[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: [email protected]. 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;
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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
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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