[Federal Register Volume 69, Number 112 (Thursday, June 10, 2004)]
[Proposed Rules]
[Pages 32467-32475]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 04-13063]


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Proposed Rules
                                                Federal Register
________________________________________________________________________

This section of the FEDERAL REGISTER contains notices to the public of 
the proposed issuance of rules and regulations. The purpose of these 
notices is to give interested persons an opportunity to participate in 
the rule making prior to the adoption of the final rules.

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Federal Register / Vol. 69, No. 112 / Thursday, June 10, 2004 / 
Proposed Rules

[[Page 32467]]



DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 312

[Docket No. 2004N-0018]


Human Subject Protection; Foreign Clinical Studies Not Conducted 
Under an Investigational New Drug Application

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is proposing to revise 
its regulations on its acceptance of foreign clinical studies not 
conducted under an investigational new drug application (IND) as 
support for an IND or marketing application for a drug or biological 
product. We are proposing to replace the requirement that such studies 
be conducted in accordance with ethical principles stated in the 
Declaration of Helsinki (Declaration) with a requirement that the 
studies be conducted in accordance with good clinical practice (GCP), 
including review and approval by an independent ethics committee (IEC). 
The proposed rule is intended to update the standards for the 
acceptance of nonIND foreign studies and to help ensure the quality and 
integrity of data obtained from such studies.

DATES: Submit written or electronic comments by September 8, 2004. 
Submit written comments on the information collection requirements by 
July 12, 2004. See section VIII of this document for the proposed 
effective date of a final rule based on this document.

ADDRESSES: You may submit comments, identified by Docket No. 2004N-
0018, by any of the following methods:
     Federal eRulemaking Portal: http://www.regulations.gov. 
Follow the instructions for submitting comments.
     Agency Web site: http://www.fda.gov/dockets/ecomments. 
Follow the instructions for submitting comments on the agency Web site.
     E-mail: fdadockets@oc.fda.gov. Include Docket No. 2004N-
0018 in the subject line of your e-mail message.
     FAX: 301-827-6870.
     Mail/Hand delivery/Courier [For paper, disk, or CD-ROM 
submissions]: Division of Dockets Management, 5630 Fishers Lane, rm. 
1061, Rockville, MD 20852.
    Instructions: All submissions received must include the agency name 
and Docket No. 2004N-0018 or Regulatory Information Number (RIN) for 
this rulemaking. All comments received will be posted without change to 
http://www.fda.gov/dockets/ecomments, including any personal 
information provided. For detailed instructions on submitting comments 
and additional information on the rulemaking process, see section IV of 
the SUPPLEMENTARY INFORMATION section of this document.
    Docket: For access to the docket to read background documents or 
comments received, go to http://www.fda.gov/dockets/ecomments and/or 
the Division of Dockets Management, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852.
    See section VI of this document for the address to which comments 
on the information collection requirements of this rule may be sent.

FOR FURTHER INFORMATION CONTACT: David A. Lepay, Office for Science and 
Health Coordination, Good Clinical Practice Programs (HF-34), Food and 
Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, 301-827-
3340.

SUPPLEMENTARY INFORMATION:

I. Introduction

A. Current Regulations on Acceptance of Foreign Studies Not Conducted 
Under an IND

    FDA regulations permit the acceptance of foreign clinical studies 
in support of an IND, a new drug application (NDA), or a biologics 
license application (BLA) if certain conditions are met. Foreign 
studies performed under an IND must meet the same requirements of part 
312 (21 CFR part 312) that apply to U.S. studies conducted under an 
IND. Under Sec.  312.120(a), we generally accept for review foreign 
clinical studies not conducted under an IND provided they are well-
designed, well-conducted, performed by qualified investigators, and 
conducted in accordance with ethical principles acceptable to the world 
community.
    With respect to such ethical principles, Sec.  312.120(c)(1) states 
that for a foreign clinical study not conducted under an IND to be used 
to support an IND or marketing application, the study must have been 
conducted in accordance with the ethical principles stated in the 
Declaration of Helsinki or the laws and regulations of the country in 
which the research was conducted, whichever represents the greater 
protection of the individual. Section 312.120(c)(4) sets forth the text 
of the 1989 version of the Declaration.
    We first incorporated the Declaration (1964 version) into our 
regulations on nonIND foreign studies in 1975 (40 FR 16053, April 9, 
1975) in what was then Sec.  312.20. We amended Sec.  312.20 in 1981 to 
replace the 1964 Declaration with the 1975 version (46 FR 8942, January 
27, 1981). In 1991, we replaced the 1975 Declaration with the 1989 
version (56 FR 22112, May 14, 1991) in what had been recodified as 
Sec.  312.120.

B. Reasons for Proposing To Revise the Regulations

    We believe that a revision of the requirements for the acceptance 
of foreign clinical studies not conducted under an IND is again needed 
for several reasons.
1. Updating Standards
    First, standards for protecting human subjects have evolved 
considerably over the past decade. For example, since we last amended 
Sec.  312.120 in 1991, several notable documents identifying ethical 
and other clinical practice-related principles have been published. 
These include the following documents:
     The 1996 and 2000 revisions of the Declaration by the 
World Medical Assembly;
     ``Ethical and Policy Issues in International Research: 
Clinical Trials in Developing Countries,'' published by the National 
Bioethics Advisory Commission;
     ``International Ethical Guidelines for Biomedical Research 
Involving Human Subjects,'' prepared by the Council for International 
Organizations of Medical

[[Page 32468]]

Sciences in collaboration with the World Health Organization; and
     Several documents issued by the International Conference 
on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH).
    The ICH documents are notable because they define and incorporate 
the standard of GCP. GCP principles are addressed comprehensively in an 
ICH document entitled ``Good Clinical Practice: Consolidated 
Guideline,'' which we adopted for use as guidance for industry in 1997 
(62 FR 25692, May 9, 1997) (Good Clinical Practice guidance). The Good 
Clinical Practice guidance defines GCP as a ``standard for the design, 
conduct, performance, monitoring, auditing, recording, analyses, and 
reporting of clinical trials that provides assurance that the data and 
reported results are credible and accurate, and that the rights, 
integrity, and confidentiality of trial subjects are protected.'' As so 
defined, GCP shares many important ethical principles with the 1989 
Declaration, such as review by an IEC, the need for freely-given 
informed consent, conduct of clinical trials only by qualified 
individuals, and a recognition that the rights, safety, and well-being 
of trial subjects take precedence over the interests of science and 
society. The GCP concept, however, provides more detail and enumeration 
of specific responsibilities of various parties, including monitoring 
of the trial and reporting adverse events. In addition to the Good 
Clinical Practice guidance, GCP principles are incorporated in other 
FDA guidances adopted from the ICH, including ``Structure and Content 
of Clinical Study Reports'' (July 1996) (recommending that any study 
submitted to us in support of an application provide an assurance that 
the study complied with GCP).\1\
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    \1\ Sponsors seeking additional guidance on GCP generally should 
consult the Good Clinical Practice guidance. Additional relevant 
guidance may be found in sections of other FDA guidances adopted 
from the ICH, including ``E11 Clinical Investigation of Medicinal 
Products in the Pediatric Population'' (December 2000) and ``E10 
Choice of Control Group and Related Issues in Clinical Trials'' (May 
2001). These guidances are available electronically at http://www.fda.gov/cder/guidance/index.htm.
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    Many of the principles underlying GCP have already been 
incorporated in FDA's regulations, including parts 50, 56, 312, 314, 
and 601 (21 CFR parts 50, 56, 314, and 601). For example, the 
regulations in subpart B of part 50 contain the requirements for 
obtaining the informed consent of human subjects in clinical 
investigations. In addition, subpart D of part 312 describes the 
responsibilities of sponsors and investigators regarding IND studies, 
including conformance to parts 50 and 56 (on the use of institutional 
review boards (IRBs)).
    We are now proposing to revise Sec.  312.120 to incorporate GCP 
into the requirements for acceptance of nonIND foreign studies.
    The GCP standard in proposed Sec.  312.120 is consistent with the 
ICH standard developed through an international collaborative process. 
We believe that the proposed standard is sufficiently flexible to 
accommodate differences in how countries regulate the conduct of 
clinical research and obtain informed consent, while helping to ensure 
adequate and comparable human subject protection.
2. Ensuring Quality of Data
    Another reason for revising Sec.  312.120, related to the adoption 
of GCP, is to help provide greater assurance of the quality of the data 
obtained from nonIND foreign studies. It has become increasingly 
recognized that the development of data that are scientifically sound 
is a critical responsibility of investigators and sponsors and is part 
of a responsible relationship between these entities and study 
subjects. The 1989 Declaration endorses this view but does not address 
in detail how to ensure study quality. The 1989 Declaration notes that 
it is unethical to enroll human subjects in poorly designed or 
conducted clinical trials because subjects may be exposed to risks 
without the opportunity for potential benefit, but the Declaration does 
not provide guidance on how to ensure proper conduct of trials. The 
proposed revisions to Sec.  312.120 seek to help ensure data quality 
and integrity in several ways including the following: (1) Specifying 
that GCP includes providing assurance that study data and reported 
results are credible and accurate and (2) requiring that supporting 
information on a nonIND foreign clinical study include a description of 
how the sponsor monitored the trial and ensured that the study was 
carried out consistent with the study protocol.
    The informed consent provisions embodied in GCP also may contribute 
to the integrity of data obtained in clinical studies. The informed 
consent process enables each subject to receive high-quality 
information about the consequences of participating in the clinical 
trial. The process also provides an opportunity for the subject and 
investigator to discuss important information about the subject's 
condition, potential adverse events, and other factors (such as use of 
concurrent therapy, illegal drug use, or alcohol abuse) that could 
confound the study results if they remained undisclosed.
3. Eliminating Reference to the Declaration
    Finally, we also are issuing this proposed rule to eliminate the 
reference in Sec.  312.120 to the Declaration. The Declaration is a 
document that is subject to change independent of FDA authority. As a 
result, it could be modified to contain provisions that are 
inconsistent with U.S. laws and regulations. Although revisions to the 
Declaration could not supersede U.S. laws and regulations, such changes 
could create the potential for confusion about the requirements for 
nonIND foreign studies.

C. Consultation with FDA

    We are confident that the requirements in proposed Sec.  312.120 
will facilitate our acceptance for review of data obtained from foreign 
studies in support of INDs and U.S. marketing applications. As always, 
we encourage applicants to meet with responsible officials in FDA's 
Center for Drug Evaluation and Research (CDER) or FDA's Center for 
Biologics Evaluation and Research (CBER) as early as possible in the 
development of a drug or biological product to determine if a 
particular foreign clinical study appears to meet the standards for 
acceptance for review.

II. Description of the Proposed Rule

A. Definitions

    We propose to add under Sec.  312.3, under definitions and 
interpretations, a definition for IEC. We propose to define an IEC as a 
``review panel 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''. An adequately constituted IEC includes a reasonable 
number of members with the qualifications and experience to perform the 
IEC's functions (see, e.g., section 3.2.1 of the Good Clinical Practice 
guidance). The definition of independent ethics committee also 
specifies that an IRB, as defined in Sec.  56.102(g) and subject to the 
requirements of part 56, is one type of IEC.

B. Requirements for Acceptance as Support for an IND or Marketing 
Application

    Current Sec.  312.120(a) states that the provision describes the 
criteria for acceptance by FDA of foreign clinical studies not 
conducted under an IND. It

[[Page 32469]]

states that, in general, FDA accepts such studies provided they are 
well-designed, well-conducted, performed by qualified investigators, 
and conducted in accordance with ethical principles acceptable to the 
world community. Section 312.120(a) further states that studies meeting 
these criteria may be utilized to support clinical investigations in 
the United States and/or marketing approval. Finally, Sec.  312.120(a) 
states that marketing approval of a new drug based solely on foreign 
clinical data is governed by Sec.  314.106.
    Current Sec.  312.120(c)(1) states that foreign clinical research 
is required to have been conducted in accordance with the ethical 
principles stated in the Declaration (which is set forth in current 
Sec.  312.120(c)(4)) or the laws and regulations of the country in 
which the research was conducted, whichever represents the greater 
protection of the individual. Section 312.120(c)(2) states that for 
each foreign clinical study submitted under Sec.  312.120, the sponsor 
must explain how the research conformed to the ethical principles in 
the Declaration or the foreign country's standards, whichever were 
used. Under Sec.  312.120(c)(3), when the research has been approved by 
an independent review committee, the sponsor must submit to FDA 
documentation of such review and approval, including the names and 
qualifications of the members of the committee. A ``review committee'' 
means a committee composed of scientists and, where practicable, 
individuals who are otherwise qualified (e.g., other health 
professionals or laymen). Section 312.120(c)(3) further states that the 
investigator may not vote on any aspect of the review of his or her 
protocol by a review committee.
    We are proposing to revise the conditions under which we will 
accept, as support for an IND or marketing application for a drug or 
biologic, a foreign clinical study not conducted under an IND, 
principally by specifically requiring conformance with GCP, including 
review and approval by an IEC, and by deleting the reference to the 
Declaration. Under proposed Sec.  312.120(a)(1), we would accept as 
support for an IND, NDA, or BLA a well-designed and well-conducted 
foreign clinical study not conducted under an IND if two conditions are 
met. The first condition, stated in proposed Sec.  312.120(a)(1)(i), is 
that the study was conducted in accordance with GCP. For purposes of 
this section, GCP would be defined as a standard for the design, 
conduct, performance, monitoring, auditing, recording, analysis, and 
reporting of clinical trials in a way that provides assurance that the 
data and reported results are credible and accurate and that the 
rights, safety, and well-being of trial subjects are protected. 
Proposed Sec.  312.120(a)(1)(i) states that GCP includes review and 
approval (or provision of a favorable opinion) by an IEC\2\ before 
initiating a study, continuing review of an ongoing study by an IEC, 
and obtaining and documenting the freely given informed consent of a 
subject (or the subject's legally authorized representative if the 
subject is unable to provide informed consent) before initiating a 
study. Proposed Sec.  312.120(a)(1)(i) further states that GCP does not 
require informed consent in life-threatening situations when the IEC 
reviewing the study finds that the conditions present are consistent 
with those described in Sec.  50.23 or Sec.  50.24(a) of this chapter 
(concerning exemptions from informed consent requirements in life-
threatening situations), or when the measures described in the study 
protocol or elsewhere will protect the rights, safety, and well-being 
of subjects and ensure compliance with applicable regulatory 
requirements. This provision would be consistent with the Good Clinical 
Practice guidance, which recommends that a legally authorized 
representative provide informed consent or that the requirement of 
informed consent be waived under such circumstances.
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    \2\ See, e.g., section 1.27 of the Good Clinical Practice 
guidance, stating that an IEC either approves or provides a 
favorable opinion on matters such as trial protocols, the 
suitability of investigators, and the methods and materials used in 
obtaining and documenting informed consent.
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    Proposed Sec.  312.120(a)(1)(ii) states the second condition for 
our acceptance of a nonIND foreign study as support for an IND, NDA, or 
BLA. We must be able to validate the data from the study through an 
onsite inspection if the agency deems it necessary. The ability to 
inspect records relating to a foreign study is essential to our ability 
to resolve any uncertainties about whether the study was conducted in 
accordance with GCP.
    Proposed Sec.  312.120(a)(2) states that although we will not 
accept as support for an IND, NDA, or BLA a study that does not meet 
the conditions of Sec.  312.120(a)(1), we will examine data from such a 
study. We remind sponsors and applicants that they must submit all 
studies and other information required under applicable FDA regulations 
for drugs and biologics, including Sec. Sec.  314.50, 314.80, 314.81, 
600.80 (21 CFR 600.80), and 601.2. For example, as part of our review 
of an NDA, we consider all relevant data bearing on the safe use of the 
proposed drug product, including data obtained in any foreign clinical 
studies not conducted under an IND--even data from studies that are not 
carried out in accordance with GCP.
    Proposed Sec.  312.120(a)(3) reiterates the statement in current 
Sec.  312.120(a) that marketing approval of a new drug based solely on 
foreign clinical data is governed by Sec.  314.106.

C. Requirements for Supporting Information

    Under current Sec.  312.120(b)(1) through (b)(5), a sponsor who 
wishes to rely on a foreign clinical study to support an IND or to 
support an application for marketing approval must submit to FDA the 
following information:
     A description of the investigator's qualifications;
     A description of the research facilities;
     A detailed summary of the protocol and results of the 
study, and, if FDA requests, case records maintained by the 
investigator or additional background data such as hospital or other 
institutional records;
     A description of the drug substance and drug product used 
in the study, including a description of components, formulation, 
specifications, and bioavailability of the specific drug product used 
in the clinical study, if available; and
     If the study is intended to support the effectiveness of a 
drug product, information showing that the study is adequate and well 
controlled under Sec.  314.126.
    Proposed Sec.  312.120(b) would retain the requirements listed in 
the previous paragraphs and would add certain requirements concerning 
IECs and other aspects of GCP. Under proposed Sec.  312.120(b), a 
sponsor or applicant who submits data from a foreign clinical study not 
conducted under an IND as support for IND, NDA, or BLA must submit to 
FDA, in addition to information required elsewhere in parts 312, 314, 
or 601, respectively, a description of the actions the sponsor or 
applicant took to ensure that the research conformed to GCP as 
described in Sec.  312.120(a)(1)(i). Under proposed Sec.  312.120(b)(1) 
through (b)(11), the description would include the following 
information:
     The investigator's qualifications;
     A description of the research facilities;
     A detailed summary of the protocol and results of the 
study, and, at FDA's request, case records maintained by the 
investigator or additional background data such as hospital or other 
institutional records;

[[Page 32470]]

     A description of the drug substance and drug product used 
in the study, including a description of the components, formulation, 
specifications, and, if available, bioavailability of the specific drug 
product used in the clinical study;
     If the study is intended to support the effectiveness of a 
drug product, information showing that the study is adequate and well-
controlled under Sec.  314.126;
     The names and qualifications of the members of the IEC 
that reviewed the study;
     A summary of the IEC's decision to approve or modify and 
approve the study, or to provide a favorable opinion;
     A description of how informed consent was obtained;
     A description of what incentives, if any, were provided to 
subjects to participate in the study;
     A description of how the sponsor(s) monitored the study 
and ensured that the study was carried out consistent with the study 
protocol; and
     A description of how investigators were trained to comply 
with GCP (as described in Sec.  312.120(a)(1)(i)) and to conduct the 
study in accordance with the study protocol, and copies of written 
commitments, if any, by investigators to comply with GCP and the 
protocol.
    We would encourage, but not require, sponsors to obtain written 
commitments by investigators to comply with GCP and the study protocol. 
If such commitments were obtained, the proposed rule would require that 
copies of the commitments be included in the supporting information for 
a nonIND foreign study.
    We believe that this proposed documentation, combined with an 
onsite inspection, if necessary, would provide us with the ability to 
determine whether a particular foreign clinical study had been 
conducted in accordance with GCP.

D. Requirements for Waiver Requests

    Under proposed Sec.  312.120(c)(1), a sponsor or applicant may 
submit a request to FDA to waive any applicable requirements under 
proposed Sec.  312.120(a)(1) and (b). A waiver request would be 
submitted in an IND or in an information amendment to an IND, or in an 
application or in an amendment or supplement to an application 
submitted under part 314 or 601. Proposed Sec.  312.120(c)(1) further 
states that under proposed Sec.  312.120(c)(1)(i) through (c)(1)(iii), 
the waiver request must contain at least one of the following:
     An explanation why the sponsor's or applicant's compliance 
with the requirement is unnecessary or cannot be achieved;
     A description of an alternative submission or course of 
action that satisfies the purpose of the requirement; or
     Other information justifying a waiver.
    Under proposed Sec.  312.120(c)(2), FDA may grant a waiver if it 
finds that doing so would be in the interest of the public health. For 
example, we may determine that a waiver is in the interest of the 
public health if alternative procedures used by the sponsor or 
applicant satisfy the purpose of these regulations.

III. Legal Authority

    We are proposing to issue this rule under the authority of the 
provisions of the Federal Food, Drug, and Cosmetic Act (the act) that 
apply to drugs (21 U.S.C. 201 et seq.) and section 351 of the Public 
Health Service Act (the PHS Act) (42 U.S.C. 262). These laws authorize 
us to issue regulations to ensure the following: (1) Data that we 
review are of adequate quality to enable us to make appropriate 
regulatory decisions; (2) clinical investigators involved in developing 
data submitted to us are qualified to conduct such clinical 
investigations and are otherwise reliable; and (3) clinical 
investigations generating data submitted in support of applications are 
well designed and well conducted in a manner supporting the reliability 
of study results.
    Section 505 of the act (21 U.S.C. 355) requires us to weigh 
evidence of effectiveness and safety to determine whether the evidence 
supports drug approval, whether data are adequate to permit a clinical 
investigation to proceed under the IND regulations, and/or whether a 
product is appropriately labeled. Section 505(d) of the act provides 
that we may approve an NDA only after finding substantial evidence as 
follows:
    ``[c]onsisting of adequate and well-controlled investigations, 
including clinical investigations, by experts qualified by 
scientific training and experience to evaluate the effectiveness of 
the drug involved, on the basis of which it could fairly and 
responsibly be concluded by such experts that the drug will have the 
effect it purports or is represented to have under the conditions of 
use prescribed, recommended, or suggested in the labeling or 
proposed labeling thereof.''
    When we review INDs, section 505(i) of the act requires us to 
determine whether the reports submitted in support of an application 
are ``adequate to justify the proposed clinical testing'' and whether 
the sponsor has submitted ``adequate reports of basic information * * * 
necessary to assess the safety of the drug for use in clinical 
investigation.''
    The act also requires us to determine whether adequate and reliable 
studies are sufficient to support a drug's labeling. Under section 
505(d)(5) of the act, evidence from clinical investigations of a drug's 
safety and effectiveness must support the conditions of use prescribed, 
recommended, or suggested in the labeling thereof.
    Section 701(a) of the act (21 U.S.C. 371(a)) vests in the Secretary 
of the Department of Health and Human Services (the Secretary) (who has 
delegated it to FDA) the authority to issue regulations for the 
efficient enforcement of the act.
    Section 351(a)(2)(B)(i)(I) of the PHS Act authorizes us (by 
delegation from the Secretary) to approve a BLA only if the applicant 
demonstrates that the product is safe, pure, and potent. Section 
351(a)(2)(A) of the PHS Act authorizes us (by delegation from the 
Secretary) to establish, by regulation, requirements for the approval, 
suspension, and revocation of biologics licenses.
    These statutory provisions authorize us to issue regulations 
describing when we may consider foreign clinical trials not conducted 
under the IND regulations as reliable evidence supporting an IND, NDA, 
or BLA.

IV. Analysis of Economic Impacts

    FDA has examined the impacts of the proposed rule under Executive 
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612), and 
the Unfunded Mandates Reform Act of 1995 (Public Law 104-4). Executive 
Order 12866 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). We believe that this 
proposed rule is consistent with the regulatory philosophy and 
principles identified in the Executive order. In addition, the proposed 
rule is not an economically significant regulatory action as defined by 
the Executive order and so is not subject to review under the Executive 
order.
    The Regulatory Flexibility Act requires agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. Because the estimated impact of the proposed rule is 
not substantial and, in any event, clinical investigators generally 
follow GCP already, the

[[Page 32471]]

agency certifies that the proposed rule will not have a significant 
economic impact on a substantial number of small entities. Therefore, 
under the Regulatory Flexibility Act, no further analysis is required.
    Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires 
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 an 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. The current threshold after adjustment for 
inflation is $110,000,000. FDA does not expect this proposed rule to 
result in any 1-year expenditure that would meet or exceed this amount.

A. Objectives of the Proposed Rule

    The objectives of the proposed rule are to ensure the quality and 
integrity of foreign clinical data supporting FDA decisionmaking on 
product applications and to help ensure the protection of human 
subjects participating in foreign clinical studies. High-quality data 
from foreign studies may be critical to the agency's decisionmaking on 
applications and product labeling. By increasing our knowledge of a 
drug, including its effect in more diverse study populations, such data 
will help us better perform these review functions.
    By incorporating the monitoring and reporting responsibilities 
under GCP, the proposed rule also would reduce the risk to subjects who 
take part in foreign clinical trials of investigational drug and 
biological products. Most investigations of new therapeutic products 
carry potential risks for trial subjects due to the investigational 
nature of the products. However, if trials are well-designed and 
carefully monitored, these risks can be minimized.

B. Background on Current Situation Regarding Foreign Studies

    The current process for marketing a new drug product or amending 
the conditions of use of an existing product requires us to review and 
approve the results of clinical investigations included in NDAs and 
BLAs. These applications contain the results of clinical investigations 
that characterize the therapeutic benefit of the new product and assess 
its risks. FDA reviews the submitted data and decides whether there is 
sufficient evidence of safety and effectiveness to grant approval.
    Clinical data included in a marketing application usually are 
collected under an IND, to which protocols of the proposed clinical 
investigations are submitted for review. An IND is needed to lawfully 
administer an unapproved pharmaceutical or biological product to humans 
in the United States. However, not all clinical trials used to support 
an NDA or BLA take place in the United States. For a variety of reasons 
(e.g., foreign developer or manufacturer), there has been an increase 
in the number of foreign clinical investigations of potential new drug 
products. According to an analysis by the Department of Health and 
Human Services' Office of the Inspector General (OIG) (Ref. 1), the 
number of foreign clinical investigators that conducted drug research 
under INDs increased from 41 in 1980 to 271 in 1990, and 4,458 in 1999. 
Although trials not conducted in the United States are not required to 
be conducted under an IND, many sponsors submit an IND before 
initiating a foreign trial. FDA has always required and reviewed the 
safety results of nonIND foreign clinical trials of drug products 
considered for marketing approval in the United States.
    According to CDER and CBER estimates, approximately 650 clinical 
investigations of investigational products intended for commercial 
marketing were initiated each year over the last 5 years. In addition, 
commercial sponsors submitted approximately 2,600 new protocols each 
year for new clinical trials under existing INDs. Therefore, in a 
typical recent year, we received approximately 3,250 new investigations 
(initial INDs and new protocols combined) for commercial development of 
new therapies.
    A CDER study of the INDs submitted to support development of new 
molecular entities (NMEs) approved between 1995 and 1999 found that up 
to 35 percent of the trials that were conducted under an IND included 
foreign sites. Thus, in an average year, we estimate that approximately 
1,140 foreign clinical trials (3,250 x 0.35) are conducted under IND 
review and oversight. However, this estimate does not include foreign 
clinical trials that were not subject to IND review. The CDER analysis 
indicates that as many as 15 percent of the trials submitted in NME 
marketing applications were not conducted under an IND. If this 
proportion holds with respect to all clinical trials, we estimate that 
approximately 3,825 clinical trials are conducted annually to develop 
data for submission to FDA in support of a marketing application 
(assuming the 3,250 clinical trials conducted annually under an IND 
constitute only 85 percent of all trials conducted to develop data for 
such an application). We can then estimate that 575 nonIND foreign 
trials are conducted annually for eventual submission to FDA as part of 
a research or marketing application (3,825 - 3,250 = 575).
    We also estimated the applications supported by data from foreign 
trials not conducted under an IND. According to CDER data, each 
marketing application may cite an average of approximately five 
investigations that provide important information relative to approval 
decisions. Lacking data on INDs, we will assume the same ratio of 
investigations to applications is true for trials that support an IND. 
Based on these estimates, we estimate that the 575 foreign trials 
conducted annually are used to support 115 research or marketing 
applications.

C. The Proposed Rule

    We are proposing that all nonIND foreign clinical research 
submitted as support for an IND or marketing application be conducted 
under GCP as defined in the proposed rule. Currently, we accept as 
support for an IND or marketing application foreign clinical studies 
not conducted under an IND provided they are well-designed, well-
conducted, performed by qualified investigators, and conducted in 
accordance with ethical principles. Sponsors of nonIND investigations 
used in support of INDs or marketing applications must either follow 
the principles of the 1989 Declaration for patient protection or 
national laws that provide even greater protection. The proposed 
regulations on acceptance of nonIND foreign studies are expected to 
provide greater assurance that such clinical investigations will 
provide results that are of satisfactory quality while ensuring that 
the investigations are conducted with subjects' informed consent and do 
not place subjects unduly at risk. We believe that this change is 
necessary to ensure that foreign clinical investigations that are 
intended to be used as support for an IND or U.S. marketing application 
are well-designed and well-conducted and provide sufficient protection 
to subjects. Consequently, under the proposed rule, we would not accept 
any nonIND foreign clinical results as support for sponsor claims of 
efficacy unless the trials were conducted in conformance with GCP. The 
results of all clinical trials must in any case be submitted with new 
product applications to evaluate the safety of the new therapy.

[[Page 32472]]

D. Costs of the Proposed Rule

    We interviewed seven pharmaceutical manufacturers that had 
submitted results from nonIND foreign clinical studies to us during 
1998 through 2001. These firms indicated that they currently conduct 
all research, including investigations not conducted under an IND, in 
accordance with ICH standards for GCP. However, the proposed regulation 
would require that an applicant submit a description of the actions 
taken to ensure that the research conformed to GCP. Several items 
included in GCP (as defined in the proposed regulation) are not 
specifically required to be documented and submitted in a marketing 
application for results to be accepted by FDA. In particular, 
documentation that includes attestations by investigators and evidence 
that study protocols have been reviewed and approved by an IEC is not 
always included in INDs and marketing applications. For studies under 
an IND, there are specific regulatory requirements for obtaining 
informed consent, ensuring IRB review, and carrying out appropriate 
monitoring. The absence of these requirements for nonIND studies makes 
it difficult for us to determine the adequacy of preinitiation review 
of study protocols. The proposed rule would help ensure that these 
documents are available for our inspection at research sites and that 
information on IEC review is included in INDs and marketing 
applications.
    The amount and detail of the necessary documentation would vary 
according to the size and complexity of the proposed clinical trial. 
The general position among the seven sponsors we interviewed was that 
providing a description of their compliance with GCP, including related 
documentation and recordkeeping, would take between 18 and 32 
additional hours for each nonIND clinical trial.
    We obtained information on typical nonproduction, salaried labor 
costs for the pharmaceutical industry from the Bureau of Labor 
Statistics (North American Industrial Classification System (NAICS) 
325412). Including wages and benefits, the average cost for these labor 
resources is slightly more than $30 per hour. As previously noted in 
this document, we estimate that approximately 575 nonIND foreign 
commercial clinical trials are conducted annually. Using the high 
estimate of the additional hours of documentation needed for each 
nonIND clinical trial, this would result in a total annual cost of 
about $552,000 to the sponsoring firms (32 hours x 575 nonIND foreign 
trials x $30 = $552,000).

E. Benefits of the Proposed Rule

    We believe that improvement in the conduct of clinical trials will 
improve the quality of clinical data submitted, allowing these data to 
provide support for marketing applications. We further believe that the 
proposed rule would decrease the likelihood that subjects in foreign 
clinical trials will be placed unnecessarily at risk.
    We have not quantified the benefit of improvements in the data 
being included with marketing applications resulting from the use of 
GCP in lieu of current requirements. However, if these data were 
determined to be adequate to support an application, beneficial 
therapies could become available earlier. Similarly, we expect that the 
greater integrity of data from nonIND studies would result in an 
additional benefit, also difficult to quantify, due to greater public 
confidence in the scientific basis for FDA decisions.

F. Small Business Impact

    The proposed rule is not expected to have a significant impact on a 
substantial number of small entities. Nevertheless, we have prepared a 
voluntary regulatory flexibility analysis.
1. Nature of the Impact
    As previously discussed in this document, we estimate that the 
proposed rule would increase total costs to sponsors of foreign 
clinical studies by approximately $552,000 per year. The increased 
costs would be due to greater costs of review and documentation of the 
approval of study protocols by IECs. The resources needed to comply 
with this proposal are not specialized. Assuming, for purposes of this 
calculation, that each of the approximately 115 marketing or research 
applications submitted annually (in which are reported approximately 
575 nonIND foreign clinical studies) is submitted by a different 
sponsor, each sponsor would incur costs of approximately $4,800 per 
year to comply with this proposal ($552,000 / 115 = $4,800).
2. The Affected Industry
    The Census of Manufacturers defines the pharmaceutical preparations 
industry in NAICS 325412. This industry consists of 712 companies and 
837 establishments. Average revenues per company are over $100 million 
annually.
    However, the Small Business Administration has defined any entity 
with 750 or fewer employees as a small entity. According to the Census 
of Manufacturers, approximately 95 percent of the industry 
establishments would meet this criterion. With the industry-wide 
average of approximately 1.2 establishments per company, it is likely 
that at least 90 percent of the companies would be considered small 
entities.
    On the other hand, the proportion of sponsors that submit original 
marketing applications is markedly different from the general industry. 
FDA examined the characteristics of sponsors of new drug product 
marketing applications between October 1996 and October 1999 (Ref. 2). 
Of the 158 firms that had sponsored marketing applications during that 
period, 56 (or about 33 percent) were considered domestic small 
entities (750 or fewer employees). The remaining firms were either 
foreign sponsors or large innovating enterprises. The 56 small firms 
submitted a total of 76 NDAs during that period, which is about 1.5 
applications each over a 3-year period (or 0.5 annually per small 
entity).
    The 76 NDAs submitted by small domestic entities represented about 
20 percent of all applications. Using this proportion, we estimate that 
20 percent of the 575 annual nonIND foreign clinical trials to develop 
data for submission in an FDA marketing application (approximately 115 
studies) could be sponsored by small entities. If these trials were 
distributed equally among each sponsoring small entity, each sponsor 
would be expected to conduct two nonIND clinical trials per year. If 
so, the compliance costs would equal about $9,600 annually per small 
entity ($4,800 x 2 = $9,600).
    The Census of Manufacturers also reports that a sizable proportion 
of the industry has an annual value of shipments of approximately $1 
million. For example, a reported 494 of the 837 establishments had 
total shipments of approximately $480 million during 1997. The expected 
cost of $9,600 per small firm would not represent a significant impact.
3. Alternatives to the Proposed Rule
    FDA considered several alternatives to the proposed rule. We 
rejected leaving Sec.  312.120 unchanged because it would not meet the 
objectives of enhancing standards for study conduct and ensuring data 
integrity. We rejected other regulatory options to increase our 
oversight of foreign clinical investigations because they would be 
either too costly or unenforceable. We considered changing the 
inspection strategy for foreign clinical trials, but this option would 
not ensure GCP compliance, a process that makes all parties to a study 
responsible for patient safety and study quality. We considered

[[Page 32473]]

but rejected allowing an exemption from the requirements in the 
proposed rule for small entities. We must have confidence that all 
clinical investigations submitted as support for a research or 
marketing application meet basic standards of reliability, patient 
safety, and data quality.
4. Outreach
    We are publishing this proposed rule in anticipation of receiving 
comments from affected small entities. The proposed rule is available 
to all interested parties through FDA's Internet Web site at http://www.fda.gov.
5. Conclusion
    For the reasons previously stated, we conclude that the proposed 
rule would not result in a significant impact on a substantial number 
of small entities.

G. References

    The following references have been placed on display in the 
Division of Dockets Management (see ADDRESSES) and may be seen by 
interested persons between 9 a.m. and 4 p.m., Monday through Friday.
    1. Department of Health and Human Services, Office of the 
Inspector General, ``The Globalization of Clinical Trials: A Growing 
Challenge in Protecting Human Subjects,'' OEI-01-00-00190, September 
2001.
    2. FDA, ``Who Submits NDAs and ANDAs,'' unpublished document, 
October 1999.

V. Environmental Impact

    FDA has determined under 21 CFR 25.30(h) that this action is of a 
type that does not individually or cumulatively have a significant 
effect on the human environment. Therefore, neither an environmental 
assessment nor an environmental impact statement is required.

VI. Paperwork Reduction Act of 1995

    This proposed rule contains information collection requirements 
that are subject to review by OMB under the Paperwork Reduction Act of 
1995 (the PRA) (44 U.S.C. 3501-3520). The title, description, and 
respondent description of the information collection provisions are 
shown below with an estimate of the annual reporting and recordkeeping 
burden. Included in the estimate is the time for reviewing 
instructions, searching existing data sources, gathering and 
maintaining the data needed, and completing and reviewing each 
collection of information.
    FDA invites comments on these topics: (1) Whether the collection of 
information is necessary for the proper performance of FDA's functions, 
including whether the information will have practical utility; (2) the 
accuracy of FDA's estimate of the burden of the proposed collection of 
information, 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.
    Title: Foreign Clinical Studies Not Conducted Under an IND
    Description: Current Sec.  312.120 states that we generally accept 
foreign clinical studies not conducted under an IND provided they are 
well-designed, well-conducted, performed by qualified investigators, 
and conducted in accordance with ethical principles. Such studies must 
be conducted in accordance with the 1989 Declaration or the laws of the 
country in which the research is conducted, whichever provides greater 
protection to subjects.
    The proposed rule would replace the requirement that nonIND foreign 
studies be conducted in accordance with the 1989 Declaration with a 
requirement to conduct such studies in accordance with GCP, including 
review and approval by an IEC. We are proposing this change for the 
following reasons: (1) We want to provide greater assurance of the 
quality of data obtained from nonIND foreign studies, (2) standards for 
protecting human subjects have evolved considerably over the past 
decade and include the adoption of GCP, and (3) we want to eliminate 
the reference in current Sec.  312.120 to the Declaration because that 
document is subject to change, independent of FDA authority, in a 
manner that is inconsistent with U.S. laws and regulations.
    Under proposed Sec.  312.120(a), we would accept for review as 
support for an IND, NDA, or BLA a well-designed and well-conducted 
foreign clinical study not conducted under an IND if the study were 
conducted in accordance with GCP and we were able to validate the data 
from the study through an onsite inspection if necessary. GCP would 
include review and approval by an IEC before initiating a study, 
continuing review of an ongoing study by an IEC, and obtaining and 
documenting the freely given informed consent of the subject before 
initiating a study.
    Current Sec.  312.120(b) requires a sponsor of a nonIND foreign 
study who wants to rely on that study as support for an IND or 
marketing application to provide certain data to FDA. Proposed Sec.  
312.120(b) would require this same information as well as the following 
information: (1) A description of the IEC and its decision to approve, 
or modify and approve, the study; (2) a description of how informed 
consent was obtained and what incentives, if any, were provided to 
subjects to participate in the study; (3) a description of how the 
sponsor monitored the trial and ensured that it was carried out 
consistent with the study protocol; and (4) a description of how 
investigators were trained to comply with GCP and to conduct the trial 
in accordance with the protocol, as well as copies of any written 
commitments by investigators to comply with GCP and the protocol.
    Proposed Sec.  312.120(c) would specify how sponsors or applicants 
could request a waiver for any of the requirements under Sec.  
312.120(a)(1) and (b). By permitting a waiver of certain requirements, 
this provision is not likely to increase the burden on a sponsor or 
applicant. Under proposed Sec.  312.120(c)(1), the waiver request would 
contain at least one of the following requirements: (1) An explanation 
why the sponsor's or applicant's compliance with the requirement is 
unnecessary or cannot be achieved, (2) a description of an alternative 
submission or course of action that satisfies the purpose of the 
requirement, or (3) other information justifying a waiver. Under 
proposed Sec.  312.120(c)(2), FDA may grant a waiver if doing so would 
be in the interest of the public health.
    Description of Respondents: Businesses.
    Burden Estimate: Table 1 of this document provides an estimate of 
the annual reporting burden associated with the proposed rule.

[[Page 32474]]



                                                     Table 1.--Estimated Annual Reporting Burden\1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                      Frequency of          Total Annual
              21 CFR Section                 No. of Respondents         Responses             Responses        Hours per Response        Total Hours
--------------------------------------------------------------------------------------------------------------------------------------------------------
312.120(d)                                         115                     5                   575                    32                18,400
Total                                       ....................  ....................  ....................  ....................      18,400
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of information.

    We estimate that, each year, 115 companies submit a total of 
approximately 575 nonIND foreign clinical studies in support of an IND 
or marketing application for a drug or biological product. We conducted 
consultations with seven large and small companies that had submitted 
nonIND foreign clinical studies to us within the past 3 years. All 
respondents indicated that they currently conduct nonIND foreign 
clinical studies in conformance with GCP and generally document all the 
items listed in proposed Sec.  312.120(b). Sponsors often plan to 
obtain marketing approval in more than one country and often conduct 
studies with the intention to submit data for review in multiple 
countries that may require compliance with GCP. Companies currently are 
required (under Sec.  312.120(b)(1) through (b)(5) and (c)(3)) to 
document the items in proposed Sec.  312.120(b)(1) through (b)(7) as 
well as to document how the research conformed to the ethical 
principles contained in the 1989 Declaration or the foreign country's 
standards, whichever represents the greater protection of the 
individual (current Sec.  312.120(c)(2)).
    Hour burden estimates will vary due to differences in size, 
complexity, and duration across studies, because each of these factors 
affects the amount and intricacy of data collected. For example, the 
applicant of a study that involves five research sites each with its 
own IEC must submit documentation of review by all five committees. 
However, if the same study is performed with one IEC overseeing all 
five sites, the hour burden estimate would be less.
    As previously stated in this document, the general position among 
the sponsors that we interviewed was that documenting their compliance 
with GCP would take between 18 and 32 hours annually for each nonIND 
foreign clinical trial. To provide a liberal estimate of costs to 
industry, we will assume that no companies currently document 
compliance with any component of GCP and that the documentation 
required under proposed Sec.  312.120(b) would require 32 hours to 
complete for each study submitted for a total of 18,400 annual burden 
hours (575 x 32 hours).
    In compliance with the PRA (44 U.S.C. 3507(d)), we have submitted 
the information collection requirements of this rule to OMB for review. 
Interested persons are requested to fax comments regarding information 
collection to the Office of Information and Regulatory Affairs, OMB, 
Attn: Fumie Yokota, Desk Officer for FDA, FAX: 202-395-6974.

VII. Federalism

    We have analyzed this proposed rule in accordance with the 
principles set forth in Executive Order 13132. We have determined that 
the rule does not contain policies that have substantial direct effects 
on the States, on the relationship between the National Government and 
the States, or on the distribution of power and responsibilities among 
the various levels of government. Accordingly, we have concluded that 
the proposed rule does not contain policies that have federalism 
implications as defined in the Executive order and, consequently, a 
federalism summary impact statement is not required.

VIII. Proposed Effective Date

    We propose to apply any final rule that may issue based on this 
proposal to foreign clinical studies for which the first subject is 
enrolled 180 days after the final rule is published in the Federal 
Register.

IX. Request for Comments

    Interested persons may submit to the Division of Dockets Management 
(see ADDRESSES) written or electronic comments on this proposal. Two 
paper copies of any comments are to be submitted, except that 
individuals may submit one paper copy. Comments are to be identified 
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.

List of Subjects in 21 CFR Part 312

    Drugs, Exports, Imports, Investigations, Labeling, Medical 
research, Reporting and recordkeeping requirements, Safety.
    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, FDA proposes 
that 21 CFR part 312 be amended to read as follows:

PART 312--INVESTIGATIONAL NEW DRUG APPLICATION

    1. The authority citation for 21 CFR part 312 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 371; 42 
U.S.C. 262.

    2. Section 312.3 is amended in paragraph (b) by alphabetically 
adding the definition for ``Independent ethics committee'' to read as 
follows:


Sec.  312.3  Definitions and interpretations.

* * * * *
    Independent ethics committee (IEC) means a review panel 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. An 
institutional review board (IRB), as defined in Sec.  56.102(g) of this 
chapter and subject to the requirements of part 56, is one type of IEC.
* * * * *
    3. Section 312.120 is revised to read as follows:


Sec.  312.120  Foreign clinical studies not conducted under an IND.

    (a) Acceptance of studies. (1) FDA will accept as support for an 
IND, a new drug application (NDA), or a biologics license application 
(BLA) a well-designed and well-conducted foreign clinical study not 
conducted under an IND, if the following conditions are met:
    (i) The study was conducted in accordance with good clinical 
practice (GCP). For the purposes of this section, GCP is defined as a 
standard for the design, conduct, performance, monitoring, auditing, 
recording, analysis, and reporting of clinical trials in a way that 
provides assurance that the data and reported results are credible and 
accurate and that the rights, safety, and well-being of trial subjects 
are protected. GCP includes review and approval (or provision of a 
favorable opinion) by an independent ethics committee (IEC) before 
initiating a study, continuing review of an

[[Page 32475]]

ongoing study by an IEC, and obtaining and documenting the freely given 
informed consent of the subject (or a subject's legally authorized 
representative, if the subject is unable to provide informed consent) 
before initiating a study. GCP does not require informed consent in 
life-threatening situations when the IEC reviewing the study finds that 
the conditions present are consistent with those described in 
Sec. Sec.  50.23 or 50.24(a) of this chapter, or when the measures 
described in the study protocol or elsewhere will protect the rights, 
safety, and well-being of subjects and ensure compliance with 
applicable regulatory requirements; and
    (ii) FDA is able to validate the data from the study through an 
onsite inspection if the agency deems it necessary.
    (2) Although FDA will not accept as support for an IND, NDA, or BLA 
a study that does not meet the conditions of paragraph (a)(1) of this 
section, FDA will examine data from such a study.
    (3) Marketing approval of a new drug based solely on foreign 
clinical data is governed by Sec.  314.106 of this chapter.
    (b) Supporting information. A sponsor or applicant who submits data 
from a foreign clinical study not conducted under an IND as support for 
an IND, NDA, or BLA must submit to FDA, in addition to information 
required elsewhere in parts 312, 314, or 601 of this chapter, 
respectively, a description of the actions the sponsor or applicant 
took to ensure that the research conformed to GCP as described in 
paragraph (a)(1)(i) of this section. The description must include the 
following:
    (1) The investigator's qualifications;
    (2) A description of the research facilities;
    (3) A detailed summary of the protocol and results of the study 
and, should FDA request, case records maintained by the investigator or 
additional background data such as hospital or other institutional 
records;
    (4) A description of the drug substance and drug product used in 
the study, including a description of the components, formulation, 
specifications, and, if available, bioavailability of the specific drug 
product used in the clinical study;
    (5) If the study is intended to support the effectiveness of a drug 
product, information showing that the study is adequate and well-
controlled under Sec.  314.126 of this chapter;
    (6) The names and qualifications for the members of the IEC that 
reviewed the study;
    (7) A summary of the IEC's decision to approve or modify and 
approve the study, or to provide a favorable opinion;
    (8) A description of how informed consent was obtained;
    (9) A description of what incentives, if any, were provided to 
subjects to participate in the study;
    (10) A description of how the sponsor(s) monitored the study and 
ensured that the study was carried out consistent with the study 
protocol; and
    (11) A description of how investigators were trained to comply with 
GCP (as described in paragraph (a)(1)(i) of this section) and to 
conduct the study in accordance with the study protocol, and copies of 
written commitments, if any, by investigators to comply with GCP and 
the protocol.
    (c) Waivers. (1) A sponsor or applicant may request FDA to waive 
any applicable requirements under paragraphs (a)(1) and (b) of this 
section. A waiver request may be submitted in an IND or in an 
information amendment to an IND, or in an application or in an 
amendment or supplement to an application submitted under part 314 or 
601 of this chapter. A waiver request is required to contain at least 
one of the following:
    (i) An explanation why the sponsor's or applicant's compliance with 
the requirement is unnecessary or cannot be achieved;
    (ii) A description of an alternative submission or course of action 
that satisfies the purpose of the requirement; or
    (iii) Other information justifying a waiver.
    (2) FDA may grant a waiver if it finds that doing so would be in 
the interest of the public health.

    Dated: February 16, 2004.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 04-13063 Filed 6-9-04; 8:45 am]
BILLING CODE 4160-01-S