[Federal Register Volume 62, Number 185 (Wednesday, September 24, 1997)]
[Proposed Rules]
[Pages 49946-49954]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-25268]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 312
[Docket No. 97N-0030]
Investigational New Drug Applications; Proposed Amendment to
Clinical Hold Regulations for Products Intended for Life-Threatening
Diseases
AGENCY: Food and Drug Administration, HHS.
ACTION: Proposed rule.
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SUMMARY: The Food and Drug Administration (FDA) is proposing to amend
the provisions of its regulations governing investigational new drug
applications (IND's) to permit FDA to place a clinical hold on one or
more studies under an IND involving a drug that is intended to treat a
life-threatening disease affecting both genders if men or women with
reproductive potential who have the disease and are otherwise eligible
but are excluded from participation in an
[[Page 49947]]
investigation only because of a risk or potential risk of reproductive
or developmental toxicity from use of the investigational drug. Women
have been excluded in the past from early clinical trials because of a
risk or potential risk of reproductive or developmental toxicity.
Therefore, the primary goal of this proposed amendment is to ensure
that women with reproductive potential who have a life-threatening
disease are not automatically excluded in the future for that reason.
The proposed rule would not impose requirements to enroll or recruit a
specific number of men or women with reproductive potential.
The proposal would implement a recommendation of both the National
Task Force on AIDS Drug Development (the AIDS Task Force) and the
Presidential Advisory Council on Human Immunodeficiency Virus/Acquired
Immune Deficiency Syndrome (HIV/AIDS).
DATES: Submit written comments by December 23, 1997. FDA proposes that
any final rule that may issue based on this proposal become effective
60 days after its date of publication in the Federal Register.
ADDRESSES: Submit written comments to the Dockets Management Branch
(HFA305), Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23,
Rockville, MD 20857.
FOR FURTHER INFORMATION CONTACT: Nancy E. Derr, Center for Drug
Evaluation and Research (HFD-5), Food and Drug Administration, 5600
Fishers Lane, Rockville, MD 20857, 301-594-5400, FAX 301-594-6197.
SUPPLEMENTARY INFORMATION:
I. Introduction
On January 19, 1995, the AIDS Task Force made a series of
recommendations related to women's participation in the drug
development process, including the recommendation that women with
reproductive potential not be excluded from studies of drugs being
tested for use against life-threatening diseases, particularly HIV- and
AIDS-related diseases. This recommendation was based, in part, on data
provided by the HIV Law Project of the AIDS Service Center (Ref. 1).
The data demonstrated that participation of women in AIDS clinical drug
trials was low.\1\
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\1\ As of January 1992, 14,799 participants were enrolled in
U.S. AIDS Clinical Trial Group studies sponsored by the National
Institute of Allergy and Infectious Diseases, of whom only 1,151
were adult women. (Pearl, M., et al., ``Women in U.S. Government
Clinical Trials,'' VIII International Conference on AIDS, 8(2: B235,
1992.)
In 1993, 21,598 participants were enrolled, while only 1,952
were adult women. (Korvick, J.A., ``Trends in Federally Sponsored
Clinical Trials,'' in Until the Cure: Caring for Women With HIV, A.
Kurth, editor, pp. 94-103, 1993).
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In the view of members of the AIDS Task Force, this low rate of
participation raised doubts as to whether a sufficient number of women
were being included in these clinical trials to provide clinically
meaningful information about the effects of HIV and AIDS drugs in the
women who would be using them. These data also raised questions and
concerns among women with HIV regarding their ability to participate in
trials for promising new experimental therapies. On December 8, 1995,
the Presidential Advisory Council on HIV/AIDS adopted the AIDS Task
Force's recommendation that FDA amend its regulations to prevent the
exclusion of women who have a life-threatening disease from any phase
of clinical investigations for that disease because of their
reproductive potential. If adopted, this proposed rule would implement
that recommendation.
FDA's policies regarding the participation of women in clinical
investigations have evolved over time. The agency now believes it is
important to codify its policies regarding the participation of women
with reproductive potential in clinical investigations of drug products
intended to treat life-threatening diseases. The proposed amendments to
the clinical hold regulations address the exclusion from clinical
trials of members of either gender who have a life-threatening disease.
The primary intent, however, is to ensure that women who have a life-
threatening disease are not automatically excluded from investigational
trials of drug products for that disease due to a perceived risk or
potential risk of reproductive or developmental toxicity from the use
of the investigational drug. The proposal would not apply to clinical
studies conducted: (1) Exclusively in healthy volunteers; (2) under
special circumstances, such as studies of a single-gender population
(e.g., studies evaluating the excretion of a drug in semen or its
effects on menstrual function); or (3) in men, as long as a study that
does not exclude subjects with reproductive potential has been planned
or is being conducted in women. For the purposes of this rulemaking,
FDA does not intend the phrase ``women with reproductive potential'' to
include pregnant women. The agency acknowledges the need for more
information on the safety and effectiveness of drugs and biological
products in pregnant women and is continuing to explore this complex
issue in other forums.
II. Clinical Hold Regulations
A clinical hold is an order, under Sec. 312.42 (21 CFR 312.42),
that FDA may issue to a sponsor to delay a proposed clinical
investigation or to suspend an ongoing investigation for the
development of a new drug, antibiotic drug, or biological product. A
clinical hold may apply to one or more of the investigations under an
IND. When FDA places a proposed study on clinical hold, subjects in
that study may not be given the investigational drug. When FDA places
an ongoing study on clinical hold, no new subjects may be recruited to
the study and placed on the investigational drug; subjects already in
the study should be taken off the therapy involving the investigational
drug unless FDA specifically permits continuation of the therapy in the
interest of patient safety.
FDA may place a clinical hold on a proposed or ongoing phase 1,
phase 2, or phase 3 investigation (Sec. Sec. 312.42(b)(1) and (b)(2)),
a proposed or ongoing treatment IND or treatment protocol
(Sec. 312.42(b)(3)), or any investigation that is not designed to be
adequate and well controlled (Sec. 312.42(b)(4)). Generally, FDA will
attempt to discuss and resolve the matter with the sponsor before
issuing a clinical hold order unless subjects are exposed to immediate
and serious risk (Sec. 312.42(c)). When the deficiency that prompts a
clinical hold is corrected by the sponsor, the investigation generally
may resume (Sec. 312.42(e)).
III. Evolution of FDA Policy Regarding Participation of Women in
Clinical Investigations
Although the proposed amendments to the clinical hold regulations
address the exclusion from trials for drug products to treat a life-
threatening disease of members of either gender who have the disease,
the primary intent of the proposed amendments is to ensure that women
who have a life-threatening disease are not excluded from clinical
trials solely because of their reproductive potential. Since 1977, when
FDA first issued guidance on the participation of women in clinical
trials, women with reproductive potential often have been excluded from
early clinical trials due to the perceived risk or potential risk of
reproductive or developmental toxicity. As the following discussion
shows, however, views on the participation of women, as well as
corresponding FDA guidance and regulations pertaining to clinical
trials of investigational drugs, reflect a
[[Page 49948]]
significant evolution of thought during the past two decades within the
agency and the scientific community. In addition, during this period
considerable public attention has been paid to questions about the
participation of women in general in clinical trials. The following
background information highlights key FDA statements on the inclusion
of women, especially women with reproductive potential, in the clinical
drug testing process. Throughout, the phrase ``reproductive toxicity''
refers to toxicities to reproductive organs, while the term
``developmental toxicity'' refers to toxicities to potential offspring.
The agency first provided formal guidance on the participation of
women with reproductive potential in clinical trials in a 1977
guideline entitled ``General Considerations for the Clinical Evaluation
of Drugs'' (the 1977 guideline). Developed within the protective
environment brought on by the thalidomide experience a decade earlier,
the 1977 guideline stated that women of childbearing potential should
not be included in phase 1 and early phase 2 trials because of the
potential for reproductive or developmental toxicity. Women with
childbearing potential could be included in later phase 2 and phase 3
studies, as long as animal teratogenicity and the female part of animal
fertility studies had been completed and there was some evidence of
effectiveness from earlier studies. The 1977 guideline made an
exception to this recommendation for early trials involving drug
products intended to treat life-threatening diseases, even in the
absence of adequate reproduction studies in animals. Despite this
exception, however, the exclusion of women of reproductive potential
from early trials was in some cases applied to trials for drug products
to treat life-threatening diseases.
Since the 1977 guideline was issued, views have evolved about the
participation of women in clinical trials. Views also have evolved
about informed individuals assuming the risks of investigational
products. Recognition has increased in the agency and among the public
that patients, especially those with a life-threatening disease, are
willing to accept considerable risks to participate in studies that may
benefit them. There is increased public recognition of ethical issues
such as fairness and an individual patient's ability to participate in
decisions that involve personal risk. There is growing understanding
that information about population subgroups, e.g., subsets grouped by
age, gender, or race, is needed to evaluate the safety and
effectiveness of therapies and to refine labeling, patient selection,
and dose selection in those groups. Failure to obtain such information
may limit the usefulness of a treatment or expose a segment of the
population to risk. These perspectives have influenced FDA policy since
the early 1980's.
In the Federal Register of July 22, 1993 (58 FR 39406), FDA issued
a ``Guideline for the Study and Evaluation of Gender Differences in the
Clinical Evaluation of Drugs'' (the 1993 guideline). That guideline
revoked the 1977 guideline's recommendation regarding restrictions on
the participation of women with reproductive potential in early
clinical trials, including clinical pharmacology studies (e.g., dose
tolerance, bioavailability, and mechanism of action studies) and early
therapeutic studies. The 1993 guideline left the determination about
whether the risks and benefits support the participation of women with
reproductive potential to patients, investigators, sponsors, and
institutional review boards (IRB's).
Although the 1993 guideline does not require participation of women
in any particular trial, it sets forth FDA's general expectations
regarding the inclusion of both women and men in drug development,
analyses of clinical data by gender, assessment of potential
pharmacokinetic differences between genders, and conduct of specific
additional studies in women, where indicated. The 1993 guideline is
consistent with an earlier guideline, issued in 1988 and entitled,
``Guideline for the Format and Content of the Clinical and Statistical
Sections of New Drug Applications'' published in the Federal Register
of October 7, 1988 (53 FR 39524), in which FDA advised that new drug
applications (NDA's) should include analyses of data for population
subsets, including age, gender, and race, to identify subgroup
differences in effectiveness and adverse reactions to investigational
drugs. The 1993 guideline notes that participants in clinical studies
should, in general, reflect the population that will receive the drug
once it is marketed and encourages the participation of women, whether
or not they have a serious disease, in early phases of all clinical
trials. It points out that including women early is particularly
important when a drug is intended for a serious disease and may become
available rapidly, for example, through distribution under a treatment
IND (Secs. 312.34 and 312.35 (21 CFR 312.34 and 312.35)), or marketing
under subpart E of part 601 (21 CFR part 601) and consisting of
Secs. 601.40 through 601.46 or subpart H of part 314 (21 CFR part 314)
and consisting of Secs. 314.500 through 314.560. (See section IV.A. of
this document for a description of these procedures.)
FDA has long recognized the importance of gender data in evaluating
the safety and efficacy of a drug. This is reflected in other FDA
guidances issued in 1993 (``New Drug Evaluation Guidance Document:
Refusal to File'' and ``Center for Biologics Evaluation and Research
(CBER): Refusal to File (RTF) Guidance for Product License Applications
(PLA's) and Establishment License Applications (ELA's)'' (58 FR 38770,
July 20, 1993). These documents state that FDA may refuse to file an
application if it contains inadequate evaluation of the safety and/or
effectiveness of a drug, biological therapeutic, or vaccine in specific
populations, such as in women, intended to use the product.
FDA also recently proposed a rule that would codify expectations
regarding presentation in NDA's of safety and effectiveness data by
gender as described in the 1993 guideline. Although it would not
require the inclusion of women with reproductive potential in clinical
investigations, the rule would require the presentation in NDA's of
certain data by specific population subgroups, including women, who are
likely to receive the drug once it is marketed (60 FR 46794, September
8, 1995).
The 1977 guideline never recommended excluding women with
reproductive potential from trials for drugs to treat life-threatening
diseases. Moreover, the 1993 guideline recommended that the exclusion
of such women be removed from all trials. Nevertheless, a recent
limited agency review of clinical trial protocols dealing with
antiviral drugs revealed that women with reproductive potential are
still being excluded from some protocols of some investigational trials
for drug products intended to treat HIV, a life-threatening disease.
The agency believes that this violates ethical principles and in some
cases could lead to inadequate data on use in women prior to wide
availability of the drug. The agency has concluded that women with
reproductive potential who have a life-threatening disease should no
longer be excluded from investigational clinical trials for drug
products to treat that disease because of a risk or potential risk of
reproductive or developmental toxicity from use of the investigational
drug, as long as patient volunteers are fully informed of the risks, in
compliance with informed
[[Page 49949]]
consent regulations in part 50 (21 CFR part 50).
IV. Rationale for the Proposed Rule
In the past, women with a life-threatening disease who have
reproductive potential often have been excluded from early
investigational clinical trials for that disease because of the
potential risk of reproductive or developmental toxicity. As a result,
although it applies to the exclusion of either gender, the primary goal
of this proposed rule is to ensure that women who have a life-
threatening disease are not excluded from investigational drug studies
for that disease because of their reproductive potential.
In lengthy discussions with representatives of industry and the
public during the development of this proposal (Ref. 2), the view was
expressed that many early clinical studies involving life-threatening
diseases offer the potential for therapeutic benefit. In some cases,
for example, participation in an early clinical study is a prerequisite
for enrollment in later studies. Based on these discussions, FDA has
concluded that all trials involving patients with life-threatening
diseases should, for purposes of this proposed rule, be considered to
have therapeutic potential and that this proposal would apply to
studies in any phase of a clinical investigation that enroll
participants with a life-threatening disease.
In developing this proposal, FDA focused on four important factors:
(1) FDA is committed to expanding access to and accelerating approval
of new therapies for life-threatening diseases; (2) important ethical
principles underlie the belief that neither gender should be excluded
from early clinical trials involving a life-threatening disease because
of their reproductive potential; (3) the mechanisms are in place, or
are available, to protect individuals who participate in clinical
trials from potential risks; and (4) FDA is committed to expanding the
collection of gender-specific data on investigational therapies,
especially for those populations who ultimately will be using the
therapies. These four factors are discussed in detail in the following
sections of this document.
A. Expanding Access and Accelerating Approval
FDA is committed to expanded patient access to potentially
beneficial therapies for life-threatening and serious diseases, such as
cancer and AIDS, through the IND process. Mechanisms for expanding
access include treatment IND's (Secs. 312.34 and 312.35), parallel
track protocols (57 FR 13250, April 15, 1992), and other open-label
protocols either for groups of patients or for one patient. Tens of
thousands of patients have received promising pharmaceuticals under
expanded access mechanisms.
In many cases, the risk-benefit assessment for investigational
drugs for life-threatening or even serious diseases differs from that
for investigational drugs for treating diseases not considered life-
threatening or serious. In establishing procedures for the
investigation of drugs for life-threatening diseases, FDA has
recognized that physicians and patients are generally willing to accept
greater risks or side effects from these medical products than they
would accept from products that treat less serious diseases (53 FR
41516 at 41518, October 21, 1988).
FDA also is committed to expediting the approval of
investigational drugs for treatment of life-threatening and serious
diseases. The agency has issued regulations for the expedited
development of new therapies intended to treat persons with life-
threatening or severely debilitating diseases (subpart E of part 312
(21 CFR part 312) procedures in Secs. 312.80 through 312.88),
especially where no satisfactory alternative therapies exist. In
addition, FDA has issued regulations for the accelerated approval of
certain new drugs (subpart H of part 314 procedures in Secs. 314.500
through 314.560) and biological products (subpart E of part 601
procedures in Secs. 601.40 through 601.46) for serious or life-
threatening diseases. For instance, accelerated approval can be based
on a surrogate endpoint that reasonably suggests clinical benefit or on
evidence of the drug's effect on a clinical endpoint other than
survival or irreversible morbidity. On March 29, 1996, President
Clinton announced a major initiative undertaken by FDA to make
promising new therapies available sooner to American cancer patients
with intractable or unresponsive malignancies. Under this initiative,
FDA proposes, among other things, to shorten approval times for cancer
treatments by recognizing that tumor shrinkage is often an early
indication of a treatment's effectiveness and by basing approval of
investigational drugs for refractory tumors on evidence of tumor
shrinkage.
In view of the agency's commitment to provide expanded access to
and accelerated approval of new therapies for life-threatening and
serious diseases, this proposed rule is intended to ensure that women
with reproductive potential who have a life-threatening disease are not
excluded from volunteering for and being included in clinical
investigational trials for drug products intended to treat their
disease. Although a risk or potential risk of reproductive or
developmental toxicity might exist, FDA recognizes that the potential
benefits that may be accrued by these women from participation in a
study for their disease may outweigh such risks and that the
availability of certain safeguards can reduce these risks. (See section
IV.C. of this document for a discussion regarding minimizing risks.)
B. Ethical Principles
In developing this proposal, FDA has carefully considered the
evolution of thought within the agency and the scientific community and
among the public regarding the participation of women in clinical
trials and the related risks or potential risks. The agency also has
considered the basic ethical principles that underlie clinical
research. Current FDA and Department of Health and Human Services
regulations related to informed consent and IRB's are based, in large
part, on the three ethical principles relevant to human subject
research discussed in the Report of the National Commission for the
Protection of Human Subjects of Biomedical and Behavioral Research (the
Belmont Report) (44 FR 23192, April 18, 1979). These principles include
respect for persons, beneficence, and justice.
The principle of respect for persons usually is cited within the
context of being certain that individuals are included in clinical
research voluntarily after being fully informed. The principle
recognizes the ability of autonomous individuals to make their own
decisions about participating in clinical research.
The principle of beneficence requires that the risks associated
with a clinical research activity be reasonable in the light of
expected benefits. Beneficence also requires that the chance for
benefits from participation be maximized, and the risk of possible
harms be minimized, consistent with sound research design. In weighing
risks and benefits, beneficence also recognizes the results of research
as a potential benefit, so long as the rights of research participants
are protected.
The principle of justice requires that the burdens and benefits of
participation in clinical research be equitably distributed across the
entire population in the place or region where the clinical research is
conducted. In general, racial, ethnic, gender, and economic status
should not be used as a basis for excluding participation in clinical
research. Furthermore, persons who are eligible for participation in
the
[[Page 49950]]
clinical research because of their disease or condition should be
provided a reasonable opportunity to be included in the research until
the research cohort is fully recruited.
An Institute of Medicine committee recently examined the issue of
women in health research (Ref. 3). As part of their deliberations, they
highlighted the ethical principle of justice and recommended that the
scientific community and the institutions that support it ensure that
scientific advances in medicine and public health fairly benefit all
people, regardless of gender, race, ethnicity, or age. The committee
concluded that clinical trials should be conducted consistent with the
principle that medical research promotes the health and well-being of
both women and men. This proposed rule would help achieve that goal by
ensuring that women with a life-threatening disease are not denied the
opportunity to contribute to the body of scientific knowledge about
their disease and its manifestations in women.
The proposed rule is consistent with the three ethical principles
in the Belmont Report and would help to ensure that women with
reproductive potential who suffer from a life-threatening disease are
no longer excluded from early clinical research.
C. Informed Consent and Other Mechanisms for Protecting People With a
Life-Threatening Disease in Early Clinical Trials
A number of mechanisms are in place to protect participants in
early clinical trials, including requirements for sound study design,
the use of sound research procedures, and the proper use of the
informed consent process. In addition to the sponsors, who have the
responsibility of designing safe clinical trials, and the
investigators, who carry them out, institutional review boards (IRB's)
play an important role in ensuring participant safety in clinical
trials. It is the responsibility of the involved IRB to determine that
specific criteria for the protection of study participants are met
before approving research subject to the IND regulations
(Sec. 56.111(a) (21 CFR 56.111(a))). For example, the IRB must
determine that risks to study participants are minimized by the use of
procedures consistent with sound research design and that risks to
study participants are reasonable in relation to anticipated benefits
(Sec. 56.111(a)(1) and (a)(2)). The IRB also is responsible for
ensuring that information given to study participants as part of the
informed consent process is in accordance with FDA's regulations under
part 50 (see Sec. 56.111(a)(4)).
Elements of informed consent require that potential study
participants be adequately informed that the study involves research
(Sec. 50.25(a)(1)) and of any foreseeable risks or discomforts
(Sec. 50.25(a)(2)). In addition, prospective study participants must be
informed, when appropriate, of certain unforeseeable risks, including
potential risks to the embryo or fetus, should a female study
participant become pregnant (Sec. 50.25(b)(1)). As FDA noted in the
1993 guideline, if animal reproductive toxicity studies are complete,
the results and an explanation of their significance in humans should
be presented as part of the informed consent process (58 FR 39406 at
39411). If these studies are not complete, that fact should be
communicated along with any other pertinent information, such as a
general assessment of reproductive and fetal toxicity associated with
other drugs that have related chemical structures or pharmacological
effects. If no relevant information is available, the informed consent
should explicitly state that fact and make clear that the potential
exists for reproductive risks and/or developmental risks to a fetus. If
needed, the IRB should require that a specific period of time lapse
between when the potential study participants receive relevant
information and when they must decide whether to participate in the
study. If in the IRB's judgment, additional information to that
required by Sec. 50.25 would add meaningfully to the protection of the
rights and welfare of study participants, the IRB may require the
imparting of that information to the study participants (21 CFR
56.109(b)).
It is also the responsibility of the IRB to determine that the
study is designed in such a way as to minimize the risk of fetal
exposure to possibly harmful agents. Developmental toxicity has been
linked to maternal exposure to certain drugs. Although a link between
paternal drug exposure and developmental toxicity has not been
conclusively established, results of some studies suggest that paternal
exposure to certain drugs might be associated with developmental
toxicity (Ref. 4). In particular, low-level, chronic genotoxic
exposures that maintain fertility might lead to fetal developmental
abnormalities, particularly when there is exposure of post-stem cell
stages of spermatozoal development. Although the agency has not issued
formal guidance on this issue, in such cases, it might be prudent to
take precautions to prevent impregnation of women by men participating
in such investigational studies.
The risk of fetal exposure can be eliminated by preventing
pregnancy (except in those studies designed to test a drug's effect
during pregnancy). The risk of fetal exposure also can be minimized by
sponsors and IRB's, who can require the use of pregnancy testing to
detect unsuspected pregnancy prior to initiation of study treatment or
at intervals during the course of drug exposure. When the study design
permits, sponsors can minimize potential developmental risks by short-
term timing of studies to coincide with the early follicular phase of
the menstrual cycle. Thus, in most of these short-term studies, the
investigational agent would be eliminated from a woman's body prior to
conception, should she inadvertently become pregnant. When the
teratogenic effects of a drug are well established, the agency,
sponsor, or IRB may require the use of contraception to prevent
pregnancy in sexually active individuals of childbearing potential.
Women and men can eliminate the possibility of pregnancy through
abstinence and reduce the possibility of pregnancy through the use of
contraception for the duration of drug exposure (which may exceed the
length of the study). In part because the cooperation of the
individual's sexual partner may be needed to ensure that abstinence
occurs, or that appropriate contraceptive methods are used, it is
important for potential study participants to be provided with an
opportunity to discuss their involvement in a clinical trial with their
sexual partner prior to deciding whether to participate in the study.
The agency believes that, through the proper use of the informed
consent process and the use of other study design mechanisms, risks to
participants in early clinical trials can be reduced. When deciding
whether to participate in a clinical trial for an investigational drug,
potential participants should be able to weigh, in consultation with
their spouse or partner, their health care provider, and their
researcher, the potential risks of their participation.
D. Expanding the Collection of Gender-Specific Data
As noted previously, the need for gender specific data was the
subject of guidances developed by the agency in 1988 and 1993 and was
addressed in a proposed rule issued in 1995. Recently, medical and
scientific issues related to gender analyses were the subject of an
FDA-sponsored workshop on ``Gender Studies in Product Development:
[[Page 49951]]
Scientific Issues and Approaches'' held from November 6 to 7, 1995
(Ref. 5). Workshop participants, including representatives from
industry, academia, government agencies, consumer groups, and patient
communities, concluded that women should be included in all stages of
drug development to fully characterize the safety and efficacy profile
of the product. It was noted by numerous participants that use of
gender-specific data from early trials may improve the efficiency of
phase 3 trials by aiding in the interpretation of expected variations
among gender groups.
In the 1993 guideline, FDA acknowledged that although drugs often
behave similarly in demographic (age, gender, race) and other
(concomitant disease, concomitant drugs) subsets of the population,
there are many differences within such subsets, for example, in dose-
response, in maximum size of effect, or in the risk of an adverse
effect (58 FR 39406 at 39409). To identify such potential differences
and to help refine labeling information, patient selection, and dose
selection, the agency believes that it is important that those women
who are likely to use an investigational agent once it is marketed be
included in clinical investigations that may identify potential gender
differences. In the case of HIV and AIDS, many of the women who are
affected are young women with reproductive potential. Therefore, early
participation by these women in clinical trials for such diseases will
help ensure that needed gender-specific safety and effectiveness data
are available for the women affected by the disease (Ref. 6).
V. Legal Authority
Section 505(i) (21 U.S.C. 355(i)) of the Federal Food, Drug, and
Cosmetic Act (the act) confers broad authority upon the Secretary of
Health and Human Services (the Secretary) (and by delegation to FDA) to
issue regulations governing the clinical investigation of new drugs to
protect the rights, safety, and welfare of human subjects (including
through informed consent provisions) and otherwise to protect the
public health. In addition, section 701 of the act (21 U.S.C. 371)
provides that the Secretary has authority to issue regulations for the
efficient enforcement of the act (including the drug-related
provisions, such as the misbranding and approval provisions of sections
502 (21 U.S.C. 352) and 505 of the act.
The proposed amendment to the clinical hold regulations is intended
to protect human subjects against being categorically excluded, based
on reproductive potential, from the opportunity to participate in
clinical trials investigating potentially beneficial treatments for a
life-threatening disease. In addition, the proposed amendment would
enhance public health protection by expanding opportunities to generate
data concerning the safety and efficacy of investigational drugs for
the treatment of life-threatening diseases.
The agency believes that prohibiting the exclusion of women with
reproductive potential who have a life-threatening disease from
clinical trials also is consistent with congressional efforts to
prevent unwarranted discrimination against women. In the employment
context, for example, the Civil Rights Act of 1964, as amended by the
Pregnancy Discrimination Act (42 U.S.C. 2000e(k), 2000e-2(e)(1)) and as
interpreted by the U.S. Supreme Court in the landmark case of
International Union, United Automobile, Aerospace and Agricultural
Implement Workers, UAW v. Johnson Controls, Inc., 111 S.Ct. 1196
(1991), prohibits the exclusion of women with childbearing capacity
from jobs they are qualified to perform solely because the working
conditions of those jobs pose potential risks to exposed fetuses.
Although the Court did not consider or hold that the Civil Rights Act
applies to clinical drug trials, which are manifestly different in
nature and purpose from private employment, FDA believes it is
appropriate to consider the Court's opinion when developing policy on
the eligibility of women with reproductive potential for participation
in clinical trials for a life-threatening disease.
VI. Description of the Proposed Rule
Current Sec. 312.42(b)(1) identifies the grounds for placing a
clinical hold on proposed or ongoing phase 1 studies under an IND, and
current Sec. 312.42(b)(2) identifies the grounds for placing a clinical
hold on proposed or ongoing phase 2 or phase 3 studies. FDA is
proposing to amend Secs. 312.42(b)(1) and (b)(2) to provide an
additional ground for placing a phase 1, phase 2, or phase 3 study
under an IND on clinical hold. Under proposed Secs. 312.42(b)(1)(v) and
(b)(2)(i), FDA may issue a clinical hold on any proposed or ongoing
clinical trial for a life-threatening illness or disease that affects
both genders if men or women with reproductive potential who have the
disease being studied are excluded from eligibility in any phase of
clinical investigation because of a risk or potential risk of
reproductive toxicity (i.e., toxicity to reproductive organs) or
developmental toxicity (i.e., toxicity to potential offspring) from use
of the investigational drug. FDA believes that such risks would be
outweighed by the potential benefits that may be accrued by
participants in a study for the treatment of their disease and that
fully informed potential participants should be able to make their own
risk-benefit determination. FDA also believes that, in the case of
developmental toxicity, potential risks can be minimized by the
prevention of pregnancy through contraception or abstinence.
The clinical hold under proposed Secs. 312.42(b)(1)(v) and
(b)(2)(i) would not apply to clinical studies conducted: (1)
Exclusively in healthy volunteers; (2) under special circumstances,
such as studies of a single-gender population (e.g., studies evaluating
the excretion of a drug in semen or its effects on menstrual function);
or (3) in men, as long as a study that does not exclude subjects with
reproductive potential has been planned or is being conducted in women.
The phrase ``women with reproductive potential'' as used in the
proposed rule does not include pregnant women. The proposed rule also
would not impose requirements to enroll or recruit a specific number of
men or women with reproductive potential.
As is true for clinical holds on any basis, FDA ordinarily would
issue a clinical hold only after attempts to convince the sponsor to
remove an exclusion had failed (Sec. 312.42(c)).
Under proposed Sec. 312.42(b)(1)(v), ``life-threatening illnesses
or diseases'' are defined as ``diseases or conditions where the
likelihood of death is high unless the course of the disease is
interrupted.'' The proposed definition is consistent with the
definition of ``life-threatening'' in the IND regulations governing
drugs intended to treat life-threatening illnesses (21 CFR
312.81(a)(1)).
The proposed definition of life-threatening illnesses or diseases
is intended to include those fatal diseases where death itself may not
be imminent, but where treatment is necessary to prevent premature
death. For example, an anti-retroviral drug might be found, on the
basis of phase 2 studies, to delay progression from the asymptomatic
state to the symptomatic state and then to AIDS when used early after
infection with HIV. Although this progression ordinarily would take
more than 12 months to occur in most patients, this condition would be
within the definition of life-threatening. Other examples of life-
threatening illnesses include cancer, certain cardiac arrhythmias,
intracranial hemorrhage, or amyotrophic lateral sclerosis.
The exclusion of subjects with reproductive potential addressed by
this proposed rule not only includes explicit
[[Page 49952]]
exclusion but also de facto exclusion. For example, a de facto
exclusion might result from setting study entry criteria that require
sterilization and would have the effect of precluding enrollment of
participants with reproductive potential. De facto exclusions also
might result from setting criteria that are inherently difficult for
subjects to meet, such as weight, or other physical requirements that
generally differ between women and men.
VII. Environmental Impact
The agency has determined under 21 CFR 25.30(h) that this action is
of a type that does not individually or cumulatively have a significant
effect on the human environment. Therefore, neither an environmental
assessment nor an environmental impact statement is required.
VIII. Paperwork Reduction Act of 1995
This proposed rule does not contain any information collection
provisions that would be subject to review by the Office of Management
and Budget (OMB) under the Paperwork Reduction Act of 1995 (44 U.S.C.
3501-3520).
IX. Analysis of Impacts
FDA has examined the impacts of the proposed rule under Executive
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612).
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). The Regulatory
Flexibility Act requires agencies to analyze regulatory options if the
proposed rule is expected to have a significant impact on a substantial
number of small entities.
The Unfunded Mandates Reform Act (Pub. L. 104-4) requires that
agencies prepare an assessment of anticipated costs and benefits before
proposing any rule that may result in an annual 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). This
proposed rule does not impose any mandates on State, local, or tribal
governments, or the private sector that will result in an annual
expenditure of $100,000,000 or more. The data for the impacts analysis
were developed by FDA's Economics Staff, Office of Management and
Systems, Office of Planning and Evaluation, and their full report is on
file at the Dockets Management Branch (address above).
A. Costs
Implementation of this proposed rule could impart additional direct
costs to the industry in one area--the cost associated with testing for
pregnancy in women with reproductive potential who volunteer to
participate in clinical trials that would have previously excluded
them.
As fully described in its detailed study (Ref. 7), FDA estimated
the direct cost in the following manner. Using an FDA protocol
database, the agency estimated the number of clinical trials for drug
products for life-threatening diseases from which women with
reproductive potential are being excluded. The agency then determined
the total number of subjects recruited for those clinical trials. Using
published information, the agency estimated the relative incidence
among women with reproductive potential for the specific life-
threatening diseases compared to the incidence in the general
population. Using the estimates of relative incidence among women with
reproductive potential for the specific disease, it was estimated how
many women would be participating in clinical trials for the specific
disease, were they not being excluded. Finally, using the approximate
length of each phase of clinical trials (phases 1, 2, and 3), the
agency calculated the number of pregnancy tests that would be necessary
to test for pregnancy in this volunteering population subset.
FDA conducted its analysis using data extracted from the majority
of the clinical trial protocols submitted to four review divisions in
the Center for Drug Evaluation and Research (CDER) during a 20-month
period between August 1, 1993, and March 31, 1995: Cardio-Renal; Anti-
Viral; Medical Imaging, Surgical and Dental; and the former Pilot Drug
Evaluation. The protocol data base includes information on the phase of
the studies (whether they are phase 1, 2, or 3), the planned size of
the trials, and the indications for which the therapies are being
studied. Data from this data base were analyzed to estimate how many
protocols were submitted to these four FDA divisions involving life-
threatening illnesses that excluded women with reproductive potential.
Forty-three protocols involving life-threatening illnesses and
excluding women with reproductive potential were identified as having
been submitted to FDA during this 20-month period.
Projecting the number of submissions from the four review divisions
across the entire agency required additional analysis because it could
not be assumed that all review divisions receive protocols for life-
threatening diseases at the same rate. To adjust for the difference
from division to division, the agency calculated the number of NDA
approvals that were granted in each division for drugs to treat life-
threatening and severely debilitating illnesses under the accelerated
approval procedures of subpart E of part 312. Using the results of this
analysis and the annualized numbers from the four analyzed review
divisions, it was possible to calculate approximately how many
protocols for life-threatening diseases that exclude women are
submitted to individual review divisions each year. It was projected
that approximately 62 protocols are submitted to FDA per year for life-
threatening diseases that exclude women with reproductive potential.
Next it was assumed that, once they are no longer excluded, women
with reproductive potential would enter clinical trials in proportion
to the relative incidence of the disease occurrence in that population
at diagnosis. Using published data on the relative incidence among
women with reproductive potential at diagnosis of AIDS, HIV, and
coronary heart disease and the number of protocols submitted to the
four divisions projected across the entire agency and annualized, the
agency estimated how many women (ages 13 to 49 years) are excluded per
year from phase 1, phase 2, and phase 3 clinical studies in the United
States. The results showed that approximately 90 women with
reproductive potential are excluded from phase 1 studies, 266 from
phase 2 studies, and 40 from phase 3 studies annually in the United
States.
If one assumes further that phase 1 studies last approximately 2
weeks, phase 2 studies approximately 3 months, and phase 3 studies
about a year, the costs for pregnancy testing can be assessed. During
phase 1 studies, approximately 1 pregnancy test would be required for
each woman with reproductive potential entering the study; during phase
2 studies, approximately 3 tests would be required; and, during phase 3
studies, approximately 12 tests would be required. At a cost of $30 per
test, the annual cost to industry is estimated to be at most about
$41,000. This estimate is summarized in Table 1.
[[Page 49953]]
Table 1.--Estimated Annual Costs of Testing for Pregnancy in Women With
Reproductive Potential in U.S. Clinical Trials for Therapies for Life-
Threatening Illnesses
------------------------------------------------------------------------
Estimated
Tests Number of
Study Phase Required per Women Cost per Test Annual Costs
Woman Annually
------------------------------------------------------------------------
1............ 1 90 $30 $2,700
2............ 3 266 $30 $23,940
3............ 12 40 $30 $14,400
Totals....... 396 $41,040
------------------------------------------------------------------------
The largest cost encountered in the 43 analyzed protocols was a phase 2
trial from which an estimated 45 women with reproductive potential were
excluded. The cost of pregnancy testing for this trial, if women with
reproductive potential had been included, would have been about $4,050.
Of the 43 protocols analyzed, 6 had estimated costs of pregnancy
testing exceeding $1,000.
The agency is aware of industry's concerns about the liability
exposure associated with the inclusion of women with reproductive
potential in clinical trials, particularly prior to completion of
animal reproductive studies. FDA believes, however, that the inclusion
in investigational studies of women with reproductive potential who
have a life-threatening disease and who have given informed consent is
not likely to lead to increased liability. Informed consent means that
a study participant has agreed to participate despite recognition and
appreciation of known or potential risks, an agreement that should
minimize the legal risks associated with drug development. Careful use
of study design and informed consent is likely to minimize exposure to
liability (Refs. 8 and 9). There is, of course, no way to guarantee
this, but there have been few instances of liability assessed against
drug manufacturers for the conduct of clinical trials.
As already stated, if a deficiency exists in a clinical
investigation that may be grounds for the imposition of a clinical
hold, FDA will generally attempt to discuss and satisfactorily resolve
the matter with the sponsor before issuing the clinical hold order
(Sec. 312.42(c)). An IND would be placed on clinical hold for
specifically excluding women with reproductive potential only as a last
resort. Only for those few protocols could there be an increase in
cost, due primarily to a delay in starting the clinical trials.
The agency believes that the societal benefits more than outweigh
the potential minimal additional costs because a considerable patient
population (women with reproductive potential who have a life-
threatening disease) could receive a potentially beneficial new
therapy.
B. Small Entities
The protocol analysis identified protocols sponsored by small
businesses. The largest additional pregnancy testing cost incurred by a
small business in the reviewed protocols under the proposed rule was
$990. Projected across all CDER/CBER review divisions and annualized,
we expect no more than nine protocol submissions per year from small
businesses that might incur additional costs under the proposed rule.
Few small firms are likely to be affected in any given year and most of
these would incur no significant additional costs. Therefore, under the
Regulatory Flexibility Act, the Commissioner of Food and Drugs
certifies that this rule will not have a significant effect on a
substantial number of small entities.
X. Request for Comments
Interested persons may, on or before December 23, 1997, submit to
the Dockets Management Branch (address above) written comments
regarding this proposal. Two copies of any comments are to be
submitted, except that individuals may submit one copy. Comments are to
be identified with the docket number found in brackets in the heading
of this document. Received comments may be seen in the office above
between 9 a.m. and 4 p.m., Monday through Friday.
XI. References
Copies of the following references have been placed on display in
the Dockets Management Branch (address above) and may be seen by
interested persons between 9 a.m. and 4 p.m., Monday through Friday.
1. McGovern, T., ``Proposal to Eliminate Obstacles Facing Women
in the Drug Development Process: A Recommendation to the National
Task Force on AIDS Drug Development,'' HIV Law Project of the AIDS
Service Center, June 30, 1994.
2. Transcript of the meeting of the National Task Force on AIDS
Drug Development, October 28, 1994 (see discussion on pp. 25 to 70).
3. Mastroianni, A. C., R. Faden, and D. Federman, editors, Women
and Health Research: Ethical and Legal Issues of Including Women in
Clinical Studies, Vol. 1, National Academy Press, Washington, pp.
75-83, 1994.
4. DeLap, R. J., J. L. Fourcroy, and G. A. Fleming, ``Fetal Harm
Due to Paternal Drug Exposure: A Potential Issue in Drug
Development,'' Drug Information Journal, 30:359-364, 1996.
5. Transcript of the FDA workshop ``Gender Studies in Product
Development: Scientific Issues and Approaches,'' November 6-7, 1995.
6. Sherman, L. A., R. Temple, and R. B. Merkatz, ``Women in
Clinical Trials: An FDA Perspective,'' Science, 269:793-795, 1995.
7. Food and Drug Administration, Office of Management and
Systems, Office of Planning and Evaluation, Impacts of Not Excluding
Women with Reproductive Potential Who Have Life-threatening
Illnesses from Clinical Trials, January 10, 1997.
8. Flannery, E., and S. N. Greenberg, ``Liability Exposure for
Exclusion and Inclusion of Women as Subjects in Clinical Studies,''
in Women and Health Research: Ethical and Legal Issues of Including
Women in Clinical Studies, Vol. 2, edited by A. C. Mastroianni, R.
Faden, and D. Federman, National Academy Press, Washington, pp. 96-
97, 1994.
9. Clayton, E. W., ``Liability Exposure When Offspring Are
Injured Because of Their Parents' Participation in Clinical
Trials,'' in Women and Health Research: Ethical and Legal Issues of
Including Women in Clinical Studies, Vol. 2, edited by A. C.
Mastroianni, R. Faden, and D. Federman, National Academy Press,
Washington, pp. 108-109, 1994.
List of Subjects in 21 CFR Part 312
Drugs, Exports, Imports, Investigations, Labeling, Medical
research, Reporting and recordkeeping requirements, Safety.
Therefore, under the Federal Food, Drug, and Cosmetic Act, the
Public Health Service Act, and under authority delegated to the
Commissioner of Food and Drugs, it is proposed that 21 CFR part 312 be
amended as follows:
PART 312--INVESTIGATIONAL NEW DRUG APPLICATION
1. The authority citation for 21 CFR part 312 continues to read as
follows:
Authority: Secs. 201, 301, 501, 502, 503, 505, 506, 507, 701 of
the Federal Food, Drug,
[[Page 49954]]
and Cosmetic Act (21 U.S.C. 321, 331, 351, 352, 353, 355, 356, 357,
371); sec. 351 of the Public Health Service Act (42 U.S.C. 262).
2. Section 312.42 is amended by adding new paragraph (b)(1)(v) and
by revising paragraph (b)(2)(i) to read as follows:
Sec. 312.42 Clinical holds and requests for modification.
* * * * *
(b) * * *
(1) * * *
(v) The IND is for the study of an investigational drug intended to
treat a life-threatening illness or disease that affects both genders,
and men or women with reproductive potential who have the disease being
studied are excluded from eligibility in any phase of clinical
investigation because of a risk or potential risk of reproductive
(i.e., toxicities to reproductive organs) or developmental (i.e.,
toxicities to potential offspring) toxicity from use of the
investigational drug. The phrase ``women with reproductive potential''
does not include pregnant women. For purposes of this paragraph,
``life-threatening illnesses or diseases'' are defined as ``diseases or
conditions where the likelihood of death is high unless the course of
the disease is interrupted.'' The clinical hold would not apply under
this paragraph to clinical studies conducted:
(A) Under special circumstances, such as studies of a single-gender
population (e.g., studies evaluating the excretion of a drug in semen
or the effects on menstrual function); or
(B) In men, as long as a study that does not exclude subjects with
reproductive potential has been planned or is being conducted in women.
(2) * * *
(i) Any of the conditions in paragraphs (b)(1)(i) through (b)(1)(v)
of this section apply; or
* * * * *
Dated: September 16, 1997.
Michael A. Friedman,
Lead Deputy Commissioner for the Food and Drug Administration.
Donna E. Shalala,
Secretary of Health and Human Services.
[FR Doc. 97-25268 Filed 9-23-97; 8:45 am]
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