOakCampusInformation/ucm241740.htm.
Submit electronic comments to http://www.regulations.gov. Submit
written comments to the Division of Dockets Management (HFA-305), Food
and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD
20852. Identify comments with the docket number found in brackets in
the heading of this document.
FOR FURTHER INFORMATION CONTACT: Indira Hills, Food and Drug
Administration, Center for Drug Evaluation and Research, 10903 New
Hampshire Ave., Bldg. 21, rm. 4508, Silver Spring, MD 20993, 301-796-
9686, FAX: 301-796-9907, email: [email protected].
SUPPLEMENTARY INFORMATION:
I. Background
A. The Requirement for Postmarketing Studies To Assess the Risk of a
New Drug
In some cases, studies submitted to FDA as part of a new drug
application or biologics license application will demonstrate that a
drug is safe and effective for its intended use (i.e., that its
benefits outweigh its identified risks), but the Agency will
nevertheless require a sponsor to conduct additional postmarketing
studies or trials under section 505(o)(3) of the Federal Food, Drug,
and Cosmetic Act (the FD&C Act)
[[Page 41150]]
(21 U.S.C. 355(o)(3)) for the following reasons: To assess a known
serious risk related to use of the drug, to assess signals of a serious
risk related to use of the drug, or to identify an unexpected risk when
available data indicate the potential for a serious risk.
B. FDA's Approach to the Approval of Drugs To Treat Type II Diabetes
For most drugs, clinical trials of reasonable size can establish a
favorable relationship of benefit to relatively common risks, but they
are not large enough to assess the risk of rare serious events such as
heart attacks, strokes, or death. Where there is concern about these
risks (e.g., concern about drugs to treat Type II diabetes mellitus
(T2DM) or to promote weight loss), development programs include CVOTs
to help assess the risk to meet the requirements for drug approval. In
some cases, applicants have conducted a metaanalysis of cardiovascular
(CV) risk from Phase 2/3 trials to help establish the safety of a drug
and a separate larger CVOT as a postmarketing requirement under section
505(o)(3) of the FD&C Act. In other cases, analyses of interim data
from a single CVOT will demonstrate that a drug is safe with regard to
CV risk for its intended use, and, if the overall risk-benefit analysis
supports approval, the applicant will further assess the CV risks by
continuing the trial as a postmarketing requirement.
The Agency has described its expectations for CV outcome data for
drugs to treat T2DM in the guidance for industry ``Diabetes Mellitus
Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat
Type 2'' (available at Diabetes'' (http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM071627.pdf), which
was issued based on the discussion at an advisory committee meeting,\1\
as well as in other available data and information. The guidance makes
recommendations about how to demonstrate that a new therapy to treat
T2DM is not associated with an unacceptable increase in CV risk.
---------------------------------------------------------------------------
\1\ On July 1 and 2, 2008, the Endocrinologic and Metabolic Drug
Advisory Committee met to discuss the role of CV assessment in the
premarketing and postmarketing settings (http://www.fda.gov/ohrms/dockets/ac/cder08.html#endocrinologicmetabolic).
---------------------------------------------------------------------------
The guidance states that before submission of a new drug
application (NDA) or biologics license application, the premarketing CV
outcome data should show that the incidence of important CV events
occurring with the investigational agent is not more than 80 percent
increase compared to the control group (i.e., that the upper bound of
the 2-sided 95 percent confidence interval for the estimated risk ratio
for CV events is less than 1.8). The guidance also states that if the
risk ratio is between 1.3 and 1.8 and the overall risk-benefit analysis
supports approval, a postmarketing trial will generally be necessary to
show that the upper bound of the 2-sided 95 percent confidence interval
for the estimated risk ratio is less than 1.3. This showing can be
achieved by conducting an adequately powered new postmarketing trial,
by combining results of separate premarketing and postmarketing trials,
or by continuing a large CVOT in which a planned interim analysis is
the basis for concluding that the risk ratio is less than 1.8. If the
risk ratio of 1.3 is ruled out based on premarket data, then a
postmarketing requirement may not be necessary.
C. Interim Analyses, the Importance of Their Confidentiality, and the
Role of the Data Monitoring Committee
Interim analyses are analyses of study data conducted partway
through an ongoing clinical trial. They can play an integral role in
clinical trials by allowing for the safety of enrolled patients to be
monitored at various intervals in the study and also by allowing for
the possibility of stopping the trial early for safety concerns, for
futility, or for early evidence of efficacy that would make it
unethical for the trial to proceed. Confidentiality of interim data is
a paramount concern: The 1998 International Conference on Harmonization
(ICH) guidance for industry ``E9 Statistical Principles for Clinical
Trials'' (ICH E9 guidance) (available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm073137.pdf)
reflects a collective view across regulatory agencies in the European
Union, Japan, and the United States when it states that ``All staff
involved in the conduct of the trial should remain blind to the results
of such analyses, because of the possibility that their attitudes to
the trial will be modified and cause changes in the characteristics of
patients to be recruited or biases in treatment comparisons.''
An independent Data Monitoring Committee (DMC) is usually
established to review the interim analysis results and make
recommendations to the sponsor about any action needed based on those
results, allowing the sponsor and other personnel associated with the
trial to remain masked to interim results. In 2006, FDA issued the
guidance for clinical trial sponsors ``Establishment and Operation of
Clinical Trial Data Monitoring Committees'' (DMC guidance) (available
at http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM127073.pdf) that reiterated many of the best practices for interim
analyses and DMCs outlined in the ICH E9 guidance. Specifically, the
guidance states that ``[p]rocedures should be established to safeguard
confidential interim data from the project team, investigators, sponsor
representatives, or anyone else outside the DMC and the statistician(s)
performing the interim analyses (see 21 CFR 314.126(b)(5) (drugs) and
21 CFR 860.7(f)(1) (devices)).'' An exception is made in considering
the need to disseminate safety data to allow for appropriate monitoring
of patients' safety.
D. Potential Adverse Consequences of Disclosure of Interim Results
The concern with widespread disclosure of interim results in an
ongoing trial, as described in the DMC guidance, stems from the
potential of the disclosure to negatively affect the conduct of the
remaining portion of the trial. The impact could include unanticipated
changes in recruitment, treatment administration, or other aspects of
trial conduct, as well as loss of objectivity in safety event
reporting. Sponsors and other interested parties with access to interim
data may have difficulty managing the remainder of the trial in an
objective manner, particularly if changes to the trial protocol are
needed for other reasons. Knowledge of interim data may influence
decisions about the trial going forward, and it is nearly impossible to
assess the impact of that influence on the trial's final results. To
ensure the integrity of the trial and the validity of its findings, the
DMC guidance strongly recommends maintaining the confidentiality of
interim data until the trial completion.
E. Partial Disclosure of Interim Trial Results by FDA and the Purpose
of This Hearing
Once FDA sends an approval letter for a new drug, the FD&C Act and
FDA regulations require that a summary or summaries of the safety and
effectiveness data and information submitted with or incorporated by
reference in the application be made available immediately for public
disclosure, with certain limited redactions. FDA's analyses of the
safety and effectiveness data and information from clinical studies
that support the approval of a new drug are typically disclosed with
little or no redaction. However, data relied on to make approval
decisions are ordinarily
[[Page 41151]]
derived from fully completed clinical trials. In the case of T2DM
therapies where a single, large CVOT to rule out CV risk was designed
to meet both the requirement for approval and the postmarketing
requirements, approval would indicate that the study had indeed ruled
out the risk ratio of 1.8, so this aspect of the interim results would
be known. But that fact would not reveal the detailed result, e.g., a
finding that CV events were actually reduced by the drug in the interim
analysis. Disclosure of detailed and more extensive information or
analyses from an ongoing trial, that is, the results of an interim
analysis, could undermine the integrity of the trial and jeopardize its
continuation, which could delay or even prevent obtaining the safety
data about serious risks that were required to be assessed at the time
of approval.
For example, in connection with a recent approval decision of a
drug to treat T2DM (see MEMORANDA: Disclosure of Interim Cardiovascular
Risk Study Data, NDA 22271, Nesina (alogliptin) tablets, and Its Fixed-
Dose Combination Product NDAs 22426 and 203414, dated March 12, 2013,
and Disclosure of Interim Cardiovascular Risk Study Data and
Information Relied on to Approve, NDA 22271, Nesina (alogliptin)
tablets, and Its Fixed-Dose Combination Product NDAs 22426 and 203414,
dated March 12, 2013, available at http://www.fda.gov/Drugs/NewsEvents/ucm398454.htm), FDA released information at the time of approval that
was considered not likely to undermine the integrity of the ongoing
trial, including (1) general background and study information; (2)
high-level summary conclusions that the trial ruled out the
prespecified risk margin recommended by FDA guidance; and (3) other
data and information from the trial unrelated to CV risk. FDA decided,
however, to delay disclosure of other information that it determined
could jeopardize successful completion of the trial, specifically point
estimates of hazard ratios and associated confidence intervals for CV
risk and detailed data on CV events and rates. Based on the
circumstances of this case, FDA determined that delaying disclosure of
these data was appropriate for a limited time. This information would
become available when FDA completed its review of the final CV risk
study report and had taken any related regulatory action based on the
final results.
The Agency is holding this hearing to solicit input from
stakeholders on the effects of disclosing information or analyses, at
various levels of detail, from an ongoing trial, and whether general
information about the trial can be disclosed without significant risk
to the integrity of the trial or its completion. Making a determination
about the effect of disclosure on a particular trial requires
consideration of the details of that trial and relevant context.
II. Scope of Public Input Requested
FDA is seeking input from the various stakeholders on the following
issues:
When a trial to evaluate CV safety of a new treatment is
ongoing at the time a drug is approved, do stakeholders agree that
disclosure of detailed analyses (such as point estimates of hazard
ratios and the associated confidence intervals) could undermine the
integrity of an ongoing trial and jeopardize its continuation,
potentially eliminating or substantially delaying the Agency's ability
to obtain needed long-term safety information?
[cir] What interim findings, if disclosed, would represent the
greatest risk to trial integrity or jeopardize trial continuation?
[cir] Can partial disclosure of interim findings at the time of
approval, essentially disclosing only that the standard for approval
has been met, offer protection of trial integrity and also provide
health care practitioners with the essential scientific information
needed to inform their use of the drug?
[cir] If the detailed interim results were disclosed at the time of
approval, and the ongoing study was discontinued at that time, would it
be feasible to conduct a new large trial as a postmarketing requirement
that would fulfill the original study objective?
Are there other, alternative trial designs that would allow
for disclosure of interim results on safety risks at the time of
product approval while also allowing for further information to be
obtained postmarket?
III. Notice of Hearing Under 21 CFR Part 15
The Commissioner of Food and Drugs is announcing that the public
hearing will be held in accordance with part 15 (21 CFR part 15). The
hearing will be conducted by a presiding officer, who will be
accompanied by FDA senior management from the Office of the
Commissioner and the Center for Drug Evaluation and Research.
Under Sec. 15.30(f), the hearing is informal and the rules of
evidence do not apply. No participant may interrupt the presentation of
another participant. Only the presiding officer and panel members may
question any person during or at the conclusion of each presentation.
Public hearings under part 15 are subject to FDA's policy and
procedures for electronic media coverage of FDA's public administrative
proceedings (part 10, subpart C (21 CFR part 10, subpart C)). Under
Sec. 10.205, representatives of the electronic media may be permitted,
subject to certain limitations, to videotape, film, or otherwise record
FDA's public administrative proceedings, including presentations by
participants. The hearing will be transcribed as stipulated in Sec.
15.30(b) (see section VI for more details). To the extent that the
conditions for the hearing, as described in this notice, conflict with
any provisions set out in part 15, this notice acts as a waiver of
those provisions as specified in Sec. 15.30(h).
IV. Attendance and Registration
The FDA Conference Center at the White Oak location is a Federal
facility with security procedures and limited seating. Individuals who
wish to attend the public hearing must register on or before July 28,
2014, by visiting https://www.surveymonkey.com/s/7L8Z66Q and contacting
Indira Hills (see FOR FURTHER INFORMATION CONTACT). Early registration
is recommended. Registration is free and will be on a first-come,
first-served basis. However, FDA may limit the number of participants
from each organization based on space limitations. Onsite registration
on the day of the hearing will be based on space availability.
FDA will provide additional background information at the time the
Federal Register notice is published and an agenda approximately 2
weeks before the hearing at FDA Meeting Information page, which is
available online at http://www.fda.gov/Drugs/NewsEvents/ucm398454.htm.
Time will be reserved during the hearing for planned presentations
from the audience. If you would like to present at the hearing, please
indicate this in your hearing registration. Time for audience
presentations is limited and will be assigned on a first-come, first-
served basis. Note also that time will be designated throughout the day
for general comments and questions from the audience following the
panel discussions.
In this Federal Register notice, FDA has included specific issues
that will be addressed by the panel. If you wish to address one or more
of these issues in your presentation, please indicate this at the time
you register so that FDA can consider that in organizing the
[[Page 41152]]
presentations. FDA will do its best to accommodate requests to speak,
and will determine the amount of time allotted to each presenter and
the approximate time that each oral presentation is scheduled to begin.
If you need special accommodations because of disability, please
contact Indira Hills (see FOR FURTHER INFORMATION CONTACT) at least 7
days before the hearing.
A live webcast of this hearing will be viewable at https://collaboration.fda.gov/dmcidcvtpart15/ on the day of the hearing. A
video record of the hearing will be available at the same Web address
for 1 year.
V. Comments
Regardless of attendance at the public hearing, interested persons
may submit either electronic comments regarding this document to http://www.regulations.gov or written comments to the Division of Dockets
Management (see ADDRESSES). It is only necessary to send one set of
comments. Identify comments with the docket number found in brackets in
the heading of this document. Received comments may be seen in the
Division of Dockets Management between 9 a.m. and 4 p.m., Monday
through Friday, and will be posted to the docket at http://www.regulations.gov.
VI. Transcripts
As soon as a transcript is available, it will be accessible at
http://www.regulations.gov. It may be viewed at the Division of Dockets
Management (see ADDRESSES). A transcript will also be available in
either hard copy or on CD-ROM, after submission of a Freedom of
Information request. Written requests are to be sent to Division of
Freedom of Information (ELEM-1029), Food and Drug Administration, 12420
Parklawn Dr., Element Bldg., Rockville, MD 20857.
Dated: July 8, 2014.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2014-16374 Filed 7-14-14; 8:45 am]
BILLING CODE 4164-01-P