Federal Register / Vol. 65, No. 106 / Thursday, June 1, 2000 / Rules and Regulations 34963

Dated: May 17, 2000.

Margaret M. Dotzel,

Acting Associate Commissioner for Policy.

[FR Doc. 00–13586 Filed 5–31–00; 8:45 am]

BILLING CODE 4160–01–F

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 lifethreatening 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 § 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 (§ 312.42(a)). Under the

proposed amendments, FDA could

impose a clinical hold on any proposed

or ongoing clinical trial for a lifethreatening 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

(§ 312.42(b)(1)) and on proposed or

ongoing phase 2 or phase 3 studies

(§ 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 lifethreatening illness or disease is

intended to be consistent with the

agency’s IND regulations

(§ 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

(§ 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

§ 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.

34964 Federal Register / Vol. 65, No. 106 / Thursday, June 1, 2000 / Rules and Regulations

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 lifethreatening 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 (§ 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 lifethreatening 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 lifethreatening 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 lifethreatening disease or condition could

Federal Register / Vol. 65, No. 106 / Thursday, June 1, 2000 / Rules and Regulations 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

(§ 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 lifethreatening 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 lifethreatening 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

34966 Federal Register / Vol. 65, No. 106 / Thursday, June 1, 2000 / Rules and Regulations

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 riskbenefit 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 (§ 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 (§ 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

Federal Register / Vol. 65, No. 106 / Thursday, June 1, 2000 / Rules and Regulations 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 FDAapproved 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 § 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 (§ 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

34968 Federal Register / Vol. 65, No. 106 / Thursday, June 1, 2000 / Rules and Regulations

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 lifethreatening 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 (§ 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 § 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 lifethreatening 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 (§ 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 § 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 lifethreatening 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

Federal Register / Vol. 65, No. 106 / Thursday, June 1, 2000 / Rules and Regulations 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

(§ 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 (§ 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

(§ 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 lifethreatening 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 §§ 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 (§ 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 (§ 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

(§ 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.

34970 Federal Register / Vol. 65, No. 106 / Thursday, June 1, 2000 / Rules and Regulations

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 HIVinfected 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 genderspecific 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.

Federal Register / Vol. 65, No. 106 / Thursday, June 1, 2000 / Rules and Regulations 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:

§ 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

DEPARTMENT OF TRANSPORTATION

Coast Guard

33 CFR Part 165

[CGD01–00–133]

RIN 2115–AA97

Safety Zone: Fireworks Display, East

River, Wards Island

AGENCY: Coast Guard, DOT.

ACTION: Temporary final rule.

SUMMARY: The Coast Guard is

establishing a temporary safety zone for

a fireworks display located on the East

River, New York. This action is

necessary to provide for the safety of life

on navigable waters during the event.

This action is intended to restrict vessel

traffic in a portion of the East River.

DATES: This rule is effective from 8:30

p.m. (e.s.t.) on June 29, 2000 until 10

p.m. (e.s.t.) on June 30, 2000.

ADDRESSES: Comments and material

received from the public, as well as

documents indicated in this preamble as

being available in the docket, are part of

docket (CGD01–00–133) and are

available for inspection or copying at

Coast Guard Activities New York, 212

Coast Guard Drive, room 205, Staten

Island, New York 10305, between 8 a.m.

and 3 p.m., Monday through Friday,

except Federal holidays. The telephone

number is (718) 354–4012.