[Federal Register Volume 65, Number 106 (Thursday, June 1, 2000)]
[Rules and Regulations]
[Pages 34963-34971]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-13664]


-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 312

[Docket No. 97N-0030]


Investigational New Drug Applications; Amendment to Clinical Hold 
Regulations for Products Intended for Life-Threatening Diseases and 
Conditions

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA) is amending the 
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 
or condition affecting both genders. The amendments permit the agency 
to place a clinical hold on such studies if men or women with 
reproductive potential who have the disease or condition are otherwise 
eligible but are categorically excluded from participation solely 
because of a perceived risk or potential risk of reproductive or 
developmental toxicity from use of the investigational drug. This rule 
was developed in response to the past practice of excluding women with 
reproductive potential from early clinical trials because of a 
perceived risk or potential risk of reproductive or developmental 
toxicity. The final rule does not impose requirements to enroll or 
recruit a specific number of men or women with reproductive potential.

DATES: The regulation is effective July 31, 2000.

FOR FURTHER INFORMATION CONTACT: Andrea C. Masciale, Center for Drug 
Evaluation and Research (HFD-7), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-594-2041.

SUPPLEMENTARY INFORMATION:

I. Background

    In the Federal Register of September 24, 1997 (62 FR 49946), FDA 
proposed to amend its regulations in Sec. 312.42 (21 CFR 312.42) 
governing clinical holds. A clinical hold is an order 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 or 
biological product (Sec. 312.42(a)). Under the proposed amendments, FDA 
could impose a clinical hold on any proposed or ongoing clinical trial 
for a life-threatening disease or condition that affects both genders 
if men or women with reproductive potential who have the disease or 
condition being studied were excluded from eligibility in any phase of 
the clinical investigation solely because of a risk or potential risk 
of reproductive toxicity or developmental toxicity from use of the 
investigational drug. As explained in the preamble to the proposed rule 
(62 FR 49946 at 49947), the amendments address the exclusion from 
clinical trials of members of either gender who have a life-threatening 
disease or condition. Because such exclusions have in the past been 
applied primarily to women, however, it is expected that the impact of 
the amendments will be to ensure that women who have a life-threatening 
disease or condition are not categorically excluded from 
investigational trials of drug products for that disease or condition 
solely because of a perceived risk or potential risk of reproductive or 
developmental toxicity from the use of the investigational drug. FDA 
provided 90 days for public comment on the proposed rule.

II. Description of the Final Rule

    FDA regulations identify the grounds for placing a clinical hold on 
proposed or ongoing phase 1 studies (Sec. 312.42(b)(1)) and on proposed 
or ongoing phase 2 or phase 3 studies (Sec. 312.42(b)(2)). FDA is 
amending these clinical hold regulations to provide an additional 
ground for placing a phase 1, phase 2, or phase 3 study on clinical 
hold. Under these amendments, FDA may impose a clinical hold on any 
proposed or ongoing clinical trial for a life-threatening disease or 
condition 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 the investigation because of a risk or 
potential risk of reproductive or developmental toxicity from use of 
the investigational drug.
    The proposed rule refers to studies under an IND involving a drug 
that is intended to treat a life-threatening illness or disease 
affecting both genders. As stated in the proposal (62 FR 49946 at 49951 
), the definition of life-threatening illness or disease is intended to 
be consistent with the agency's IND regulations (Sec. 312.81(a)(1)). 
Under the IND regulations, the term life-threatening is applied to 
``conditions'' or ``diseases.'' To remain consistent with current 
terminology, the agency is amending the final rule to refer to ``life-
threatening diseases or conditions.''
    The clinical hold under these amendments would not apply to 
clinical studies conducted under special circumstances, such as studies 
pertinent to only one gender (e.g., to evaluate the excretion of a drug 
in semen or its effects on menstrual function).
    As described in the proposed rule, a clinical hold would not be 
applied to a clinical study conducted 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 agency expects that in an active 
IND, studies that do not exclude women or men with reproductive 
potential will be underway or will commence in a timely manner. To 
clarify this expectation, the final rule has been modified to state 
that a clinical hold would not be ordered for a study conducted only in 
men or only in women, as long as a study that does not exclude members 
of the other gender with reproductive potential is being conducted 
concurrently or will take place within a reasonable time agreed upon by 
the agency (Sec. 312.42(b)(1)(v)(B)). FDA expects that a discussion 
between the sponsor and the agency concerning a reasonable time for 
carrying out the study would take place at a pre-IND meeting or with 
the submission of the IND.
    As stated in the proposed rule, this amendment to the IND 
regulations would not apply to clinical studies conducted exclusively 
in healthy volunteers (62 FR 49946 at 49951). The final rule has been 
modified in Sec. 312.42(b)(1)(v) by adding paragraph (C) to clarify 
that the rule applies to clinical investigations that are conducted 
only in subjects who have the disease or condition that the drug is 
intended to treat.

III. Comments on the Proposed Rule

    FDA received 26 letters, including letters from manufacturers, 
individuals, advocacy groups, and trade associations, commenting on the 
proposed rule. The majority of comments supported FDA's proposal to 
prohibit the exclusion of women from investigational studies through 
the clinical hold mechanism. Many comments suggested changes that would 
have narrowed or broadened the proposal.

[[Page 34964]]

A. General Comments

    1. Several comments indicated that if women with reproductive 
potential are capable of acquiring a disease, such women should be 
included in clinical trials regardless of their ability to become 
pregnant. Many comments stated that FDA's goal of ensuring that women 
with reproductive potential who have a life-threatening disease are not 
categorically excluded from trials in the future is ``an unassailable 
position.'' Another comment strongly recommended that FDA finalize the 
proposed rule, noting that despite FDA's 1993 ``Guideline for the Study 
and Evaluation of Gender Differences in the Clinical Evaluation of 
Drugs,'' there has been little improvement in opening enrollments 
(especially in phase 1 and phase 2 trials) to fertile women and in 
increasing enrollment of women overall. The agency agrees with these 
comments.
    2. One comment stated that women of reproductive age with life-
threatening diseases who are fully informed should be included in all 
stages of product development. The same comment urged FDA to closely 
monitor the implementation of the new rule and to continue the 
development of policies that would minimize risks while allowing 
productive research on women and men.
    FDA will monitor the implementation of this final rule as part of 
the general IND process and will continue to encourage research on the 
treatment and prevention of diseases and conditions in all individuals.

B. Applicability/Scope of the Proposed Rule

    3. Section 312.42(a) states that ``[w]hen an ongoing study is 
placed on a clinical hold, * * * patients already in the study should 
be taken off therapy involving the investigational drug unless 
specifically permitted by FDA in the interest of patient safety.'' One 
comment noted that FDA did not define ``patient safety'' in the 
preamble to the proposed rule. The comment requested that the agency 
consider indirect harm to patients in an evaluation of whether 
continuation of therapy involving an investigational drug is in the 
interest of patient safety.
    Generally, studies are placed on clinical hold because FDA 
considers it unsafe to carry the studies forward. In the present case, 
the hold does not imply such a conclusion. FDA generally intends to 
place trials that inappropriately exclude individuals with reproductive 
potential on hold at the time of protocol submission. However, if a 
trial that has begun is placed on clinical hold under this rule, it 
usually should not be necessary to stop an individual subject's 
treatment.
    4. Three comments discussed the definition of the term ``life-
threatening.'' Two comments expressed concern that the definition could 
be construed to include acute and chronic illnesses, such as status 
asthmaticus, epilepticus, anaphylaxis, diabetes, hypertension, and 
severe hypercholesterolemia. One proposed narrowing the definition to 
encompass only those diseases identified in the proposed rule as being 
of concern to FDA. The third comment suggested broadening the 
definition to include chronic conditions such as epilepsy.
    The definition of life-threatening is not intended to be limited to 
only those diseases and conditions where death is imminent, or broad 
enough to include acute or chronic diseases where death from the 
disease or condition is unlikely. The definition of life-threatening 
encompasses any disease or condition where the likelihood of death is 
high unless the course of the disease is interrupted. This rule is 
grounded in FDA's belief that people who are suffering from a disease 
or condition that is life-threatening despite available therapy should 
have an opportunity to participate in a clinical trial intended to 
address the disease or condition. Although many acute and chronic 
illnesses are adequately controlled by existing therapies, some of 
these illnesses may have stages or aspects that continue to carry a 
high likelihood of death despite existing therapies. Such a condition 
or disease would be considered life-threatening within the meaning of 
this rule.
    5. The agency received two comments addressing the need to balance 
access to investigational drugs and risks to study participants. One 
comment stated that while risks can be minimized through mechanisms 
such as informed consent and study design, the rule needs to be 
sufficiently flexible to address exceptional circumstances where 
potential risks of a drug may outweigh the potential benefit. Another 
comment stated that balancing the need for access to investigational 
drugs and minimizing patient risk would be better served by data-driven 
dialogue between sponsors and FDA than by the rule.
    The agency acknowledges that balancing access and patient risk is 
complex and that the specific circumstances of the trial may be 
pertinent. Physicians and patients are generally willing to accept 
greater risks from use of medical products that treat life-threatening 
diseases or conditions than they would accept from those that treat 
less serious conditions (53 FR 41516 at 41518, October 21, 1988; 62 FR 
49946 at 49949). Nonetheless, institutional review boards (IRB's) must 
still determine that risks to study participants are minimized by the 
use of procedures consistent with sound research design and that the 
risks to study participants are reasonable in relation to anticipated 
benefits (21 CFR 56.111(a)(1) and (a)(2)).
    FDA provides frequent opportunities for sponsors to meet with the 
agency to discuss the details of clinical investigations. For example, 
the clinical hold regulations specifically encourage discussion about 
deficiencies in an investigation. FDA will attempt to discuss and 
satisfactorily resolve the matter with the sponsor before issuing the 
clinical hold order (Sec. 312.42(c)). As stated in the proposed rule, a 
study would be placed on clinical hold only as a last resort (62 FR 
49946 at 49953).
    6. The agency received divergent comments about the scope of the 
rule. Two comments stated that FDA should expand the regulation to 
include all clinical trials.
    The agency declines the suggestion to expand the scope of the 
regulation to include all trials. At this time, there is an ethical 
basis for seeking to ensure that women with reproductive potential are 
not categorically excluded from trials of products being developed to 
treat life-threatening diseases and conditions. As discussed in the 
preamble to the proposed rule (62 FR 49946 at 49949), FDA has concluded 
that all trials involving patients with life-threatening diseases or 
conditions should, for the purposes of the rule, be considered to have 
therapeutic benefit. The ethical principle of justice does not support 
categorical exclusion of one group that might benefit from 
participation in clinical research for life-threatening diseases and 
conditions. Although similar considerations might apply to all human 
drug trials, the agency recognizes that the potential detriment of 
being excluded from a trial is greater when the subjects have life-
threatening diseases or conditions.
    7. One comment stated that because all new drugs are potentially 
teratogenic, FDA should not permit administration of any drug to women 
with reproductive potential until there is evidence of general safety 
and effectiveness from phase 1 and phase 2 trials.
    Although a risk or potential risk of developmental toxicity might 
exist from participation in a study, benefits that might accrue to a 
woman with reproductive potential who has the life-threatening disease 
or condition could

[[Page 34965]]

outweigh such a risk. Furthermore, such risks can be reduced or 
eliminated (62 FR 49946 at 49949).
    The risk of fetal exposure is eliminated by preventing pregnancy. 
Sponsors and IRB's can require the use of pregnancy testing to detect 
unsuspected pregnancy prior to initiation of study treatment and at 
intervals during the course of drug exposure. When the study design 
permits, sponsors can minimize potential fetal exposure in the short 
term by timing studies to coincide with the early follicular phase of 
the menstrual cycle. Women and men can eliminate the possibility of 
pregnancy through abstinence and can reduce the possibility of 
pregnancy through the use of one or more methods of contraception for 
the duration of drug exposure (62 FR 49946 at 49950). The agency finds 
that exclusion of women from early trials is not medically necessary 
because the risk of fetal exposure can be minimized. Initial 
determinations about whether the risk is adequately addressed are 
properly left to patients, physicians, local IRB's, and sponsors, with 
appropriate review and guidance by FDA (58 FR 39406 at 39408, July 22, 
1993).
    8. The agency received multiple comments stating that historically, 
IRB's have been a source of exclusionary policies without scientific 
justification, and FDA needs to be active in ensuring that IRB's do not 
wrongly exclude women with reproductive potential. One comment 
suggested that FDA adopt new procedures to carefully monitor IRB's and 
encouraged quick enforcement of this rule if women with reproductive 
potential are inappropriately excluded.
    Initial determinations about risk and other aspects of the safety 
of proposed investigations are properly left to patients, physicians, 
sponsors, and local IRB's with appropriate review and guidance by FDA 
(58 FR 39408). FDA has established procedures for IRB's at part 56 (21 
CFR part 56). Although IRB's play a role in the determination of 
eligibility criteria for investigations, FDA plans to ensure compliance 
with this rule primarily through review of IND submissions for drugs 
that are intended to treat life-threatening diseases and conditions. If 
the agency makes an initial determination that unwarranted restrictions 
were placed on the eligibility of women, FDA will attempt to discuss 
and satisfactorily resolve the matter with the sponsor prior to issuing 
the clinical hold order (Sec. 312.42(c)). If a satisfactory resolution 
cannot be found, an IND may be placed on clinical hold.
    9. Another comment recommended that FDA encourage trial sponsors 
and IRB's to broadly interpret ``de facto exclusion'' to avoid 
unnecessarily excluding women with reproductive potential.
    The exclusion of subjects with reproductive potential addressed by 
this rule includes both explicit exclusion and de facto exclusion. De 
facto exclusion would result from study criteria that are not essential 
to accomplish the goals of the study and that have the effect of 
precluding enrollment of participants with reproductive potential 
(e.g., requiring sterilization or requiring weight or other physical 
characteristics).
    10. Two comments suggested that the agency strengthen its policies 
by requiring that data collected under IND's be analyzed by gender.
    The suggestions are outside the scope of this rulemaking, but in 
the Federal Register of February 11, 1998 (63 FR 6854), FDA issued the 
demographic subgroup rule, which revised new drug application (NDA) 
content and format regulations at 21 CFR 314.50(d)(5). The regulation 
requires that effectiveness and safety data be presented in each NDA 
for demographic subgroups, including gender subgroups. This regulation 
will ensure that data collected under IND's and submitted to the agency 
will be analyzed by gender.
    11. Many comments expressed disappointment that the proposed rule 
did not contain requirements to enroll or recruit a significant number 
of women with reproductive potential in clinical trials. Several other 
comments misunderstood the intent of the rule and questioned its 
adequacy in ensuring appropriate enrollment and retention of women in 
trials. An additional comment stated that the proposed rule did not 
address requirements for appropriate recruitment strategies to ensure 
that low-income women are represented in clinical trials.
    As stated in the preamble to the proposed rule, the primary goal of 
the rule is to ensure that women with reproductive potential who have a 
life-threatening disease or condition are not categorically excluded 
from participation in clinical investigations because of their 
reproductive capacity (62 FR 49946 at 49947). This rule is thus 
concerned with eligibility criteria for individual studies. Issues 
related to the enrollment of significant numbers of women with 
reproductive potential in clinical trials are under consideration by 
the agency.
    The demographic subgroup rule also includes a requirement (21 CFR 
312.33(a)(2)) that IND annual reports provide demographic data on 
subjects of trials. Although the demographic subgroup rule does not 
require the inclusion of a particular number of individuals from 
specific subgroups, it will further focus sponsors' attention 
throughout the drug development process on clinical trial enrollment. 
The demographic subgroup rule should also help sponsors better evaluate 
in their applications the safety and efficacy profiles of drugs for 
various subgroups, including gender.
    12. The agency received one comment stating that pregnant women 
have the same right to make informed decisions about their own 
treatment as other women with reproductive potential. The comment 
concluded by recommending that the proposed regulation also apply if 
pregnant women are excluded from clinical trials for life-threatening 
diseases.
    For the purpose of this rulemaking, FDA does not intend the phrase 
``women with reproductive potential'' to include pregnant women (62 FR 
49946 at 49947). The agency does not question the ability of pregnant 
women to provide informed consent. There is, however, increased 
complexity in conducting clinical trials with pregnant women because of 
their changing physiology. FDA will continue to explore this issue in 
other forums.
    13. One comment recommended that the final rule clearly state that 
it applies to the exclusion of men in clinical trials and that the 
agency will carefully monitor the use of the clinical hold in studies 
that exclude men.
    As explained in the preamble to the proposed rule, although men 
have rarely been excluded from studies because of reproductive 
potential, the rule addresses the exclusion from clinical trials of 
members of either gender who have a life-threatening disease (62 FR 
49946 at 49947). Section 312.42(b)(1)(v) and (b)(2)(i) state that FDA 
may place any phase of a proposed or ongoing investigation on clinical 
hold if

    [t]he IND is for the study of an investigational drug intended 
to treat a life-threatening disease or condition 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 * * * or developmental * * * toxicity * * *.

    (emphasis added). As part of the IND process, FDA reviews protocol 
inclusion and exclusion criteria, including gender-related eligibility.
    14. In the preamble to the proposed rule, the agency stated that it 
is important for potential study participants to be provided with an

[[Page 34966]]

opportunity to discuss their involvement in a clinical trial with their 
sexual partner. FDA further stated that when deciding whether to 
participate in a clinical trial for an investigational drug, potential 
participants should be able to weigh the potential risks of their 
participation in consultation with their spouse or partner, their 
health care provider, and their researcher (62 FR 49946 at 49950). Two 
comments expressed concern that these statements could be construed to 
mean that such consultation with a partner must occur prior to 
enrollment. One comment indicated that many women are not sufficiently 
empowered to resist intimidation by their partner to make an 
independent decision if their partner agrees or disagrees with 
participation in a clinical trial. The second comment indicated that 
not all potential participants have one sexual partner and that no one 
should be excluded from participating in a clinical trial because of 
multiple sexual partners. This comment also indicated that women who 
are unable to negotiate the terms of sexual behavior or the cooperation 
of their partner(s) with contraceptives should not be categorically 
excluded from participation in clinical trials.
    Women and men can eliminate the possibility of pregnancy through 
abstinence and can reduce the possibility of pregnancy through the use 
of contraception for the duration of drug exposure, which may exceed 
the length of the clinical trial. The cooperation of an individual's 
sexual partner(s) may be needed to ensure that abstinence occurs or 
that appropriate contraceptive methods are used, but such cooperation 
is not always essential. Potential participants should be able to make 
autonomous decisions about contraception. Potential study participants 
should discuss with investigators their ability to maintain adequate 
contraception prior to determining whether they should participate in 
the study. The rule is not intended to ignore the risks associated with 
an unintended pregnancy, including the potential for developmental 
toxicity; rather it is based on the view that IRB's, investigators, and 
subjects can manage those risks.
    Risks to participants in early clinical trials can also be reduced 
through the proper use of the informed consent process. Potential 
participants who are heterosexually active must be aware of the need to 
ensure that appropriate contraceptive measures are taken to prevent 
pregnancy and of any additional risks in the event of pregnancy. While 
individuals should be encouraged to involve their sexual partner(s) in 
their decisionmaking process, the ultimate decision concerning whether 
to volunteer for a clinical trial should rest with the individual.

C. Reduction of Risks to Participants

    15. The agency received several comments on the discussion of the 
informed consent process in the preamble to the proposed rule. The 
majority of comments concerning informed consent supported the agency's 
reliance on this process and other mechanisms to protect participants 
in early clinical trials. Two comments stated that the informed consent 
process may encourage potential study participants to act responsibly 
and make their own risk-benefit analysis. One comment stated that 
participants need to be adequately informed about available information 
and about areas in which data are lacking. Two other comments noted the 
importance of animal reproductive toxicity studies and the inclusion of 
information obtained as a result of such studies in the informed 
consent process.
    There are a number of mechanisms, including the proper use of 
informed consent, to protect participants in clinical trials. Sponsors, 
investigators, and IRB's have responsibility for ensuring participant 
safety and protecting the rights of participants. FDA's informed 
consent regulations require that potential study participants be 
adequately informed that the study involves research, that there may be 
foreseeable risks or discomforts, and that there may be unforeseeable 
risks, such as potential risks to the embryo or fetus if a female study 
participant becomes pregnant (Sec. 50.25(b)(1) (21 CFR 50.25)(b)(1)). 
The existence of appropriate alternative procedures or courses of 
treatment, if any, must also be disclosed to the potential study 
participant (Sec. 50.25(a)(4)). Any reasonably foreseeable risks to the 
participant shown from the results of completed animal reproductive 
toxicity studies must be discussed in informed consent. When 
preclinical teratology and reproductive toxicity studies are not 
completed prior to the initial studies in humans, male and female study 
subjects should be informed about the lack of full characterization of 
the test article as well as the potential and unknown effects of the 
test agent on conception and fetal development. All study subjects 
should be provided with new pertinent information arising from 
preclinical studies as it becomes available, and informed consent 
documents should be updated when appropriate. If there is no relevant 
information, the informed consent should explicitly state this fact and 
should indicate the risks that cannot be ruled out.
    16. The agency stated in the preamble to the proposed rule (62 FR 
49946 at 49950) that 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 with 
reproductive potential. One comment noted this statement and suggested 
that the regulation clearly state that all women in all clinical trials 
have the right to be fully informed and to balance the risks and 
benefits of participation.
    In most circumstances, a study protocol does not need to require 
specific contraceptive approaches. In accordance with good medical 
practice, it is expected that volunteers in clinical trials will take 
appropriate precautions against becoming pregnant. The agency, sponsor, 
or IRB may require that a protocol provide for instructions to the 
volunteer about effective measures to avoid pregnancy. Other 
appropriate precautions include efforts to ensure that a woman 
volunteer is not pregnant at the time a trial begins, such as pregnancy 
testing to detect the beta subunit of the human chorionic gonadotropin 
molecule. Pregnancy testing may need to continue during the trial and 
after the drug administration portion of the trial has ended, based on 
the half-life of the drug under study and other considerations. 
Contraceptive counseling by a qualified health care provider should be 
offered and provided to trial participants with a focus on the use of 
highly effective contraception, allowing for abstinence if a woman has 
successfully used that as her chosen method of birth control. Although 
women retain control over their reproductive decisions, women and the 
investigator should consider together the benefits and risks of 
participation, including the risks resulting from an inability to 
maintain adequate contraception. In some cases, notably where a drug is 
clearly teratogenic, a protocol may need to require specific approaches 
to contraception.
    17. One comment stated that sponsors must retain the right to 
exclude women of childbearing age from clinical trials involving 
compounds with the potential for teratogenic effects, unless Congress 
enacts meaningful protection against liability. The comment based its 
concern on the potential liability of sponsors for any adverse effect 
on the offspring of study participants. The comment noted that many 
States permit

[[Page 34967]]

a child adversely affected by a parent's medical decision, who has 
reached the age of majority, to sue for injuries alleged to have been 
caused by the drug. The comment also noted that, in some States, a 
parent's consent based on information in an FDA-approved warning does 
not preclude lawsuits by adult children.
    FDA recognizes that, in some States, a child who has reached the 
age of majority or spouse may have the right to sue for injuries caused 
by a parent's medical decision to use a drug. To succeed in such a 
lawsuit, the child or spouse must show, among other things, that 
warnings about the use of the drug were inadequate or that consent was 
not fully informed.
    FDA also recognizes that, in some States, parental consent based on 
FDA-approved warnings for marketed drugs might not preclude a child 
from filing a lawsuit. In States permitting such lawsuits, the courts 
have described FDA standards for such warnings as minimum requirements 
for disclosing risk information. Because manufacturers and sponsors 
have the ultimate responsibility to provide risk information to FDA as 
well as to consumers, in some States, FDA approval of warning 
statements for marketed drugs is evidence of the warning's adequacy but 
is not dispositive. These cases suggest that a warning might be 
inadequate when a sponsor or manufacturer obscures or withholds risk 
information from FDA, or delays submission of supplemental risk 
information obtained after the product was approved.
    The sponsor or investigator, with IRB oversight, is responsible for 
providing risk information to subjects and obtaining informed consent 
from them. (See Sec. 312.50 and 21 CFR 312.53(c)(1)(vi)(d); part 50 (21 
CFR part 50) and part 56.) Few liability cases have been reported 
involving injuries from experimental drugs and even fewer involving 
such injuries to offspring. In those cases involving injuries to the 
offspring of mothers who ingested experimental drugs, the inadequacy of 
warnings, or the lack of informed consent, was an essential element of 
the lawsuit. (See Craft v. Vanderbilt University, 940 F. Supp. 1185 
(M.D. Tenn. 1996); Wetherill v. iversity of Chicago, 570 F. Supp. 1124 
(N.D. Ill. 1983); Mink v. University of Chicago, 460 F. Supp. 713 (N.D. 
Ill. 1978); and Diaz v. Hillsborough County Hospital Authority, 165 
F.R.D. 689 (M.D. Fla. 1996).) Although these cases involved research 
subjects who were pregnant women, they show that liability can be 
precluded when patients are informed adequately about a study and its 
risks. The women who brought these lawsuits claimed that they were not 
told that research was being conducted, much less asked for informed 
consent. The present rule is firmly grounded on informed consent and a 
fully informed patient.
    The agency has found no reported case in which a sponsor or 
manufacturer of a drug was held liable when warnings were found to be 
adequate or the consent to be informed. In all of the strict liability 
cases involving marketed drug products, the adequacy of the warnings 
remains an essential element for avoiding liability. In determining the 
adequacy of a warning for prescription drug products, the standard 
generally applied is the drug maker's actual or constructive knowledge 
of the risk at the time the product was sold or distributed.
    Considering all the relevant cases, the comment's concern about 
liability for injuries to offspring of study participants appears 
overstated. If anything, these cases show that the risk of liability 
for injuries to offspring resulting from their mother's ingestion of an 
experimental drug is remote. Sponsors and manufacturers can generally 
avoid liability by providing adequate warnings and obtaining fully 
informed consent.
    This final rule applies to one narrow category of beneficial drugs, 
that is, experimental drugs being studied for their safety and 
effectiveness in treating life-threatening diseases or conditions. The 
rule also reduces the exposure to liability lawsuits by applying only 
to studies that seek subjects who are suffering from the life-
threatening disease or condition at issue. The risk of liability is 
further minimized when the sponsor uses informed consent with careful 
study design, pregnancy screening techniques, and counseling about 
contraception and abstinence.
    18. One comment expressed concern that informed consent alone may 
not be adequate to reduce the risk of injury to a participant and, 
thus, the risk of liability to a sponsor. Specifically, the comment 
states that, in many situations, the full nature and extent of any 
potential reproductive toxicity may not be sufficiently characterized 
at the time of desired access to a given investigational therapy to 
allow IRB's, investigators, or potential study subjects to make a 
complete determination of any potential risk. To provide patients with 
complete risk and benefit information for certain developmental 
compounds or studies, consent forms would have to be worded in a way 
that could effectively discourage participation in these trials by the 
very population intended to benefit from the proposed regulation.
    An inherent danger in the use of every experimental drug is that 
unknown safety risks may exist for human research subjects. The purpose 
of informed consent is to provide research volunteers with sufficient 
information to determine for themselves whether the risks are 
justified. Informed consent regulations require a sponsor, when 
appropriate, to describe the reasonably foreseeable risks, and 
currently unforeseeable risks, to the participant or to an embryo or 
fetus in the event the participant should become pregnant during the 
study (Sec. 50.26(b)(1)). That the disclosure of complete risk and 
benefit information might discourage participation is not a reason to 
withhold information or to preempt the opportunity to participate in a 
study. On the contrary, disclosure serves the interests of self-
determination regarding a person's decision to participate in medical 
research and ensures informed decisionmaking as to whether the risks 
are indeed outweighed by the benefits.
    19. One comment stated that exceptional circumstances may exist 
where the potential risk of the drug to the participant outweighs the 
potential benefit. As an example, the comment indicated that it may not 
be advisable to include treatment-naive human immunodeficiency virus 
(HIV)-infected women with reproductive potential in clinical trials for 
a drug that has a high (or undetermined) risk to a fetus if there are 
other effective and safe agents in the same class available for use in 
these women.
    HIV-infected women who are treatment-naive should not be excluded 
from participating in clinical trials solely because of their 
reproductive potential. HIV-infected women should have a choice, as 
should HIV-infected men, of enrolling in clinical trials, as long as 
there is a proper informed consent process that acknowledges the 
availability of safe and effective treatment options and, if the 
potential participants are sexually active, abstinence or contraception 
is used. After sponsor, FDA, and local IRB decisions on the protocol, 
the ultimate risk-benefit analysis in such circumstances is best left 
to the patient and the physician.

D. Increased Costs

    20. Two comments supported the agency's position that the societal 
benefits outweigh the increased costs associated with the participation 
of women with reproductive potential who have a life-threatening 
disease in

[[Page 34968]]

clinical trials. Both comments specifically highlighted the advantage 
of obtaining gender-specific data in this population.
    Based on the analysis of economic impacts described in the proposed 
rule, the agency believes that the societal benefits outweigh the 
potential minimal additional costs because a considerable patient 
population (i.e., women with reproductive potential who have a life-
threatening disease or condition) could receive a potentially 
beneficial new therapy (62 FR 49946 at 49953).

E. The Use of a Clinical Hold

    21. The agency received divergent comments about the use of a 
clinical hold to achieve the objectives of the proposal. One comment 
stated a belief that it is appropriate for FDA to use its ability to 
place a clinical trial on hold if the sponsor excludes women for 
inappropriate reasons. However, another comment asserted that the use 
of a clinical hold in these circumstances is not consistent with the 
original intent of the clinical hold regulations and turns a clinical 
hold into a punitive measure.
    A clinical hold is an order 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 or biological product 
(Sec. 312.42). The agency has determined that it is appropriate to 
impose a clinical hold on an investigation that categorically excludes 
women or men with reproductive potential who have a life-threatening 
disease or condition.
    The imposition of a clinical hold under these amendments to 
Sec. 312.42 is not punitive. The aim of these amendments is to ensure 
that women with reproductive potential who have a life-threatening 
disease or condition are not categorically excluded from participation 
in clinical trials. The rationale for this action, as discussed in the 
preamble to the proposed rule (62 FR 49946 at 49949 through 49951), is 
based on four factors: (1) FDA is committed to expanding access to and 
accelerating approval of new therapies for life-threatening diseases 
and conditions; (2) important ethical principles underlie the belief 
that neither gender should be excluded from early clinical trials 
involving a life-threatening disease or condition because of 
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 investigative therapies, 
especially for those populations who ultimately will be using the 
therapies. Furthermore, FDA intends to issue a clinical hold order as a 
last resort, only after the review division's attempt to discuss and 
satisfactorily resolve the matter with the sponsor (Sec. 312.42(c)). As 
explained in Center for Drug Evaluation and Research (CDER) internal 
policy statements, CDER experience is that most potential holds can be 
avoided through such discussion (CDER Manual of Policy and Procedure 
(MAPP) 6030.1).
    In the preamble to the proposed rule (62 FR 49946 at 49951), FDA 
discussed its legal authority to issue this rule under section 505(i) 
of the Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 
355(i)). Since publication of the proposed rule, on November 21, 1997, 
the President signed into law the Food and Drug Administration 
Modernization Act of 1997 (the Modernization Act) (Public Law 105-115). 
Section 117 of the Modernization Act amends section 505(i) of the act 
to include specific provisions authorizing the imposition of a clinical 
hold on an investigation if ``the drug involved represents an 
unreasonable risk to the safety of the persons who are the subjects of 
the clinical investigation * * * or * * * for such other reasons as the 
Secretary may by regulation establish'' (section 505(i)(3)(B) of the 
act). The Modernization Act makes explicit the agency's authority to 
issue regulations for the imposition of a clinical hold for reasons 
other than unreasonable risks to the safety of the subjects involved in 
the investigation.
    22. One comment noted a distinction between a clinical hold imposed 
for a regulatory purpose (e.g., because a sponsor has not made adequate 
provision for the inclusion of women with reproductive potential in a 
clinical trial) and one imposed due to safety concerns. The comment 
suggested that the agency establish a new set of regulations for this 
``regulatory clinical hold,'' rather than provide for it in the 
already-established clinical hold regulations.
    FDA's regulations governing IND's are located in part 312 (21 CFR 
part 312), and the agency's clinical hold regulations are in 
Sec. 312.42. FDA declines the suggestion to create a new set of 
regulations to accommodate these amendments because this change would 
serve no purpose and would be confusing, placing bases for clinical 
holds in two locations although the procedures for holds in both cases 
are identical. Furthermore, since President Clinton issued the 
``Regulatory Reinvention Initiative'' memorandum on March 4, 1995, FDA 
has sought to consolidate its regulations and to eliminate duplicative 
ones. The creation of a new set of clinical hold regulations would be 
contrary to the objectives of regulatory reinvention.
    23. One comment proposed safeguards to protect the interests of 
subjects already participating in a clinical trial and to ensure that a 
clinical hold is used only as a last resort. The comment proposed the 
following safeguards: (1) A limitation of the rule to those clinical 
trials that are intended to demonstrate effectiveness and (2) 
procedures to ensure a dialogue between the sponsor and the agency to 
help avoid the imposition of the clinical hold. The comment recommended 
that when a clinical hold is issued for inadequate participation of 
women in the trial, procedural safeguards should include: (1) The 
concurrence of the Center Director after personal consultation between 
the Division Director and the sponsor; (2) communication of the reason 
for the hold to the sponsor in writing within 10 days of the imposition 
of a clinical hold; and (3) review by the Clinical Hold Review 
Committee at the first meeting following the hold.
    The comment states that under this rule, a clinical hold may be 
issued for inadequate participation of women in a clinical trial. This 
statement erroneously implies that the rule imposes requirements to 
enroll or recruit a specific number of women in trials. To the 
contrary, the rule prohibits the exclusion of women with reproductive 
potential but does not require a quota or specific number of women for 
any trial.
    The agency declines the suggestion to limit the scope of the rule 
to those clinical trials that are intended to demonstrate 
effectiveness. As explained in the preamble to the proposed rule (62 FR 
49946 at 49949), many early clinical studies involving life-threatening 
diseases offer the potential for therapeutic benefit, especially when 
participation in an early clinical study is a prerequisite for 
enrollment in later studies. FDA has concluded that all trials 
involving patients with life-threatening diseases and conditions 
should, for purposes of this rule, be considered to have therapeutic 
potential. This rule, therefore, applies to studies in any phase of a 
clinical investigation that enroll participants with a life-threatening 
disease or condition.
    The agency's clinical hold regulations provide a process for 
discussion between a sponsor and FDA about deficiencies in an 
investigation to ensure that a clinical hold is imposed as

[[Page 34969]]

a measure of last resort. Whenever FDA concludes that a deficiency 
exists in a clinical investigation that may be grounds for the 
imposition of a clinical hold, FDA will, unless patients are exposed to 
immediate and serious risk, attempt to discuss and satisfactorily 
resolve the matter with the sponsor before issuing the clinical hold 
order (Sec. 312.42(c)).
    Under FDA regulations, the Division Director that is responsible 
for reviewing the application for the underlying drug product has the 
authority to determine whether to impose a clinical hold 
(Sec. 312.42(d)). The agency does not find that concurrence by the 
Center Director is necessary to ensure that a clinical hold is imposed 
only as a last resort because, as discussed above, the agency's 
regulations and internal procedures already provide for discussion 
between the sponsor and the agency concerning the need for the clinical 
hold. Division directors in CDER and the Center for Biologics 
Evaluation and Research (CBER) have the authority to ensure that agency 
personnel follow these regulations and procedures.
    FDA regulations state that the agency will communicate to the 
sponsor in writing the reasons for a clinical hold as soon as possible, 
and no more than 30 days after imposing the hold (Sec. 312.42(d)). A 
clinical hold is usually imposed only after discussion between FDA and 
a sponsor. Because the Division Director, or designee, generally 
provides a brief explanation of the reasons for the hold by telephone 
at the time the clinical hold is ordered, the agency finds it 
unnecessary to shorten the 30-day requirement for a written 
explanation.
    CDER and CBER have established committees to review clinical holds 
and promote consistency throughout the Centers in issuing clinical 
holds. Under CDER policy, the CDER Clinical Holds Peer Review Committee 
meets quarterly to review all commercial IND clinical holds issued 
during the previous quarter (CDER MAPP 6030.1). The CBER Clinical Hold 
Oversight Committee reviews selected clinical holds that have been 
issued. The procedures for these committees will apply to clinical 
holds imposed by CDER or CBER under this rule.
    24. Two comments indicated that this use of a clinical hold is not 
the optimal mechanism to achieve the agency's objectives and may 
threaten other agency goals (e.g., expediting the development of 
innovative therapies to treat life-threatening diseases and conditions 
in both men and women). One comment further noted that the best way to 
ensure that women and men of reproductive potential are able to 
participate in clinical trials is to address the issue during the 
development of the protocol for the trial early in the IND process. The 
comment recommended that a plan be developed in the IND process for 
including women of reproductive potential in clinical studies or 
articulating a clear rationale for their exclusion. The sponsor and the 
agency should agree on the plan as part of the IND with compliance tied 
to the plan and progress reported in routine annual reports to the IND.
    Although developing data bases that include both men and women is 
an important goal, this rule does not address the content of an NDA or 
biologics license application (BLA) data set. Rather, this rule seeks 
to prevent exclusions of people suffering from life-threatening 
conditions or diseases from participation in trials based on 
reproductive potential.
    Overall protocol development is addressed under several regulatory 
programs for the development and review of products that are intended 
to treat life-threatening diseases or conditions. The agency recognizes 
that agreement between a sponsor and FDA on a protocol for a clinical 
trial is an important step towards ensuring that women with 
reproductive potential who have a life-threatening disease or condition 
are not excluded from the clinical trial. Under the agency's 
regulations at Secs. 312.80 through 312.88, sponsors are encouraged to 
work with the agency during the development of drugs intended to treat 
life-threatening and severely debilitating illnesses. Sponsors may ask 
to meet with FDA early in the drug development process to review and 
reach agreement on the design of necessary preclinical and clinical 
studies (Sec. 312.82). Such meetings may take place prior to the 
submission of the IND or at the end of phase 1. Furthermore, under 
section 112 of the Modernization Act, the agency has developed 
procedures to facilitate the development and expedite the review of 
products that are intended to treat serious or life-threatening 
conditions and demonstrate the potential to address an unmet medical 
need. Such procedures, described in the FDA guidance entitled ``Fast 
Track Drug Development Programs--Designation, Development, and 
Application Review'' (October 1998), encourage appropriately timed 
meetings and regular contact between sponsors and FDA.
    Section 119(a) of the Modernization Act directs FDA to work 
towards, and achieve, agreement with sponsors and applicants on the 
design and size of clinical trials intended to form the primary basis 
of an effectiveness claim in an NDA or BLA. In conjunction with the 
reauthorization of the Prescription Drug User Fee Act in November 1997, 
FDA agreed to specific performance goals for the management of 
activities associated with the development and approval of products in 
human drug applications that are defined in section 735(1) of the act 
(21 U.S.C. 379g(1)). Under the goals, FDA will, upon request by a 
sponsor, evaluate certain protocols and issues relating to the 
protocols to assess whether their design is adequate to meet scientific 
and regulatory requirements identified by the sponsor. One type of 
protocol that is eligible for this special protocol assessment is a 
clinical protocol for a phase 3 trial whose data will form the primary 
basis for an efficacy claim. Section 119(a) of the Modernization Act 
and the performance goals recognize the importance of early agency 
review and agreement with sponsors regarding protocols for clinical 
trials.
    Sponsors are required to submit information regarding the progress 
of IND's in their annual reports to the agency (Sec. 312.33). Any 
specific information regarding a clinical protocol agreement should be 
included in the annual report. Furthermore, sponsors of clinical 
studies for drug and biologic products are now required to tabulate in 
annual reports the numbers of subjects enrolled in the trial, 
specifying gender and other demographic subgroups (Sec. 312.33) (see 63 
FR 6854).

F. International Issues

    25. FDA received two comments concerning the effect of the 
regulation on international drug development. One comment questioned 
how the regulation will affect compliance with the International 
Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals for Human Use (ICH) ``Draft Guideline on the Timing 
of Nonclinical Studies for the Conduct of Human Clinical Trials for 
Pharmaceuticals.'' The comment stated that the impact of the rule on 
global drug development remains unclear and questioned whether data 
collected from trials conducted under the rule would be acceptable to 
the regulatory agencies in Europe or Japan. Another comment raised the 
possibility of regulatory difficulties in including women of 
reproductive potential in some early studies when those studies are 
subject to regulation by agencies in other countries. The comment urged 
FDA to consider the effects of the proposed rule on multicountry 
studies.

[[Page 34970]]

    The final rule is consistent with ICH initiatives. In July 1997, 
FDA issued a final ICH guidance entitled ``M3 Nonclinical Safety 
Studies for the Conduct of Human Clinical Trials for Pharmaceuticals'' 
(ICH M3 guidance) (published in 62 FR 62922, November 25,1997). The ICH 
M3 guidance, which supersedes the draft guideline cited in the comment, 
notes that there are regional differences in the timing of reproductive 
toxicity studies to support the inclusion of women with reproductive 
potential in clinical trials for all pharmaceuticals. As described in 
the ICH M3 guidance, women with reproductive potential may be included 
in early, carefully monitored studies in the United States without 
reproduction toxicity studies provided appropriate precautions are 
taken to minimize risk. Such precautions include pregnancy testing, use 
of a highly effective method of birth control, and entry after a 
confirmed menstrual period. Continued testing and monitoring during the 
trial should be sufficient to ensure compliance with the measures for 
avoiding pregnancy during the period of drug exposure (which may exceed 
the length of the study). To support this approach, informed consent 
should include any known pertinent information related to reproductive 
toxicity, such as a general assessment of potential toxicity of 
pharmaceuticals with related structures or pharmacological effects. If 
no relevant information is available, the informed consent should 
clearly note the potential for risk (ICH M3 guidance, p. 7).
    In multicountry studies, provided that there is not a categorical 
exclusion based on reproductive potential in the United States, FDA 
does not intend to impose a hold for such exclusions on studies in 
foreign sites. Foreign data with such exclusions may be submitted to 
the agency.

G. HIV/Acquired Immune Deficiency Syndrome (AIDS)

    26. One comment discussed the Center for Disease Control's reports 
of a steady decline in AIDS incidence and mortality rates in the United 
States since 1993 and highlighted the disparities related to women. The 
comment noted that the number of AIDS deaths in 1996 declined among all 
racial/ethnic groups but increased 3 percent among women and among 
those who acquired the infection through heterosexual contact. The 
comment emphasized the treatment and prevention challenges affecting 
HIV-infected women, highlighted the need for gender-specific data, and 
advocated the enrollment of women in clinical trials in numbers 
equivalent to the prevalence of women with AIDS in America.
    As discussed in the preamble to the proposed rule (62 FR 49946 at 
49950 and 49951), FDA is committed to expanding the collection of 
gender-specific data on investigative therapies, especially for those 
populations who are likely to use an investigational agent once it is 
marketed. Because many of the women who are affected by HIV and AIDS 
are women with reproductive potential, this rule will prevent their 
exclusion from participation in clinical trials for such diseases 
solely because of a perceived risk or potential risk of reproductive or 
developmental toxicity.
    The Division of Antiviral Drug Products in CDER and other 
components in CDER and CBER that review HIV/AIDS-related products 
encourage sponsors to include women of all age groups early in the drug 
development process and support the concept of allowing each eligible 
female participant to make her own informed decision regarding the 
risks and benefits of participating in a trial.
    The comment suggested that women be enrolled in clinical trials for 
AIDS therapies in numbers equivalent to the prevalence of women with 
AIDS in America. The comment is outside the scope of this rule. The 
rule does not require that particular numbers of women be enrolled in 
trials for investigational therapies. The rule only prohibits the 
exclusion of women with reproductive potential from eligibility for a 
clinical trial.
    27. One comment indicated that the proposal is a broad-based 
solution to a focused problem that the agency has identified within a 
single drug class--antiviral drugs.
    Although FDA prepared this proposal largely in response to 
recommendations made by the National Task Force on AIDS Drug 
Development and the Presidential Advisory Council on HIV/AIDS, the 
recommendations are applicable to all life-threatening diseases and 
conditions, and the agency has concluded that this problem is a general 
one. Additionally, when conducting its cost analysis, the agency used a 
protocol data base that included information from four CDER review 
divisions. Of the 43 protocols involving life-threatening diseases or 
conditions that were identified as having precluded the opportunity for 
women with reproductive potential to participate in trials, 28 percent 
were from the Division of Antiviral Drug Products, 67 percent were from 
the Division of Cardio-Renal Drug Products, and the remaining 5 percent 
were from the Division of Medical Imaging, Surgical, and Dental Drug 
Products and the Pilot Drug Evaluation Staff. The project did not 
include representation of all divisions in CDER and CBER. However, it 
was assumed that the available data were representative of all CDER and 
CBER review divisions regarding the exclusion of women with 
reproductive potential.

IV. Analysis of Impacts

    FDA has examined the impacts of the final rule under Executive 
Order 12866 and the Regulatory Flexibility Act (Public Law 96-354). 
Executive Order 12866 directs agencies to assess all costs and benefits 
or 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). Under the Regulatory Flexibility Act (5 U.S.C. 601-612), 
unless an agency certifies that a rule will not have a significant 
economic impact on small entities, the agency must analyze regulatory 
options that would minimize the impact of the rule on small entities. 
Title II of the Unfunded Mandates Reform Act (Public Law 104-7) (in 
section 202) requires that agencies prepare an assessment of 
anticipated costs and benefits before proposing any rule that may 
result in an expenditure in any 1 year by State, local, and tribal 
governments, in the aggregate, or by the private sector, of $100 
million or more (adjusted annually for inflation).
    The agency has reviewed this rule and has determined that it is 
consistent with the regulatory philosophy and principles identified in 
Executive Order 12866, and in these two statutes. In addition, the 
final rule is not a significant regulatory action as defined by the 
Executive Order and so is not subject to review under the Executive 
Order. With respect to the Regulatory Flexibility Act, the agency 
certifies that the rule will not have a significant effect on a 
substantial number or small entities. Because the final rule does not 
impose any mandates on State, local, or tribal governments, or the 
private sector that will result in a 1-year expenditure of $100 million 
or more, FDA is not required to perform a cost-benefit analysis under 
the Unfunded Mandates Reform Act.

A. Costs

    The Costs section of the Analysis of Impacts in the proposed rule 
(62 FR 49952) remains essentially unchanged and is not repeated here. 
However, two items require additional comment.

[[Page 34971]]

    None of the cost estimates in the proposed rule were corrected for 
the incidence of pregnant women having diseases under study (but not 
having been included in the studies). Hence, the cost estimates 
discussed in the proposed rule were overstated. The agency believes 
that the effect of this overstatement is relatively insignificant.
    The agency is aware of industry's concerns about liability exposure 
associated with the inclusion of women with reproductive potential in 
clinical trials and the potential for harm to offspring. Although there 
are cases of injury to offspring of mothers who ingested experimental 
drugs, the inadequacy of warnings or the lack of informed consent has 
been an essential element of such lawsuits. The agency is not aware of 
any reported case in which a sponsor of an investigational drug was 
held liable for injuries to offspring when the sponsor provided 
adequate warnings and obtained fully informed consent. Therefore, the 
agency assumes that this rule adds nothing to current liability costs 
under existing law.

B. Small Entities

    The analysis in the proposed rule identified protocols sponsored by 
small businesses. The largest additional pregnancy testing cost 
incurred by a small business in the reviewed protocols under the rule 
was $990. Projected across all CDER and CBER review divisions and 
annualized, FDA expects no more than 9 protocol submissions per year 
from small businesses that might incur increased costs. Few small firms 
are likely to be affected in any given year, and most of these firms 
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.

V. 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.

VI. Paperwork Reduction Act of 1995

    This final rule contains no collections of information. Therefore, 
clearance by the Office of Management and Budget under the Paperwork 
Reduction Act of 1995 is not required.

VII. Federalism

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

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, 21 CFR part 312 is amended as follows:

PART 312--INVESTIGATIONAL NEW DRUG APPLICATION

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

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


    2. Section 312.42 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 disease or condition that affects both 
genders, and men or women with reproductive potential who have the 
disease or condition being studied are excluded from eligibility 
because of a risk or potential risk from use of the investigational 
drug of reproductive toxicity (i.e., affecting reproductive organs) or 
developmental toxicity (i.e., affecting potential offspring). 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 pertinent only to 
one gender (e.g., studies evaluating the excretion of a drug in semen 
or the effects on menstrual function);
    (B) Only in men or women, as long as a study that does not exclude 
members of the other gender with reproductive potential is being 
conducted concurrently, has been conducted, or will take place within a 
reasonable time agreed upon by the agency; or
    (C) Only in subjects who do not suffer from the disease or 
condition for which the drug is being studied.
    (2) * * *
    (i) Any of the conditions in paragraphs (b)(1)(i) through (b)(1)(v) 
of this section apply; or
* * * * *

    Dated: May 24, 2000.
Jane E. Henney,
Commissioner of Food and Drugs.
Donna E. Shalala,
Secretary of Health and Human Services.
[FR Doc. 00-13664 Filed 5-31-00; 8:45 am]
BILLING CODE 4160-01-F