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[Federal Register Volume 73, Number 82 (Monday, April 28, 2008)]
[Rules and Regulations]
[Pages 22800-22816]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc #: E8-9200]
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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: Final rule.
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SUMMARY: The Food and Drug Administration (FDA) is amending its
regulations on acceptance of foreign clinical studies not conducted
under an investigational new drug application (IND) (non-IND foreign
clinical studies) as support for an IND or application for marketing
approval for a drug or biological product. The final rule replaces the
requirement that these studies be conducted in accordance with ethical
principles stated in the Declaration of Helsinki (Declaration) issued
by the World Medical Association (WMA), specifically the 1989 version
(1989 Declaration), with a requirement that the studies be conducted in
good clinical practice (GCP), including review and
approval by an independent ethics committee (IEC). The final rule
updates the standards for the acceptance of foreign clinical studies
not conducted under an IND and help ensure the protection of human
subjects and the quality and integrity of data obtained from these
studies.
DATES: This rule is effective October 27, 2008.
FOR FURTHER INFORMATION CONTACT:
Janet Norden, Office of Medical Policy, Center for Drug Evaluation
and Research, Food and Drug Administration, 10903 New Hampshire Ave.,
Bldg. 22, rm. 4200, Silver Spring, MD 20993-0002, 301-796-2270; and
Stephen Ripley, Center for Biologics Evaluation and Research (HFM-
17), Food and Drug Administration, 1401 Rockville Pike, suite 200N ,
Rockville, MD 20852-1448, 301-827-6210.
SUPPLEMENTARY INFORMATION:
Table of Contacts
I. Background
II. Overview of the Final Rule, Including Changes to the Proposed Rule
A. Acceptance of Studies
B. Supporting Information
C. Waivers
D. Records
III. Comments on the Proposed Rule
A. Replacement of the Declaration With GCP
B. Definition of Independent Ethics Committee
C. Local Laws and Regulations
D. Acceptance of Studies
E. Definition of Good Clinical Practice
F. IEC Review and Approval
G. Onsite Inspection
H. Data From Studies Not Conducted in Accordance With GCP
I. Supporting Information
1. General Comments
2. Investigator Qualifications and Description of Research Facilities
3. Detailed Summary of Protocol and Results of the Study
4. Names and Qualifications of IEC Members
5. Summary of the IEC's Decision
6. Description of Informed Consent Process
7. Description of Incentives to Subjects
8. Description of Study Monitoring
9. Description of Investigator Training and Signed Written Commitments
J. Waivers
IV. Implementation
V. Legal Authority
VI. Paperwork Reduction Act of 1995
VII. Environmental Impact
VIII. Federalism
IX. Analysis of Economic Impacts
A. Objectives of the Final Rule
B. Background on Current Situation Regarding Foreign Studies
C. The Final Rule
D. Costs of the Final Rule
E. Benefits of the Final Rule
F. Small Business Impact
1. 
End of
Translation
Nature of the Impact
2. The Affected Industry
3. Alternatives to the Final Rule
4. Outreach
5. Conclusion
G. References
I. Background
In the Federal Register of June 10, 2004 (69 FR 32467), we
published a proposed rule that would revise our regulations in part 312
(21 CFR part 312) on the conditions under which we will accept non-IND
foreign clinical studies as support for an IND, a new drug application
(NDA), or a biologics license application (BLA). As discussed in
section III.A of this document, we revised the language used to refer
to an application (other than an IND) that may be supported by non-IND
foreign clinical studies from ``NDA or BLA'' or ``marketing
application'' to ``application for marketing approval,'' which we
define as an application under section 505 of the Federal Food, Drug,
and Cosmetic Act (the act) (21 U.S.C. 355) or section 351 of the Public
Health Service Act (the PHS Act) (42 U.S.C. 262), to make it clear that
the regulation also applies to foreign clinical studies supporting
abbreviated new drug applications (ANDAs). Previous Sec. 312.120(a)
stated that we generally accepted for review non-IND foreign clinical
studies provided they were well designed, well conducted, performed by
qualified clinical investigators, and conducted in accordance with
ethical principles acceptable to the world community. With respect to
such ethical principles, Sec. 312.120(c)(1) stated that for a foreign
clinical study not conducted under an IND to be used to support an
[[Page 22801]]
IND or application for marketing approval, the study must have been
conducted in accordance with the ethical principles stated in the 1989
Declaration 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) set forth the text of the 1989
Declaration.
We proposed to replace the requirement that non-IND foreign
clinical studies be conducted in accordance with ethical principles
stated in the 1989 Declaration with a requirement that the studies be
conducted in accordance with GCP. We proposed to define GCP 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 also would include review and approval by an IEC
before initiating a study, continuing IEC review of ongoing studies,
and obtaining and documenting freely given informed consent of study
subjects.
In the preamble to the proposed rule, we provided several reasons
for our proposed change in requirements for non-IND foreign clinical
studies. First, we noted that standards for protecting human subjects
have evolved considerably over the past decade, as evidenced by
revisions of the Declaration by the WMA's General Assembly and the
issuance of several documents by the International Conference on
Harmonisation of Technical Requirements for Registration of
Pharmaceuticals for Human Use (ICH). We noted that the ICH document
``E6 Good Clinical Practice: Consolidated Guideline'' (ICH E6), which
we adopted for use as guidance for industry in 1997 (62 FR 25692, May
9, 1997), includes a definition of GCP that shares many important
ethical principles with the 1989 Declaration.\1\ However, we stated
that the concept of GCP in ICH E6 provides more detail and enumeration
of specific responsibilities of various parties, including monitoring
of the trial and reporting adverse events. Although we did not
specifically incorporate ICH E6 into the proposed revision of Sec.
312.120, we stated that the standard of GCP that we proposed for Sec.
312.120 was consistent with that in ICH E6 and was 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.
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\1\ICH E6 and other FDA guidances adopted from the ICH are
available electronically at http://www.fda.gov/cder/guidance/index.htm.
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Another reason we stated for proposing to revise Sec. 312.120 was
that the adoption of a GCP requirement for non-IND foreign clinical
studies would help provide greater assurance of the quality of the data
obtained from these studies. Although the Declaration states that it is
unethical to enroll human subjects in poorly designed or conducted
clinical trials, it does not provide guidance on how to ensure proper
conduct of trials. We proposed the GCP provisions to help ensure data
quality and integrity by, among other things, specifying that GCP
includes providing assurance that data are credible and accurate and
requiring the submission of information on study monitoring and
conformance with protocols.
Finally, we stated that deleting the reference in Sec. 312.120 to
the Declaration was necessary to eliminate the potential for confusion
about the requirements for non-IND foreign clinical studies that could
result from potential revisions of the Declaration. We noted that the
Declaration is a document that is subject to change independent of FDA
authority and, therefore, could be modified to contain provisions that
are inconsistent with U.S. laws and regulations. We further noted that
although revisions to the Declaration could not supersede U.S. laws and
regulations, the changes might be confusing for sponsors.
We received 32 comments on the proposed rule, which we address in
section III of this document.
II. Overview of the Final Rule, Including Changes to the Proposed Rule
We are revising our regulations in Sec. 312.120 on the conditions
under which we will accept as support for an IND or application for
marketing approval (an application under section 505 of the act or
section 351 of the PHS Act) a foreign clinical study not conducted
under an IND.
A. Acceptance of Studies
Under revised Sec. 312.120(a)(1), we will accept as support for an
IND or application for marketing approval a well-designed, well-
conducted, non-IND foreign clinical study if it was conducted in
accordance with GCP and we are able to validate the data from the study
through an onsite inspection, if necessary.
Under Sec. 312.120(a)(1)(i), 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 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 (or a subject's legally
authorized representative, if the subject is unable to provide informed
consent) before initiating a study. (An IEC is defined in Sec. 312.3
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.) GCP does not require informed consent in
life-threatening situations under limited circumstances, as specified
in Sec. 312.120(a)(1)(i).
Section 312.120(a)(2) states that although we will not accept as
support for an IND or application for marketing approval a study that
does not meet the conditions in Sec. 312.120(a)(1), we will examine
data from such a study. We will do so because we require the submission
of such data under applicable regulations for drugs and biologics
(e.g., Sec. Sec. 314.50, 314.80, 600.80, 601.2 (21 CFR 314.50, 314.80,
600.80, 601.2)) and because the data may have a bearing on the safety
of a drug.
B. Supporting Information
The final rule revises the regulations on the information that a
sponsor or applicant who wishes to rely on a non-IND foreign clinical
study to support an IND or application for marketing approval must
submit to us to demonstrate that the study conformed to GCP. In
response to comments, we revised Sec. 312.120(b) to make clear that a
sponsor or applicant is not required to duplicate information already
submitted in the IND or application for marketing approval. Instead,
the sponsor or applicant may either submit the supporting information
listed in Sec. 312.120(b) or provide a cross reference to another
section of the submission where the information is located (see comment
21 of this document).
Under Sec. 312.120(b), the sponsor or applicant must submit the
information described in paragraphs (b)(1) through (b)(11). In response
to comments, we changed the information requirements in Sec.
312.120(b)(6) and (b)(11) of the proposed rule as noted in the
following description. Under Sec. 312.120(b), the
[[Page 22802]]
sponsor or applicant must submit the following information:
The investigator's qualifications (Sec. 312.120(b)(1)).
A description of the research facilities (Sec.
312.120(b)(2)).
A detailed summary of the protocol and study results and,
if we request, case records or additional background data (Sec.
312.120(b)(3)).
A description of the drug substance and drug product,
including the components, formulation, specifications, and, if
available, the bioavailability of the drug product (Sec.
312.120(b)(4)).
Information showing that the study is adequate and well
controlled (if the study is intended to support the effectiveness of a
drug product) (Sec. 312.120(b)(5)).
The name and address of the IEC that reviewed the study
and a statement that the IEC meets the definition in Sec. 312.3
(records supporting the statement, including the names and
qualifications of IEC members, must be maintained by the sponsor or
applicant and be available for agency review) (Sec. 312.120(b)(6)).
(The proposed rule would have required submission to FDA of the names
and qualifications of the IEC members that reviewed the study (see
comment 25 of this document).) A summary of the IEC's decision to approve or modify and
approve the study, or to provide a favorable opinion (Sec.
312.120(b)(7)).
A description of how informed consent was obtained (Sec.
312.120(b)(8)).
A description of what incentives, if any, were provided to
subjects to participate (Sec. 312.120(b)(9)).
A description of how the sponsors monitored the study and
ensured that the study was consistent with the protocol (Sec.
312.120(b)(10)).
A description of how investigators were trained to comply
with GCP and to conduct the study in accordance with the study
protocol, and a statement on whether written commitments by
investigators to comply with GCP and the protocol were obtained (any
signed commitments must be maintained and available for agency review)
(Sec. 312.120(b)(11)). (The proposed rule would have required sponsors
and applicants to submit copies of any written commitments (see comment
32 of this document).)
C. Waivers
The final rule includes a provision (Sec. 312.120(c)) under which
a sponsor or applicant may request that we waive any requirement in
Sec. 312.120(a)(1) or (b).
D. Records
In response to comments, we included in the final rule a provision
on record retention requirements. Section 312.120(d) states that a
sponsor or applicant must retain the records required by Sec. 312.120
for 2 years after the agency's decision on an application for marketing
approval for a drug or, if a study is submitted in support of an IND
but not an application for marketing approval, for 2 years after the
submission of the IND. The requirement to maintain appropriate records
was implicit in the requirement, in proposed Sec. 312.120(a)(1)(ii),
that FDA be able to validate the data from a study through an onsite
inspection if necessary, and under the proposed rule, the record
retention requirements of Sec. 312.57(c) would have applied to non-IND
foreign clinical studies. However, we have concluded that it is
appropriate to set forth record retention requirements specifically for
these studies in Sec. 312.120(d) (see comment 24 of this document).
III. Comments on the Proposed Rule
We received 32 comments on the proposed rule. Comments were
received from manufacturers, trade associations, advocacy groups,
foreign bioethics organizations, and individual health care providers,
researchers, and consumers. Summaries of the comments received and our
responses follow:
A. Replacement of the Declaration With GCP
Section 312.120(a)(1)(i) of the proposed rule stated that we would
accept as support for an IND or application for marketing approval a
well-designed and well-conducted foreign clinical study not conducted
under an IND if the study was conducted in accordance with GCP. The
requirement for conducting a study in accordance with GCP would replace
the former requirement in Sec. 312.120(c)(1) that such a study be
conducted in accordance with the ethical principles stated in the 1989
Declaration or the laws and regulations of the country in which the
research was conducted, whichever represents the greater protection of
the individual.
At our own initiative, we revised the language used to refer to an
application (other than an IND) that may be supported by non-IND
foreign clinical studies to ``application for marketing approval''
instead of ``NDA or BLA'' or ``marketing application.'' Under Sec.
312.120(a)(1), we further clarified that an ``application for marketing
approval'' means ``an application under section 505 of the act or
section 351 of the * * * PHS Act.'' Applications for marketing approval
under section 505 of the act include both NDAs and ANDAs. The phrase
``application for marketing approval'' tracks the language used in
previous Sec. 312.120. We made these revisions to avoid speculation
that this final rule differed in scope from previous Sec. 312.120,
which was not our intention.
(Comment 1) Several comments expressed support for adoption of the
GCP requirement and deletion of the reference to the Declaration, for
the following reasons:
The proposed changes are appropriate measures to improve
public assurance of the quality of the science and ethics supporting
data for non-IND studies.
Relying on GCP reflects the adoption of ICH E6 as a global
standard for the conduct of sponsored clinical research.
The 13 principles of GCP set forth in ICH E6 are very
encompassing and are in line with the guidelines used for domestic
studies.
The principles of the Declaration are within GCP and form
the basis for the ethical considerations in those guidelines.
The change from the Declaration to GCP would update the
standards for the acceptance of foreign studies and help ensure the
quality and integrity of data obtained from such studies.
Applying GCP standards to foreign studies not conducted
under an IND brings logical symmetry with FDA regulation of studies
conducted in the United States and ends the need to comply with the
strict wording of the Declaration, which lacks the detail needed to
describe usefully the intended compliance.
The proposal to rely on GCP is a more coherent approach to
the multitude of complex issues that arise in overseas research than
the Declaration provides.
(Response) We agree with the comments stating that the requirement
to conduct studies in accordance with GCP will ensure that these
foreign studies will be conducted in a manner that is comparable to
that required for domestic studies conducted under an IND. We also
agree that the principles of the Declaration are reflected in the
concept of GCP codified in Sec. 312.120(a)(1)(i). We also agree with
the comment that application of the GCP standard will protect human
subjects while also enhancing the quality and integrity of data
generated in these foreign studies.
[[Page 22803]]
(Comment 2) One comment recommended that we give attention to the
current development of international standards for the ethical review
of clinical studies, including the work done by the Office for Human
Research Protections (OHRP) (of the U.S. Department of Health and Human
Services), the European Forum for GCP, the World Health Organization
(WHO), and the Strategic Initiative for Developing Capacity in Ethical
Review.
(Response) We agree that it is important for us to monitor the
development of international standards for the ethical review of
clinical studies. However, for purposes of determining whether data
from non-IND foreign clinical studies can be used in support of an IND
or application for marketing approval under Sec. 312.120, we have
concluded that it is appropriate to require that these studies be
conducted in accordance with GCP for the reasons stated in section I of
this document. Although the international standards noted by the
comment are important, they are not legally binding on sponsors and
applicants under Sec. 312.120, and incorporating these standards into
our regulations would present the same problems as codifying a
reference to the Declaration, as explained in our response to comment 4
of this document.
(Comment 3) Several comments opposed the proposal to delete the
reference to the Declaration in Sec. 312.120. Several comments stated
that the Declaration represents the international standard or paradigm
for the ethical conduct of clinical studies and the protection of human
subjects. One comment stated that the Declaration is a living document
that remains extremely influential and forms the substance of what
people understand as the guiding principles of ethical research.
(Response) As stated in the preamble to the proposed rule, we
believe that our GCP standard will ensure adequate protection of human
subjects while providing the flexibility necessary to accommodate
differences in how countries regulate clinical research and obtain
informed consent. We acknowledge the prominence of the Declaration
among international standards on the treatment of human subjects in
medical research, but other national and international ethical
guidelines for research, such as the Belmont Report and guidelines
issued by the Council for International Organizations of Medical
Sciences, also are important.
The U.S. Government continues to support the Declaration's
underlying principles. However, as discussed in our response to comment
7 of this document, the U.S. Government does not fully support the 2000
version of the Declaration because it contains certain statements that
may be inconsistent with U.S. law and policy (e.g., concerning use of
placebos in clinical trials). We believe that the requirement to
conduct non-IND foreign studies in accordance with GCP, which includes
a requirement to protect the rights, safety, and well-being of
subjects, ensures adequate protection of subjects without a need for
reference to the Declaration.
(Comment 4) Four comments stated that our statement in the proposed
rule that the Declaration can be modified independent of FDA authority
does not provide a basis for deleting the Declaration. These comments
stated that we acknowledged that revisions to the Declaration could not
supersede U.S. laws and regulations. These comments added that FDA
declared in 2001 (in our guidance on ``Acceptance of Foreign Clinical
Studies'') that the reference to the Declaration in FDA regulations was
to the 1989 version. One comment stated that the possibility that the
40-year-old Declaration might become inconsistent with U.S. ethics
regulations is minimal.
(Response) The comments appear to misunderstand our statements
concerning the effect of modification of the Declaration. As we stated
in the preamble to the proposed rule, the Declaration was not
established under our authority and is subject to change independent of
our control. We proposed to remove from the regulations the 1989
Declaration, which, because it was not the most recent version approved
by the WMA, had the potential to cause confusion about the requirements
for non-IND foreign clinical studies. The potential for confusion may
increase with each subsequent revision of the Declaration. Moreover,
initiating a rulemaking to revise Sec. 312.120 each time the
Declaration is changed would be burdensome and would not be possible if
the changes were inconsistent with U.S. law and policy. For these
reasons, the comments' statements regarding modification of the
Declaration do not support retaining a reference to the Declaration in
Sec. 312.120.
(Comment 5) One comment stated that eliminating the reference to
the Declaration would damage international medical ethics and undermine
the human rights approach and traditional foundations of research
ethics in the Declaration, the Nuremberg Code, and the Universal
Declaration of Human Rights. One comment stated that deleting the
reference to the Declaration might send a message that FDA no longer
supports high standards of ethics in research involving human subjects
in foreign countries. One comment stated that the policy of
unilaterally deciding not to rely on one of the most respected ethical
documents is worrying. One comment stated that dismissing the relevance
of the Declaration would encourage every other country to do the same.
(Response) We disagree with these comments. We remain firmly
committed to protecting the rights, safety, and well-being of subjects
in both foreign and domestic research, and this commitment is reflected
in Sec. 312.120, our IND regulations, and our guidance documents,
including ICH E6. We do not believe that deleting the reference to the
Declaration in Sec. 312.120 will damage international medical ethics
or result in harm to research subjects because sponsors and applicants
will need to comply with GCP, which includes protection of human
subjects. It is also worth noting that the United States is not alone
in declining to adopt the Declaration as the standard to apply. For
example, the European Union (EU) recognizes the importance of the
Declaration, noting in Directive 2001/20/EC on the implementation of
GCP in the conduct of clinical trials that the ``accepted basis for the
conduct of clinical trials * * * is founded in the protection of human
rights and the dignity of the human being with regard to the
application of biology and medicine, as for instance reflected in the
1996 version of the Helsinki Declaration.'' Nevertheless, Directive
2001/20/EC does not incorporate the Declaration in the articles of the
directive. Similarly, we do not believe that codification of the
Declaration in our regulations is needed to ensure that foreign studies
used to support U.S. drug applications are conducted in accordance with
high ethical standards.
(Comment 6) Several comments stated that they preferred the
Declaration over GCP (as described in ICH E6) as a standard for ethical
principles. Several comments stated that the Declaration is produced by
the WMA, which is comprised of 82 national medical associations,
whereas ICH documents are the product of the regulatory authorities and
pharmaceutical industries of the United States, the EU, and Japan. One
comment stated that the Declaration is independent of any one nation
and represents a consensus, albeit sometimes uneasy, between many
different parties with many diverse interests. One comment stated that
the ethical principles in the 2000
[[Page 22804]]
Declaration were produced under an international and democratic process
conducted by the WMA. One comment stated that it is improper for FDA to
dismiss the views of the academicians, researchers, and clinicians who
comprise the WMA and who have adopted the Declaration provisions.
(Response) Although we appreciate the significance of the
Declaration, we do not agree that the manner in which it was adopted
makes it the most appropriate standard for the conduct of clinical
studies. In fact, our regulations do not require that studies conducted
in the United States under an IND be conducted in accordance with the
Declaration. Furthermore, although we have not incorporated ICH E6 into
our regulations (see comment 9 of this document), we disagree with the
comment's characterization of the process for developing ICH
guidelines. Twenty-seven countries (the United States, Japan, and the
25 member-states of the EU) participate in the ICH process, and Canada,
Switzerland, and the WHO are observers. In addition to input from
regulatory authorities and drug manufacturers, there is considerable
opportunity for public health organizations, consumers, researchers,
academicians, and others to comment publicly on proposed ICH
guidelines, both before their adoption at the international level and
before they are incorporated into the regulatory framework of
individual ICH countries. Finally, by deleting the reference to the
Declaration, we are not dismissing the views of WMA members regarding
the protection of human subjects. Instead, we simply conclude that it
is most appropriate and effective to ensure that studies are properly
conducted by requiring compliance with GCP, as defined in Sec.
312.120(a)(1)(i).
(Comment 7) In objecting to the deletion of the reference to the
Declaration, several comments cited the United States' objection to
paragraphs 29 and 30 of the version of the Declaration adopted in 2000
(paragraphs 29 and 30). Paragraph 29 states: ``The benefits, risks,
burdens and effectiveness of a new method should be tested against
those of the best current prophylactic, diagnostic, and therapeutic
methods. This does not exclude the use of placebo, or no treatment, in
studies where no proven prophylactic, diagnostic or therapeutic method
exists.'' Paragraph 30 states: ``At the conclusion of the study, every
patient entered into the study should be assured of access to the best
proven prophylactic, diagnostic and therapeutic methods identified by
the study.'' Several comments were critical of the United States'
objection to paragraphs 29 and 30 and expressed concern about its
impact on research subjects. On the other hand, one comment expressed
opposition to paragraphs 29 and 30.
(Response) Compliance with the GCP standard will ensure adequate
protection of human subjects in foreign clinical studies while
accommodating differences in local authorities' regulation of these
studies. As stated in our response to comment 3 of this document, we
cannot endorse the 2000 version of the Declaration. We believe that
paragraph 29 is inconsistent with U.S. law and policy because it would
impose a standard for the design of clinical trials that is different
from the standard of ``adequate and well-controlled investigations,''
which the act requires us to apply. Paragraph 30 invokes issues of
health care policy that are not directly related to FDA's mission of
ensuring that medical products are safe and effective. In addition, we
do not believe that this rulemaking is the proper forum for debating or
resolving issues concerning particular paragraphs of the Declaration,
such as use of placebo controls or continued access to therapy after a
study is concluded.
(Comment 8) Several comments stated that deletion of the reference
to the Declaration will have an adverse impact on the populations of
developing countries, who are vulnerable to abuse, exploitation, and
negligence because of their relative poverty and lack of education. One
comment stated that the proposed rule is consistent with FDA's
purported purpose of weakening items in the Declaration related to
protection of human subjects in developing countries. One comment
stated that deletion of the Declaration would imply that FDA believes
that non-U.S. study populations do not need access to study results or
that non-U.S. populations could be studied and put at risk only to
identify medical products that would benefit the U.S. population.
(Response) We do not agree that deleting the reference to the
Declaration will have a negative impact on research subjects in
developing countries or result in less protection for subjects in
foreign studies. Human subject protection is essential to GCP as
defined in revised Sec. 312.120, which, among other things, requires
the protection of the rights, safety, and well-being of trial subjects,
and review and approval of studies by an IEC. We do not believe that
referencing the Declaration in our regulations would provide additional
protection to the populations of developing countries beyond the
protections set forth in revised Sec. 312.120.
(Comment 9) Several comments stated that ICH E6 is concerned
primarily with procedural and technical issues, not overarching ethical
issues. One comment stated that GCP does not encompass the range of
concerns about the protection of human subjects that is provided for in
the Declaration. One comment stated that while the Declaration focuses
on researchers' ethical conduct and the primacy of patient welfare, ICH
E6 focuses on the relations between researchers and pharmaceutical
sponsors. One comment stated that ICH E6 is designed to improve data
quality but is unconcerned with ethics.
(Response) We disagree with the comments. Most importantly, we note
that the definition of GCP contained in Sec. 312.120 is the standard
that will apply to these studies, rather than the procedures set forth
in ICH E6. The regulation requires, among other things, that the
rights, safety, and well-being of subjects be protected, that an IEC
review and approve (or provide a favorable opinion on) each study
before initiation, and that subjects give informed consent.
As for ICH E6 itself, protecting the interests of human subjects is
one of its two fundamental purposes, along with helping to ensure the
quality of data from clinical studies. The first paragraph of the
introduction to ICH E6 states that compliance with GCP ``provides
public assurance that the rights, safety, and well-being of trial
subjects are protected, consistent with the principles that have their
origin in the Declaration of Helsinki, and that the clinical trial data
are credible'' (p. 6). In addition, the first principle of GCP listed
in ICH E6 (section 2.1) is that ``[c]linical trials should be conducted
in accordance with the ethical principles that have their origin in the
Declaration of Helsinki, and that are consistent with GCP and the
applicable regulatory requirement(s)'' (p. 8). Sections 3.1 and 4.3/4.8
of ICH E6 address the responsibilities of institutional review boards
(IRBs)/IECs and investigators, respectively, concerning matters related
to the care and treatment of research subjects,\2\ including provisions
on informed consent and medical care of subjects. Thus, although ICH E6
does address procedural issues, ethical issues are another principal
focus of the document.
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\2\ICH E6 at pp. 10-11, 14-15, 17-21.
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(Comment 10) Several comments recommended that FDA simply add to
the regulations a requirement to comply with GCP rather than delete the
reference to the Declaration. One comment stated that it understood the
[[Page 22805]]
need for data standardization and urged us to add GCP requirements
without eliminating the reference to the Declaration. One comment
stated that international studies, as they have been conducted in the
past, can comply with both documents. Another comment stated that
adherence to both documents would not cause the quality of these
foreign studies to suffer. Several comments stated that the GCP
guidance does not address conflict of interest or the need to publish
results, which are both included in the Declaration. These comments
stated that the two documents are complementary and that the
regulations could require that affected studies comply with both
documents.
(Response) For the reasons stated previously in this document, it
is no longer appropriate for Sec. 312.120 to require compliance with
the Declaration, either the 1989 version, the current (2000) version,
or some other future or past version. Moreover, we believe that because
of the requirement in Sec. 312.120 that acceptable foreign studies be
conducted in accordance with GCP, which includes ensuring that the
rights, safety, and well-being of trial subjects are protected, a
specific reference to the Declaration will not enhance protection of
human subjects. Nor do we believe that Sec. 312.120 should address
conflicts of interest or the need to publish study results. Other FDA
regulations address conflicts of interest in these foreign studies (for
example, the provisions on financial disclosure by clinical
investigators in part 54 (21 CFR part 54) are applicable to studies
submitted in support of an NDA, ANDA, or BLA under Sec. 314.50(k), 21
CFR 314.94(a), and Sec. 601.2(a), respectively). With respect to the
publication of study results, we note that section 801 of the Food and
Drug Administration Amendments Act of 2007 (42 U.S.C. 282(j)(3))
provides for publication in a results data bank of the results of
``applicable clinical trials'' under certain circumstances. In
addition, we strongly encourage sponsors to seek publication in peer-
reviewed journals.
B. Definition of Independent Ethics Committee
We proposed to add, under Sec. 312.3, a definition for IEC. We
proposed to define IEC to mean 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 IRB, as defined
in Sec. 56.102(g) (21 CFR 56.102(g)) of this chapter and subject to
the requirements of part 56 (21 CFR part 56), is one type of IEC.
(Comment 11) Several comments stated that the proposed definition
of IEC differed from the definition in ICH E6, and requested that we
provide clarification of the term ``adequately constituted'' in the
definition of IEC. One comment suggested either defining ``adequately
constituted'' as ``if its composition and membership complies with
[part] 56, subpart B of this chapter,'' or omitting ``adequately
constituted'' from the definition of IEC, making it consistent with the
definition in ICH E6. Other comments suggested defining IEC as in
section 1.27 or 3.2 of ICH E6.
(Response) The requirement in Sec. 312.3 that the IEC be
``adequately constituted'' emphasizes the importance of the IEC having
appropriate expertise to perform its critical role in the protection of
human subjects. As described in the preamble to the proposed rule, we
would consider an IEC to be adequately constituted if it ``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 [ICH E6])'' (69 FR 32467 at 32468). Such an
``adequately constituted'' IEC is responsible for ensuring the
protection of the rights, safety, and well-being of human subjects
involved in a clinical investigation. Although the definition of an IEC
in ICH E6 does not include the term ``adequately constituted,'' ICH E6
defines an IEC as being ``constituted of medical/scientific
professionals and nonmedical/nonscientific members whose responsibility
it is to ensure the protection of the rights, safety and well-being of
human subjects'' (section 1.27). We view our proposed definition of IEC
as consistent with the definition of IEC in ICH E6 but at the level of
specificity and detail appropriate for regulation. We recognize that
the organization and membership of IECs may differ among countries
because of the local needs of the host country, but we believe that
such variation should not affect an IEC's ability to perform its
functions. Our regulations must be sufficiently flexible to accommodate
differences in how countries regulate the conduct of clinical research,
including the composition of an IEC. Therefore, we will not
specifically define IEC membership in the regulations or require that
an IEC comply with the requirements in subpart B of part 56, or with
the recommendations for membership in ICH E6. However, we would
consider an IEC that is constituted to comply with part 56 or with ICH
E6 to be ``adequately constituted.'' In fact, the definition of IEC in
Sec. 312.3 clarifies that an IRB, as defined in Sec. 56.102(g) and
subject to the requirements of part 56, is one type of IEC. For these
reasons, we decline to omit ``adequately constituted'' from the
definition of IEC in Sec. 312.3.
C. Local Laws and Regulations
(Comment 12) Some comments stated that the proposed rule would
delete the provision in former Sec. 312.120(c)(1) requiring that
foreign clinical research be conducted according to the laws and
regulations of the country in which the research was conducted, when
such laws provided for greater protection of human research subjects
than the principles of the Declaration. Some comments stated that
deleting the reference to compliance with local laws of the host
country supported the notion that FDA could accept data collected in
violation of those laws.
(Response) We do not agree that deletion of this provision will
lead to FDA accepting studies not conducted in accordance with local
laws. Sponsors, IECs, investigators, and research sites and/or
institutions are all responsible for complying with the local
requirements for conducting research, including any requirements that
may be more stringent than the requirements in Sec. 312.120. A host
country may deny a sponsor's request to conduct research in the country
if the sponsor does not comply with local requirements, or may stop a
study that is in progress in violation of the host country's laws. New
Sec. 312.120 sets forth U.S. standards for acceptance of foreign
clinical studies in support of an IND or application for marketing
approval, including that the study be conducted in accordance with GCP.
We are confident that these standards provide for the protection of
human subjects, and we will accept a study only if these standards are
met. In addition, sponsors or applicants that currently conduct
clinical trials in accordance with ICH E6 would comply with local
requirements because ICH E6 states that one of the principles of GCP is
that clinical trials be conducted consistent with the applicable
regulatory requirements (i.e., any laws and regulations addressing the
conduct of clinical trials of investigational products of the
jurisdiction where a trial is conducted).
(Comment 13) One comment stated that although proposed Sec.
312.120 referenced general GCP standards, it did not clarify whether
GCP as interpreted by the host country was at all relevant to
acceptance of data or whether the
[[Page 22806]]
ethics committee that must be used was one approved by the host
country.
(Response) The host country's interpretation of GCP is relevant to
these non-IND foreign clinical studies because the host country
requires the sponsor to comply with its laws. However, we will only
accept data from studies that we determine were conducted in accordance
with GCP as described in Sec. 312.120(a)(1)(i). As to whether the IEC
must be approved by the host country, if a host country requires by law
that the host country approve the IEC, the sponsor would need to comply
with that requirement. However, we will not specifically require in
Sec. 312.120 that an adequately constituted IEC be approved by the
host country. We do not believe that such approval is essential to
ensuring the quality of data or the protection of human subjects.
Therefore, this matter is left to the discretion of the host country.
(Comment 14) One comment recommended including a provision in Sec.
312.120 to continue to allow a sponsor to document that the study was
conducted in a country where the laws and regulations already provide
for strict adherence to the principles of GCP, which would clearly
provide for the assurance of protection of human research subjects and
quality of clinical data. As support for this approach, the comment
stated that clinical trials conducted in Europe must now meet the
requirements of the EU Clinical Trials Directive and its implementing
guidance for the conduct of clinical trials under GCP.
(Response) We believe that the supporting documentation required
under Sec. 312.120(b), combined with an onsite inspection if
necessary, will provide us with the ability to determine if a foreign
clinical investigation was conducted in accordance with GCP. If the
country adheres to the principles of GCP and the study complied with
those principles, this should be reflected in the documentation
submitted to us. Therefore, it is not necessary to add a provision as
suggested by the comment.
D. Acceptance of Studies
(Comment 15) One comment stated that the proposed rule should be
consistent with FDA's 1998 guidance ``FDA Approval of New Cancer
Treatment Uses for Marketed Drug and Biological Products'' (New Cancer
Treatment Guidance). The comment stated that section III.B of the New
Cancer Treatment Guidance allows certain data to be submitted to us
without additional data collection, auditing, or analyses by a
pharmaceutical company submitting a marketing application, depending on
the quality and credibility of the institutions providing such data.
(Response) We do not agree that this rule and the New Cancer
Treatment Guidance concern the same issues. Although the guidance
addresses the submission of certain data without the applicant being
subject to auditing, this is applicable only to data from studies
conducted by independent cancer clinical trials organizations that have
well-established and publicly available procedures for research data
management, monitoring, and auditing, and a track record of high-
quality research (e.g., U.S. National Cancer Institute-sponsored
cooperative cancer research groups and other highly credible
organizations that have no commercial interest in study outcomes). The
guidance does not address the submission of foreign clinical data and
is limited in scope to drugs for treating cancer. We will not accept
foreign clinical studies in support of an IND or application for
marketing approval except as set forth in Sec. 312.120.
(Comment 16) One comment recommended including the following
statement in Sec. 312.120 to reduce the potential regulatory burden:
``The information to be provided in support of the IND does not need to
be submitted to FDA throughout the study. The supporting information
may be provided at the time the clinical study report is filed to the
FDA in support of an NDA and/or made available upon request.''
(Response) We do not agree that including such a statement in Sec.
312.120 is necessary because the submission and reporting requirements
are already clear. Information required under Sec. 312.120 to be
submitted in support of an IND or application for marketing approval
would be submitted at the time the application is submitted to the
agency. Once an application is pending before the agency, the
applicable reporting requirements for INDs, NDAs, ANDAs, or BLAs under
part 312, 314, or 601 (21 CFR parts 314 and 601), apply.
E. Definition of Good Clinical Practice
For the purposes of Sec. 312.120, we proposed, in Sec.
312.120(a)(1)(i), to define GCP 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. We also proposed to
require that GCP include oversight by an IEC and obtaining informed
consent of subjects.
The final rule clarifies the limited circumstances in which GCP
would not require informed consent. The proposed rule stated 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. Sec. 50.23 or 50.24(a) (21 CFR
50.23 or 50.24(a)), 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. We explained in the preamble that this provision would be
consistent with the GCP guidance, which recommends that a legally
authorized representative provide informed consent or that the
requirement of informed consent be waived under such circumstances. In
the final rule, we have made more explicit two conditions that were
implicit in the proposed rule: The IEC review must occur before
initiation of the study and the IEC must find that informed consent is
not feasible.
In addition, we deleted the provision referring to the IEC ensuring
compliance with applicable regulatory requirements. Upon
reconsideration, we recognized that the reference to ``applicable
regulatory requirements'' was not clear. We had not described the
requirements we considered to be applicable, and without additional
clarity, the phrase did not provide additional protections for subjects
in the study. Therefore, we decided that the provision would be clearer
without this phrase.
(Comment 17) Several comments requested confirmation that
compliance with ICH E6 would be adequate to assure compliance with
Sec. 312.120 and questioned whether citing compliance with ICH E6,
rather than submitting the supporting documentation required under
312.120(b), would be acceptable. One comment requested that we waive
requirements in the proposed rule for any study conducted in EU member
states, provided the member can submit a EudraCT (a database of
clinical trials in the EU) number, and for any studies that have been
conducted in Japan under Japanese Good Clinical Practices. One comment
stated that the rule should explicitly require following ICH E6 because
imposing a U.S. standard ``consistent with'' an international standard
seemed insufficient. One comment recommended that if Sec. 312.120 does
not specifically require following ICH E6, we should acknowledge in the
final rule or subsequent guidance that ICH E6 should be taken into
account as one GCP
[[Page 22807]]
standard that we find acceptable, and describe in what ways the
standard set forth in Sec. 312.120 differs from that in ICH E6.
(Response) As noted in the preamble to the proposed rule, we have
already incorporated many of the principles of GCP into our existing
regulations. However, we have not specifically incorporated all of ICH
E6 into our regulations, and we will not do so in Sec. 312.120, for
several reasons. First, for one of the same reasons that we deleted the
reference to the Declaration from Sec. 312.120, we do not believe that
it is appropriate to reference in a regulation a document that is
subject to change independent of our control. Second, although we
adopted ICH E6 in 1997 for use as guidance for industry, there are
other international documents that provide acceptable standards for
GCP. Specific incorporation of ICH E6 into Sec. 312.120 would
constrain our ability to accept data from non-IND foreign clinical
studies from countries that use other comparable GCP standards.
Finally, ICH E6 contains a level of detail and specificity that is not
appropriate for regulations. We believe that the GCP standard in Sec.
312.120 is appropriate because it provides sufficient flexibility to
accommodate differences in how countries regulate the conduct of
clinical research, while still ensuring adequate and comparable human
subject protection. Therefore, we do not require that sponsors or
applicants follow ICH E6, but a study conducted in compliance with ICH
E6 would meet the GCP requirements in Sec. 312.120. However, for the
agency to evaluate such a study, the information required under Sec.
312.120(b) must be submitted. It would not be adequate to simply submit
a statement that ICH E6 or Japanese GCP were followed, or to provide
only a EudraCT number.
F. IEC Review and Approval
Proposed Sec. 312.120(a)(1)(i) stated that GCP includes review and
approval (or provision of a favorable opinion) by an IEC before
initiating a study and continuing review of an ongoing study by an IEC.
(Comment 18) One comment stated that the requirement for review and
approval by an IEC does not guarantee protection of the participants
unless the guidelines that the IEC must follow are stated explicitly
and are not weaker than the Declaration.
(Response) We disagree. Although Sec. 312.120(a)(1)(i) requires
review and approval of a clinical study before initiation, the
regulation does not specify the procedures that the IEC must follow
because different procedures offering equivalent human subject
protection may be followed in different countries. As previously
stated, we believe that the GCP standards in Sec. 312.120, including
the requirement for review and approval by an IEC, are and should be
sufficiently flexible to accommodate differences in how countries
regulate the conduct of clinical research, while ensuring adequate and
comparable human subject protection.
G. Onsite Inspection
Proposed Sec. 312.120(a)(1)(ii) would have required, as a
condition of acceptance of a study submitted under this section, that
we be able to validate the data from the study through an onsite
inspection if we deem it necessary.
(Comment 19) One comment recommended that we give attention to the
current development of national and regional (e.g., European Medicines
Agency) inspections outside the United States and the role they might
play in providing public assurance for the quality of data and the
protection of human subjects.
(Response) Although this rule does not address the process for
conducting inspections outside the United States, we can review and
consider information from inspections by foreign authorities. However,
if deemed necessary, we are also able, under Sec. 312.120(a)(1)(ii),
to conduct an onsite inspection to validate the data from a study.
H. Data From Studies Not Conducted in Accordance With GCP
Proposed Sec. 312.120(a)(2) stated 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)(i), we will examine data from such a
study.
(Comment 20) One comment requested that we clarify the meaning of
proposed Sec. 312.120(a)(2). The comment asked if this provision means
that a sponsor should submit studies conducted on the investigational
product but differentiate studies that comply for FDA review of safety
and efficacy, or that we will review noncompliant studies as
supportive.
(Response) The provision states that we ``will not accept as
support'' for an IND or application for marketing approval a study that
does not meet the conditions of Sec. 312.120(a)(1) (i.e., a
``noncompliant'' study). Nonetheless, a sponsor or applicant of an IND
or application for marketing approval must submit all studies and other
information required under applicable FDA regulations for drugs and
biologics, including ``noncompliant'' studies. We would review
information from ``noncompliant'' studies because they might have
bearing on the safe use of the product. In the application, a sponsor
or applicant should identify any studies that do not meet the
conditions of Sec. 312.120(a)(1).
I. Supporting Information
Proposed Sec. 312.120(b) would have required a sponsor or
applicant submitting a non-IND foreign clinical study in support of an
IND, NDA, or BLA to submit, in addition to information required
elsewhere in parts 312, 314, or 601, supporting information that
describes the actions taken to ensure that the research conformed to
GCP.
1. General Comments
(Comment 21) Some comments stated that certain of the proposed
requirements for submission of supporting information in Sec.
312.120(b) are not entirely consistent with guidance provided in other
relevant ICH documents. One comment requested that we confirm that
conducting a study in accordance with ICH E6 and reporting and
submitting the study according to ICH E3 (``Structure and Content of
Clinical Study Reports''), ICH M4 (``Common Technical Document for the
Registration of Pharmaceuticals for Human Use''), and FDA's
corresponding guidance documents satisfies all the requirements of
proposed Sec. 312.120(b). In addition, the comment requested that in
cases where the requirements in Sec. 312.120(b) differed from ICH E3
and M4 standards, we consider modifying the requirements, thereby
allowing sponsors to submit IND and non-IND studies according to a
single standard.
(Response) Conducting a study in accordance with ICH E6 and
reporting and submitting the study according to ICH E3, ICH M4, and
FDA's corresponding guidance documents would not satisfy all the
requirements of Sec. 312.120(b). The supporting documentation required
in Sec. 312.120(b) must describe the actions the sponsor or applicant
took to ensure that the research conformed to GCP. This supporting
documentation will supplement information required elsewhere in parts
312, 314, or 601. If any of the supporting information is already
included in another section of the IND or application for marketing
approval, the sponsor or applicant would not be required to submit this
information more than once. We revised Sec. 312.120(b) to clarify
that, in submitting the description of the actions taken to ensure that
research conformed
[[Page 22808]]
to GCP, the sponsor or applicant is not required to duplicate
information already submitted in the IND or application for marketing
approval. Instead, the description submitted must provide either the
supporting information required in Sec. 312.120(b)(1) through (b)(11)
or a cross-reference to another section of the submission where the
information is located.
In some cases, it would be necessary to supplement studies
submitted according to ICH E3 and M4 with additional information to
adequately describe the actions the sponsor or applicant took to ensure
that research conformed to GCP. ICH E3 provides advice on structuring
and reporting data from a clinical trial, and ICH M4 provides advice on
the organization of information in an application. These documents,
unlike ICH E6, were not developed to address GCP.
2. Investigator Qualifications and Description of Research Facilities
Proposed Sec. 312.120(b)(1) would have required submission of the
investigator's qualifications, and proposed Sec. 312.120(b)(2) would
have required submission of a description of the research facilities.
(Comment 22) One comment stated that we were imposing an additional
regulatory burden by requiring a description of the investigator's
qualifications and a description of the research facilities. The
comment stated that the information provided should be similar to that
currently provided to FDA by sponsors for studies conducted under an
IND.
(Response) We do not agree that the rule would impose any
additional regulatory burden related to investigator's qualifications
and description of research facilities. Section 312.120(b)(1) and
(b)(2) of the final rule are unchanged from previous Sec.
312.120(b)(1) and (b)(2), so there is no greater or lesser regulatory
burden compared to what was previously required. In addition, we
believe that assessment of the qualifications of the investigators and
the adequacy of the research facilities are important factors in
determining the reliability of the data generated by the study. IND
sponsors are required to submit information about investigator
qualifications and the name and address of the research facilities
(whether domestic or foreign) to be used for each protocol (Sec.
312.23(a)(6)(iii)(b)). This rule does not require more information
about investigator qualifications from sponsors of non-IND foreign
studies. However, we generally are less likely to be familiar with the
research facilities in which those studies are conducted. Therefore, we
believe that it is appropriate to require a description of the research
facilities for these studies to help us determine the adequacy of the
facilities and to prioritize the need for an onsite inspection.
3. Detailed Summary of Protocol and Results of the Study
Proposed Sec. 312.120(b)(3) would have required submission of a
detailed summary of the protocol and results of the study. In addition,
the sponsor or applicant would have been required to submit case
records maintained by the investigator or additional background data,
such as hospital records or other institutional records, if requested
by FDA.
(Comment 23) One comment recommended that we modify the requirement
in proposed Sec. 312.120(b)(3) to allow sponsors to follow ICH E3, in
which annex I, ``Synopsis,'' provides the template for the detailed
summary of the protocol.
(Response) We do not agree that submitting only the Synopsis from
annex I of ICH E3 would be adequate to meet the requirements in Sec.
312.120(b)(3) because the synopsis would not provide sufficient detail
about the study protocol or results. Therefore, we have not modified
the requirement as suggested by the comment. Although following ICH E3
is not required, an integrated, full clinical study report submitted in
accordance with ICH E3 would be acceptable for meeting the requirements
for providing summaries of the study protocol and results in Sec.
312.120(b)(3). In addition, sponsors and applicants must submit
information required elsewhere in parts 312, 314, or 601.
(Comment 24) One comment indicated that the reference to ``hospital
records'' in Sec. 312.120(b)(3) suggests that we could request
hospital records instead of a description of medical records maintained
by an investigator, which might lead to data privacy concerns. One
comment stated that the requirements for recordkeeping by investigators
described in ICH E6, which it said were comparable to the requirements
for investigator recordkeeping in Sec. 312.62, should be included in
the final rule.
(Response) Proposed Sec. 312.120(b)(3) was unchanged from previous
Sec. 312.120(b)(3). If we need source documents such as hospital
records to verify data, these records must be available during an
onsite inspection or provided upon request. If the necessary records
are not available, we might not accept the study as support for an IND
or application for marketing approval. We believe that informed consent
documents should notify subjects that regulatory authorities will have
direct access to the subject's original medical records for
verification of clinical trial procedures and data, which is consistent
with ICH E6, section 4.8.10(n). However, if a sponsor or applicant
cannot disclose foreign records because it is prohibited by foreign
law, the sponsor or applicant and FDA would need to agree upon an
alternative validating procedure if the agency is to rely on the data.
With respect to investigator recordkeeping, this rule does not
address individual investigator responsibilities, but rather describes
the requirements for sponsors or applicants who are submitting non-IND
foreign clinical studies in support of an IND or application for
marketing approval. Sponsors or applicants are responsible for ensuring
that their investigators meet their responsibilities. As originally
proposed, the retention requirements in Sec. 312.57(c) for records and
reports required under part 312 would have applied to records required
under this rule. However, we decided to clarify the record retention
requirements applicable to records required under this rule and
incorporate the provision directly into Sec. 312.120. Accordingly, we
have added the following provision at Sec. 312.120(d): A sponsor or
applicant must retain the records required by this section for a
foreign clinical study not conducted under an IND as follows: (1) If
the study is submitted in support of an application for marketing
approval, retain records for 2 years after an agency decision on that
application; (2) if the study is submitted in support of an IND but not
an application for marketing approval, retain records for 2 years after
the submission of the IND. This record retention provision is similar
to the requirements set forth in Sec. 312.57(c).
4. Names and Qualifications of IEC Members
Proposed Sec. 312.120(b)(6) would have required submission of the
names and qualifications for the members of the IEC that reviewed the
study.
(Comment 25) One comment stated that although the requirement to
provide names and qualifications of IEC members is in current Sec.
312.120(c)(3), the regulation should allow for situations where it is
impossible for a sponsor or clinical investigator to obtain this
information. One comment stated that because of privacy concerns, some
IECs only provide sponsors with letters to confirm that the
constitution of the IEC is in agreement with GCP. The
[[Page 22809]]
comment stated that ICH E6 requires that the investigator files include
the IEC composition to document that the IEC is so constituted, and
that this information is available in sponsor files. The comment
recommended that as an alternative we consider requiring the name and
address of each IEC that approved a study. One comment requested
allowing a statement from the IEC that it is properly constituted
within the applicable laws that they must follow. Another comment
suggested that we change the requirement to ``information on the
composition (preferably names and qualifications, but at a minimum
qualifications) of the IEC that reviewed the study to ensure that the
IEC is duly constituted.'' Another comment recommended that we only
require a statement from the IEC that it is organized and operates
according to ICH E6 and the applicable laws and regulations, which the
comment stated was consistent with ICH E6, section 5.11.1(b). Two
comments stated that the proposed requirement deviated from ICH E3,
which includes a list of IECs or IRBs (plus the name of the committee
chair, if required by the regulatory authority). The comments
recommended that the requirement be revised to be consistent with ICH
E3.
(Response) Because oversight by an adequately constituted IEC is an
essential component of human subject protection, it is critical that
there be adequate documentation of the IEC composition. We believe that
submission of the names and qualifications of the members of the IEC
that reviewed the study, as proposed, is one way to document the
adequacy of the committee. Nevertheless, in response to concerns raised
by some of the comments, we have developed an alternative approach that
provides comparable assurance. As revised, Sec. 312.120(b)(6) requires
submission of the name and address of the IEC that reviewed the study
and a statement that the IEC meets the definition of IEC in Sec.
312.3. Section 312.120(b)(6) also states that the sponsor or applicant
must maintain records supporting the statement, including records of
the names and qualifications of IEC members, and make these records
available for agency review upon request. We specify that the retained
records must include records of the names and qualifications of IEC
members because we do not believe it is possible to verify that an IEC
is adequately constituted without knowing about the IEC members.
Because sponsors or applicants were already required under previous
Sec. 312.120(c)(3) to submit the names and qualifications of IEC
members, this change lessens the burden on sponsors and applicants. In
addition, sponsors or applicants who comply with ICH E6 would also
obtain and retain records on the information required in Sec.
312.120(b)(6) (see sections 3.4 and 5.5.11 of ICH E6).
(Comment 26) One comment recommended that we clarify the type of
information that must be provided to document the qualifications of the
IEC because it will be difficult to assess meaningfully the true
qualifications of IEC members simply by review of their formal
professional qualifications. One comment recommended that FDA clarify
that ``qualifications'' means not only formal academic certifications
but also evidence that the members of the IEC, individually and as a
group, are competent to protect clinical trial participants and ensure
that the study is conducted in compliance with GCP. The comment
suggested that the sponsor be required to provide evidence that the IEC
members received training in bioethics and the principles of GCP or
provide evidence that the IEC was accredited.
(Response) We believe that submitting a statement that the IEC
meets the definition in Sec. 312.3 and maintaining the records
specified in Sec. 312.120(b)(6) will provide sufficient documentation
that the committee is adequately constituted to provide assurance that
the rights, safety, and well-being of human subjects are protected. We
believe that it is appropriate to allow flexibility in the composition
and training of the IEC. If we deem it necessary in a particular case,
we will inspect the sponsor's or applicant's records. Therefore, we
will not require sponsors and applicants to provide evidence of
training or IEC accreditation.
5. Summary of the IEC's Decision
Proposed Sec. 312.120(b)(7) would have required submission of a
summary of the IEC's decision to approve or modify and approve the
study, or to provide a favorable opinion.
(Comment 27) One comment requested clarification of the requirement
to provide ``a summary of the IEC's decision to approve or modify and
approve the study, or to provide a favorable opinion.'' The comment
asked if it would be acceptable to provide a general statement that the
IEC approved the study protocol prior to its conduct, noting any
modifications required by the IEC (along with such items as amendments
and consent forms). One comment recommended that IEC review and
approval should continue to be documented by receipt of the approval
letter from the committee. The comment stated that these letters are
usually issued in the local language of the country in which the study
is conducted and official translations could be provided. If approval
letters are acceptable, the comment requested clarification on whether
we would expect approval letters for only the original protocol or for
all protocol amendments as well. One comment recommended that the
requirement under Sec. 312.120(b)(7) also account for documenting
continuing review by the IEC under Sec. 312.120(a)(1)(i).
(Response) We agree that it would be sufficient to provide a brief
summary of the IEC's actions to approve or modify and approve the
study, prior to the initiation of the study. For example, it would be
acceptable to provide the name of the IEC and a list of IEC actions and
dates (e.g., initial approval date, date of approval of modification to
study (if any)). Alternatively, it would be acceptable to provide
approval letter(s) from the IEC, including those for protocol
amendments. Although continuing review by the IEC is required under
Sec. 312.120(a)(1)(i), documentation of such review does not need to
be submitted under Sec. 312.120(b)(7).
6. Description of Informed Consent Process
Proposed Sec. 312.120(b)(8) would have required submission of a
description of how informed consent was obtained.
(Comment 28) Two comments recommended that we modify the
requirement in Sec. 312.120(b)(8) so that it is acceptable to follow
ICH E3, section 5.3, which calls for a description of how and when
consent was obtained (the representative written information for the
research subject (if any), and the sample informed consent are provided
in accordance with appendix 16.1.3). One comment stated that the
proposed rule requests more stringent supporting information on how
informed consent was obtained than what is currently required in part
314 for studies conducted under an IND and submitted in an NDA.
(Response) We do not believe it is necessary to modify the
requirement as suggested. The requirement to provide a description of
how informed consent was obtained allows for flexibility regarding the
manner in which this information can be submitted. For example, ICH E6,
section 4.8, provides standards for the informed consent process,
including who obtains informed consent, as well as how and when it
should be obtained. Submitting
[[Page 22810]]
documentation of this process would be acceptable to meet the
requirement in Sec. 312.120(b)(8). Likewise, it would be acceptable
for sponsors or applicants to follow the relevant provisions in ICH E3
to meet the requirements. We do not agree that Sec. 312.120(b)(8) is
more stringent than the corresponding requirements in part 314 for
studies conducted under an IND. Sponsors conducting studies under an
IND would have to meet the requirements in parts 50, 56, and 312, which
include detailed requirements for obtaining informed consent.
7. Description of Incentives to Subjects
Proposed Sec. 312.120(b)(9) would have required submission of a
description of what incentives, if any, were provided to subjects to
participate in the study.
(Comment 29) Two comments recommended that we clarify the
requirements of Sec. 312.120(b)(9). One comment stated that it should
be acceptable to provide a general statement in the protocol, study
report, and sample consent that subjects were reimbursed for their time
and travel costs or that subjects were paid for participation. Two
comments stated that it should be adequate to follow ICH E3 (appendix
16.1.3), which includes providing a sample or model informed consent
form, since it would describe any incentives.
(Response) We believe that there should be some flexibility in how
sponsors or applicants comply with Sec. 312.120(b)(9). If the sponsor
or applicant follows ICH E6, informed consent would include an
explanation of any incentives provided to subjects (section 4.8.10), so
a sponsor or applicant could submit a model consent form to meet Sec.
312.120(b)(9). Alternatively, we agree that following ICH E3 and
providing a sample or model informed consent form that describes any
incentives provided, as specified in appendix 16.1.3 of ICH E3, would
be sufficient to satisfy Sec. 312.120(b)(9). A sponsor or applicant
could also satisfy Sec. 312.120(b)(9) by submitting a brief
description of any incentives provided to subjects to participate in
the study.
8. Description of Study Monitoring
Proposed Sec. 312.120(b)(10) would have required submission of a
description of how the sponsor monitored the study and ensured that the
study was carried out consistent with the study protocol.
(Comment 30) Two comments asked that we modify the requirements to
state that it is acceptable to follow ICH E3, section 9.6, Data Quality
Assurance, which would mean providing a description of any steps taken
at the investigational sites or centrally to ensure the use of standard
terminology and the collection of accurate, consistent, complete, and
reliable data; steps might include training sessions, monitoring of
investigators, use of centralized testing, and data audits. One comment
recommended that the proposed rule be revised to allow the submission
of a general description of what activities were used to ensure the
quality of data (e.g., monitoring, investigator training), in keeping
with part 314.
(Response) As with the other requirements for submission of
supporting information, we believe that there should be some
flexibility in how sponsors or applicants meet the requirements in
Sec. 312.120(b)(10). We agree that following ICH E3, section 9.6,
would be acceptable to meet these requirements. Alternatively, sponsors
or applicants could provide a description of how the study was
monitored as specified in ICH E6, section 5.18. Although it is
acceptable to follow these sections of ICH E3 or E6 to comply with
Sec. 312.120(b)(10), we will not require that they be followed, and a
sponsor or applicant might use an alternative approach to comply with
this provision.
9. Description of Investigator Training and Signed Written Commitments
Proposed Sec. 312.120(b)(11) would have required submission of a
description of how investigators were trained to comply with GCP and to
conduct the study in accordance with the study protocol. In addition,
the sponsor or applicant would have been required to submit copies of
written commitments, if any, by investigators to comply with GCP and
the protocol.
(Comment 31) Some comments requested that we clarify the
requirements in Sec. 312.120(b)(11). One comment asked if submission
of a general statement in the study report that investigators were
trained at an investigators meeting and/or during site initiation
visits would be acceptable. Two comments stated that investigator
training was included in ICH E3, section 9.6, and recommended that we
modify the requirement so that it is acceptable to reference this
section of the clinical study report.
(Response) We agree that submitting a statement in accordance with
ICH E3, section 9.6 (i.e., whether investigator meetings or other steps
were taken to prepare investigators and standardize performance), would
be an acceptable means of complying with Sec. 312.120(b)(11), provided
that the description included how investigators were trained to comply
with GCP and to conduct the study in accordance with the study
protocol. As previously stated with respect to other supporting
documentation requirements, a sponsor or applicant might use an
alternative approach to meet this requirement.
(Comment 32) Several comments recommended that we eliminate the
proposed requirement to submit copies of written commitments, if any,
by investigators to comply with GCP and the protocol. Three comments
stated that written investigator commitments are usually included on
the investigator signature page of the study protocol. Under ICH E3,
appendix 16.1.1, a blank copy of this page is provided with the
protocol. In addition, ICH E6, section 8.2.2, advises sponsors to
archive individual investigators' signature pages in the sponsor's
trial master file. The comments stated that to comply with this part of
Sec. 312.120(b)(11), it should suffice to submit a description of how
the investigator commitment to comply with GCP and the protocol was
obtained, and we should eliminate the proposed requirement to submit an
individual form for each participating investigator. Two comments
requested that the proposed rule be revised to require that the signed
investigator agreements be available in the sponsor's files, to be
provided to us upon request. One comment stated that there is no need
to submit an individual form for each investigator because this
information has already been obtained by the sponsor. One comment
recommended that we require sponsors to obtain written commitments from
investigators to comply with GCP and the study protocol.
(Response) We agree that submitting individual copies of signed
investigator agreements is unnecessary. We recognize that, for those
sponsors following ICH E3 and E6, these documents would be either
submitted with the clinical study report or kept on file with the
sponsor. We believe that it would be acceptable to submit a statement
indicating whether written commitments by investigators to comply with
GCP and the protocol were obtained and, if so, to maintain such
commitments on file to be provided upon the agency's request.
Therefore, we revised Sec. 312.120(b)(11) to require submission of
such a statement instead of copies of signed investigator commitments.
We believe that evaluation of the statements regarding commitments,
combined with the availability of the signed commitments (if any) for
our inspection, provides adequate assurance that investigators received
GCP training and minimizes
[[Page 22811]]
the burden on sponsors and the agency. We disagree with the comment
that recommended requiring signed investigator commitments. Although we
encourage sponsors to obtain written commitments, such commitments may
not be required in all countries, and we do not want to preclude
submission of ethically conducted foreign clinical studies solely
because a written commitment was not obtained.
J. Waivers
Proposed Sec. 312.120(c) would have permitted sponsors or
applicants to request that FDA waive any applicable requirements under
Sec. 312.120(a)(1) and (b). Under proposed Sec. 312.120(c)(2), we
could have granted a waiver if we found that doing so would be in the
interest of the public health.
(Comment 33) One comment stated that proposed Sec. 312.120(c)(2)
could be construed as placing the interest of public health ahead of
the need to protect trial participants in foreign countries. The
comment recommended that we clarify the provision to indicate that a
waiver would not be granted if this would compromise the sponsor's
obligation to show that trial participants had been protected at all
times, even though the waiver might be in the interest of public
health.
(Response) In providing for this waiver, we are giving the agency a
measure of discretion to avoid inappropriate results. We envision that
we might use this provision to allow us to accept a non-IND foreign
clinical study conducted before the effective date of this rule, if the
study is in compliance with the provisions of Sec. 312.120 prevailing
at the time it was conducted, but out of technical compliance with the
terms of this rule. Section 312.120(c)(2) allows us to decide whether
to grant or deny waivers on a case-by-case basis, taking into account
all appropriate circumstances.
IV. Implementation
The proposed effective date would have applied the rule, when
final, to foreign clinical studies for which the first subject is
enrolled 180 days after the date of publication of the final rule. As
proposed, a clinical trial that is currently ongoing, which might not
be completed and for which the results might not be submitted to FDA
(in an IND or application for marketing approval) for several years,
would be submitted under previous Sec. 312.120.
We have determined that it is appropriate to make the rule
effective 180 days after the date of publication in the Federal
Register and applicable to foreign clinical studies regardless of the
status of subject enrollment (e.g., ongoing, completed, not yet
initiated). We have made this change to decrease the potential for
confusion about which version of Sec. 312.120 (new or previous) is
applicable to ongoing clinical studies. We do not believe that this
change will affect the ability of most sponsors or applicants to comply
with Sec. 312.120 because most foreign clinical trials are currently
being conducted in accordance with GCP principles. If necessary, we can
use the waiver provision under Sec. 312.120(c) to accept studies
initiated before the effective date of the rule if doing so would be in
the interest of the public health.
V. Legal Authority
We are issuing this rule under the authority of the provisions of
the act that apply to drugs (section 201 et seq. (21 U.S.C. 321 et
seq.)) and section 351 of the PHS Act. These laws authorize the
agency\3\ 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.
---------------------------------------------------------------------------
\3\In light of section 903(d) of the act (21 U.S.C. 393(d)) and
the Secretary of Health and Human Services' (the Secretary's)
delegations to the Commissioner of Food and Drugs, statutory
references to ``the Secretary'' in the discussion of legal authority
have been changed to ``FDA'' or the ``agency.''
---------------------------------------------------------------------------
Section 505 of the act 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, and to weigh evidence of
bioequivalence for generic drug approvals. Section 505(d) of the act
provides that we may approve an NDA only after finding substantial
evidence ``consisting 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), 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 505(j)(2)(A)(iv) of the act further requires us to assess
information submitted in an ANDA demonstrating, among other things,
that the ANDA drug is either bioequivalent to an already approved new
drug which is the subject of an approved NDA, or can be expected to
have the same therapeutic effect as such a drug, as determined by a
petition submitted under section 505(j)(2)(C) of the act.
Section 701(a) of the act (21 U.S.C. 371(a)) authorizes the agency
to issue regulations for the efficient enforcement of the act.
Section 351(a)(2)(C)(i)(I) of the PHS Act authorizes the agency 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
the agency 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 studies not conducted
under the IND regulations as reliable evidence supporting an IND or
application for marketing approval.
VI. Paperwork Reduction Act of 1995
This final rule contains information collection requirements that
are subject to review by the Office of Management and Budget (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 in the following paragraphs
with an estimate of the annual reporting and recordkeeping burden. The
estimate includes the time for reviewing instructions, searching
existing data sources, gathering and maintaining the data needed, and
completing and reviewing each collection of information.
[[Page 22812]]
Title: Foreign Clinical Studies Not Conducted Under an IND
Description: Previous Sec. 312.120 stated 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. It further stated
that 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 final rule replaces the requirement that non-IND 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 making this change for the
following reasons: (1) We want to provide greater assurance of the
quality of data obtained from non-IND 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 to the Declaration because that document is subject to
change, independent of FDA authority, in a manner that might be
inconsistent with U.S. laws and regulations, and referring to a
superseded version of the Declaration could create the potential for
confusion about the requirements for non-IND foreign studies.
Under revised Sec. 312.120(a), we will accept as support for an
IND or application for marketing approval a well-designed and well-
conducted foreign clinical study not conducted under an IND if the
study is conducted in accordance with GCP and we are able to validate
the data from the study through an onsite inspection if necessary. GCP
includes 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.
Previous Sec. 312.120(b) required a sponsor of a non-IND foreign
study who wanted to rely on that study as support for an IND or
application for marketing approval to provide certain data to FDA.
Revised Sec. 312.120(b) requires this same information as well as the
following: (1) The name and address of the IEC and a summary of 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 consistently 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 a
statement on whether written commitments by investigators to comply
with GCP and the protocol were obtained.
Revised Sec. 312.120(c) specifies how sponsors or applicants can
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
revised Sec. 312.120(c)(1), a waiver request must contain at least one
of the following: (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 revised 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 rule:
Table 1.--Estimated Annual Reporting Burden\1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
No. of Frequency of Total Annual Hours per
21 CFR Section Respondents Responses Responses Response Total Hours
--------------------------------------------------------------------------------------------------------------------------------------------------------
312.120 115 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 non-IND foreign clinical studies in support of an IND
or application for marketing approval for a drug or biological product.
We conducted consultations with seven large and small companies that
had submitted non-IND foreign clinical studies to us during 1998
through 2001. All respondents indicated that they currently conduct
non-IND foreign clinical studies in conformance with GCP and generally
document all the items listed in revised 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
previously were required (under previous Sec. 312.120(b)(1) through
(b)(5) and (c)(3)) to document the items in revised 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 represented the greater protection of
the individual (previous 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 non-IND
foreign clinical trial. To provide a liberal estimate of costs to
industry, we assumed that no companies currently document compliance
with any component of GCP and that the documentation required under
revised 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 addition to the reporting requirements set forth in table 1 of
this document, the final rule includes a
[[Page 22813]]
provision, Sec. 312.120(d), stating how long sponsors and applicants
must retain records required by Sec. 312.120. Under the proposed rule,
the retention requirements in Sec. 312.57(c), for records and reports
required under part 312, would have applied to these records. However,
we decided to clarify the recordkeeping requirements applicable to
records required under this rule by establishing Sec. 312.120(d).
Under Sec. 312.120(d), if a study is submitted in support of an
application for marketing approval, records must be retained for 2
years after an agency decision on that application; if a study is
submitted in support of an IND but not an application for marketing
approval, records must be retained for 2 years after the submission of
the IND. The recordkeeping requirements for studies under part 312 are
approved under OMB control number 0910-0014 until May 31, 2009.
In compliance with the PRA (44 U.S.C. 3507(d)), we submitted a copy
of this rule to OMB for its review and approval of these information
collections.
The reporting requirements of this final rule have been approved
under OMB control number 0910-0622. This approval expires on April 11,
2011. An agency may not conduct or sponsor, and a person is not
required to respond to, a collection of information unless the
information collection displays a currently valid OMB control number.
VII. Environmental Impact
We have 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.
VIII. Federalism
We have analyzed this final 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
final 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.
IX. Analysis of Economic Impacts
We have examined the impacts of the final 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
final rule is not an economically significant regulatory action under
the Executive order.
The Regulatory Flexibility Act requires agencies to analyze
regulatory options that would minimize any significant impact of the
rule on small entities. Because the estimated impact of the final rule
is not substantial and, in any event, clinical investigators generally
follow GCP already, we certify that the final rule will not have a
significant economic impact on a substantial number of small entities.
Section 202(a) of the Unfunded Mandates Reform Act 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 the expenditure by
State, local, and tribal governments, in the aggregate, or by the
private sector, of $100,000,000 or more (adjusted annually for
inflation) in any one year.'' The current threshold after adjustment
for inflation is approximately $127 million, using the most current
(2006) Implicit Price Deflator for the Gross Domestic Product.
We do not expect this final rule to result in any 1-year
expenditure that would meet or exceed this amount.
A. Objectives of the Final Rule
The objectives of the final 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 our 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 final rule also will 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 applications
for marketing approval. These applications contain the results of
clinical investigations that characterize the therapeutic benefit of
the new product and assess its risks. We review the submitted data and
decide whether there is sufficient evidence of safety and effectiveness
to grant approval.
Clinical data included in an application for marketing approval
usually are collected under an IND, for 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 application for marketing approval 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. However,
we have always required and reviewed the safety results of non-IND
foreign clinical trials of drug products considered for marketing
approval in the United States.
According to estimates from the Center for Drug Evaluation and
Research (CDER) and the Center for Biologics Evaluation and Research
(CBER), approximately 650 clinical investigations of investigational
products intended for commercial marketing were initiated each year
from 1995 through 1999. In addition, commercial sponsors submitted
approximately 2,600 new protocols each
[[Page 22814]]
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 an application for marketing
approval (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 non-IND
foreign trials are conducted annually for eventual submission to FDA as
part of an IND or application for marketing approval (3,825 - 3,250 =
575).
We also estimated the number of applications supported by data from
foreign trials not conducted under an IND. According to CDER data, each
application for marketing approval may cite an average of approximately
five investigations that provide important information relative to
approval decisions. Lacking data on INDs supported by data from non-IND
foreign trials, we will assume the same ratio of investigations to
applications is true. Based on these estimates, we estimate that the
575 foreign trials conducted annually are used to support 115 INDs or
applications for marketing approval.
C. The Final Rule
Under the final rule, all non-IND foreign clinical studies
submitted as support for an IND or application for marketing approval
must be conducted under GCP as defined in the rule. Under previous
Sec. 312.120, we accepted as support for an IND or application for
marketing approval foreign clinical studies not conducted under an IND
provided they were well designed, well conducted, performed by
qualified investigators, and conducted in accordance with ethical
principles. Sponsors of non-IND investigations used in support of INDs
or applications for marketing approval were required to follow either
the principles of the 1989 Declaration for patient protection or
national laws that provide even greater protection. The final rule is
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. application for
marketing approval are well designed and well conducted and provide
sufficient protection to subjects. Consequently, under the final rule,
we will not accept any non-IND foreign clinical results as support for
sponsor claims of efficacy unless the trials are 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.
D. Costs of the Final Rule
We interviewed seven pharmaceutical manufacturers that had
submitted results from non-IND 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 final rule requires
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 final rule) are not specifically required to be
documented and submitted in an application for marketing approval 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 applications for marketing approval. 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 non-IND studies makes
it difficult for us to determine the adequacy of pre-initiation review
of study protocols. The final rule will help ensure that these
documents are available for our inspection at research sites and that
information on IEC review is included in INDs and applications for
marketing approval.
The amount and detail of the necessary documentation will 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 non-IND 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 noted previously in
this document, we estimate that approximately 575 non-IND foreign
commercial clinical trials are conducted annually. Using the high
estimate of the additional hours of documentation needed for each non-
IND clinical trial, this would result in a total annual cost of about
$552,000 to the sponsoring firms (32 hours x 575 non-IND foreign trials
x $30 = $552,000).
E. Benefits of the Final 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 applications for marketing approval. We further
believe that the final rule will decrease the possibility 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 applications for marketing approval resulting from
the use of GCP in lieu of previous 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 non-IND studies will result in an
additional benefit, also difficult to quantify, due to better quality
data about the safety and effectiveness of products and greater public
confidence in the scientific basis for FDA decisions.
F. Small Business Impact
The final 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.
[[Page 22815]]
1. Nature of the Impact
As discussed previously in this document, we estimate that the
final rule will increase total costs to sponsors of foreign clinical
studies by approximately $552,000 per year. The increased costs will be
due to greater costs of review and documentation of the approval of
study protocols by IECs. The resources needed to comply with this rule
are not specialized. Assuming, for purposes of this calculation, that
each of the approximately 115 INDs or applications for marketing
approval submitted annually (in which are reported approximately 575
non-IND foreign clinical studies) is submitted by a different sponsor,
each sponsor would incur costs of approximately $4,800 per year to
comply with the final rule ($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
applications for marketing approval is markedly different from the
general industry. We examined the characteristics of sponsors of new
drug product applications for marketing approval between October 1996
and October 1999 (Ref. 2). Of the 158 firms that had sponsored
applications for marketing approval 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 non-IND foreign clinical trials to develop
data for submission in an FDA application for marketing approval
(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 non-IND 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 Final Rule
We considered several alternatives to the final 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 but
rejected allowing an exemption from the requirements in the final rule
for small entities. We must have confidence that all clinical
investigations submitted as support for an IND or application for
marketing approval meet basic standards of reliability, patient safety,
and data quality.
4. Outreach
We received 32 comments on the proposed rule. There were no
comments on the ``Analysis of Impacts'' discussion.
5. Conclusion
For the reasons stated previously, we conclude that the final rule
will 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 (HFA-305), Food and Drug Administration,
5630 Fishers Lane, rm. 1061, Rockville, MD 20852, 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.
List of Subjects in 21 CFR Part 312
Drugs, Exports, Imports, Investigations, Labeling, Medical
research, Reporting and recordkeeping requirements, Safety.
0
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, 21 CFR part
312 is amended as follows:
PART 312--INVESTIGATIONAL NEW DRUG APPLICATION
0
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, 356, 371,
381, 382, 383, 393; 42 U.S.C. 262.
0
2. Section 312.3 is amended in paragraph (b) by alphabetically adding a
definition for ``Independent ethics committee'' to read as follows:
Sec. 312.3 Definitions and interpretations.
* * * * *
(b) * * *
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 of this chapter, is
one type of IEC.
* * * * *
0
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 or application for marketing approval (an application under section
505 of the act or section 351 of the Public Health Service Act (the PHS
Act) (42 U.S.C. 262)) 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,
[[Page 22816]]
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 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, before initiation of
the study, that informed consent is not feasible and either that the
conditions present are consistent with those described in Sec. 50.23
or Sec. 50.24(a) of this chapter, or that the measures described in
the study protocol or elsewhere will protect the rights, safety, and
well-being of subjects; 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 or
application for marketing approval 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 or application for marketing approval must submit to FDA, in
addition to information required elsewhere in parts 312, 314, or 601 of
this chapter, 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 is not required to
duplicate information already submitted in the IND or application for
marketing approval. Instead, the description must provide either the
following information or a cross-reference to another section of the
submission where the information is located:
(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 name and address of the IEC that reviewed the study and a
statement that the IEC meets the definition in Sec. 312.3 of this
chapter. The sponsor or applicant must maintain records supporting such
statement, including records of the names and qualifications of IEC
members, and make these records available for agency review upon
request;
(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 consistently 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 a
statement on whether written commitments by investigators to comply
with GCP and the protocol were obtained. Any signed written commitments
by investigators must be maintained by the sponsor or applicant and
made available for agency review upon request.
(c) Waivers. (1) A sponsor or applicant may ask 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.
(d) Records. A sponsor or applicant must retain the records
required by this section for a foreign clinical study not conducted
under an IND as follows:
(1) If the study is submitted in support of an application for
marketing approval, for 2 years after an agency decision on that
application;
(2) If the study is submitted in support of an IND but not an
application for marketing approval, for 2 years after the submission of
the IND.
Dated: April 21, 2008.
Jeffrey Shuren,
Associate Commissioner for Policy and Planning.
[FR Doc. E8-9200 Filed 4-25-08; 8:45 am]
BILLING CODE 4160-01-S