[Federal Register: September 24, 1997 (Volume 62, Number 185)]
[Proposed Rules]               
[Page 49946-49954]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr24se97-18]

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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]
BILLING CODE 4160-01-F

Posted by Office of Special Health Issues, HF-12, September 25, 1997