49946 Federal Register / Vol. 62, No. 185 / Wednesday, September 24, 1997 / Proposed Rules

FAA defining the low cycle fatigue life

of GE 90 rotating components. The

analysis included an updated material

property data base and other

refinements that resulted in a reduction

of the published low cycle fatigue

retirement life limit for certain rotating

components. The FAA has determined

that this AD is necessary to mandate

reduced life limits for certain rotating

components installed in GE90–76B

engines. If not corrected, this condition

could result in a low cycle fatigue

failure of a rotating component and

possibly an uncontained engine failure.

The FAA has reviewed and approved

the technical contents of General

Electric Company GE90 Alert Service

Bulletin (ASB) No. 72–A318, dated June

27, 1997, that describes reduced life

limits for certain rotating components.

Since an unsafe condition has been

identified that is likely to exist or

develop on other products of this same

type design, the proposed AD would

require reduced life limits for certain

rotating components. The actions would

be required to be accomplished in

accordance with the ASB described

previously.

There are approximately twenty-five

engines of the affected design in the

worldwide fleet. The manufacturer has

advised the FAA that there are currently

no engines installed on aircraft of U.S.

registry that would be affected by this

proposed AD. Therefore, there is no

associated cost impact on U.S. operators

as a result of this proposed AD.

The FAA estimates that the most

representative engines would have four

of the seven life-limited-reduced

components installed. Assuming the

four components are the High Pressure

Compressor Rotor (HPCR) 2–6 spool,

HPCR stage 7 disk, HPCR CDP seal and

the Low Pressure Turbine cone shaft

and that the parts cost is proportional to

the reduction of the low cycle fatigue

retirement lives, the required parts

would cost approximately $189,123 per

engine. Based on these figures, the FAA

estimates the total cost impact of this

proposed AD would be $189,123 per

engine.

The regulations proposed herein

would not have substantial direct effects

on the States, on the relationship

between the national government and

the States, or on the distribution of

power and responsibilities among the

various levels of government. Therefore,

in accordance with Executive Order

12612, it is determined that this

proposal would not have sufficient

federalism implications to warrant the

preparation of a Federalism Assessment.

For the reasons discussed above, I

certify that this proposed regulation: (1)

Is not a ‘‘significant regulatory action’’

under Executive Order 12866; (2) is not

a ‘‘significant rule’’ under the DOT

Regulatory Policies and Procedures (44

FR 11034, February 26, 1979); and (3) if

promulgated, will not have a significant

economic impact, positive or negative,

on a substantial number of small entities

under the criteria of the Regulatory

Flexibility Act. A copy of the draft

regulatory evaluation prepared for this

action is contained in the rules docket.

A copy of it may be obtained by

contacting the rules docket at the

location provided under the caption

ADDRESSES.

List of Subjects in 14 CFR Part 39

Air transportation, Aircraft, Aviation

safety, Safety.

The Proposed Amendment

Accordingly, pursuant to the

authority delegated to me by the

Administrator, the Federal Aviation

Administration proposes to amend part

39 of the Federal Aviation Regulations

(14 CFR part 39) as follows:

PART 39—AIRWORTHINESS

DIRECTIVES

1. The authority citation for part 39

continues to read as follows:

Authority: 49 U.S.C. 106(g), 40113, 44701.

§ 39.13 [Amended]

2. Section 39.13 is amended by

adding the following new airworthiness

directive:

General Electric Company: Docket No. 97–

ANE–28–AD.

Applicability: General Electric Company

(GE) GE90–76B model turbofan engines

installed on but not limited to Boeing 777

aircraft.

Note 1: This airworthiness directive (AD)

applies to each engine identified in the

preceding applicability provision, regardless

of whether it has been modified, altered, or

repaired in the area subject to the

requirements of this AD. For engines that

have been modified, altered, or repaired so

that the performance of the requirements of

this AD is affected, the owner/operator must

request approval for an alternative method of

compliance in accordance with paragraph (c)

of this AD. The request should include an

assessment of the effect of the modification,

alteration, or repair on the unsafe condition

addressed by this AD; and, if the unsafe

condition has not been eliminated, the

request should include specific proposed

actions to address it.

Compliance: Required as indicated, unless

accomplished previously.

To prevent a low cycle fatigue failure of a

rotating component and possibly an

uncontained engine failure, accomplish the

following:

(a) Remove from service those components

listed in Table 1 of GE Alert Service Bulletin

(ASB) No. 72–A318, dated June 27, 1997, and

replace with a serviceable component, prior

to exceeding the new cyclic life limits

established in paragraph (d) of ASB No. 72–

A318, dated June 27, 1997.

Note 2: These revised component life

limits will be added to the GE90 Engine

Manual, Chapter 05–11–00, Life Limits 001

in the August 1, 1997, Revision.

(b) Except as provided in paragraph (c) of

this AD, no replacement times may be

approved for these parts.

(c) An alternative method of compliance or

adjustment of the compliance time that

provides an acceptable level of safety may be

used if approved by the Manager, Engine

Certification Office. Operators shall submit

their requests through an appropriate FAA

Principal Maintenance Inspector, who may

add comments and then send it to the

Manager, Engine Certification Office.

Note 3: Information concerning the

existence of approved alternative methods of

compliance with this airworthiness directive,

if any, may be obtained from the Engine

Certification Office.

(d) Special flight permits may be issued in

accordance with sections 21.197 and 21.199

of the Federal Aviation Regulations (14 CFR

21.197 and 21.199) to operate the aircraft to

a location where the requirements of this AD

can be accomplished.

Issued in Burlington, Massachusetts, on

September 18, 1997.

Mark C. Fulmer,

Acting Manager, Engine and Propeller

Directorate, Aircraft Certification Service.

[FR Doc. 97–25312 Filed 9–23–97; 8:45 am]

BILLING CODE 4910–13–U

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Food and Drug Administration

21 CFR Part 312

[Docket No. 97N–0030]

Investigational New Drug Applications;

Proposed Amendment to Clinical Hold

Regulations for Products Intended for

Life-Threatening Diseases

AGENCY: Food and Drug Administration,

HHS.

ACTION: Proposed rule.

SUMMARY: The Food and Drug

Administration (FDA) is proposing to

amend the provisions of its regulations

governing investigational new drug

applications (IND’s) to permit FDA to

place a clinical hold on one or more

studies under an IND involving a drug

that is intended to treat a lifethreatening disease affecting both

genders if men or women with

reproductive potential who have the

disease and are otherwise eligible but

are excluded from participation in an
Federal Register / Vol. 62, No. 185 / Wednesday, September 24, 1997 / Proposed Rules 49947

1As of January 1992, 14,799 participants were

enrolled in U.S. AIDS Clinical Trial Group studies

sponsored by the National Institute of Allergy and

Infectious Diseases, of whom only 1,151 were adult

women. (Pearl, M., et al., ‘‘Women in U.S.

Government Clinical Trials,’’ VIII International

Conference on AIDS, 8(2: B235, 1992.)

In 1993, 21,598 participants were enrolled, while

only 1,952 were adult women. (Korvick, J.A.,

‘‘Trends in Federally Sponsored Clinical Trials,’’ in

Until the Cure: Caring for Women With HIV, A.

Kurth, editor, pp. 94–103, 1993).

investigation only because of a risk or

potential risk of reproductive or

developmental toxicity from use of the

investigational drug. Women have been

excluded in the past from early clinical

trials because of a risk or potential risk

of reproductive or developmental

toxicity. Therefore, the primary goal of

this proposed amendment is to ensure

that women with reproductive potential

who have a life-threatening disease are

not automatically excluded in the future

for that reason. The proposed rule

would not impose requirements to

enroll or recruit a specific number of

men or women with reproductive

potential.

The proposal would implement a

recommendation of both the National

Task Force on AIDS Drug Development

(the AIDS Task Force) and the

Presidential Advisory Council on

Human Immunodeficiency Virus/

Acquired Immune Deficiency Syndrome

(HIV/AIDS).

DATES: Submit written comments by

December 23, 1997. FDA proposes that

any final rule that may issue based on

this proposal become effective 60 days

after its date of publication in the

Federal Register.

ADDRESSES: Submit written comments

to the Dockets Management Branch

(HFA305), Food and Drug

Administration, 12420 Parklawn Dr.,

rm. 1–23, Rockville, MD 20857.

FOR FURTHER INFORMATION CONTACT:

Nancy E. Derr, Center for Drug

Evaluation and Research (HFD–5), Food

and Drug Administration, 5600 Fishers

Lane, Rockville, MD 20857, 301–594–

5400, FAX 301–594–6197.

SUPPLEMENTARY INFORMATION:

I. Introduction

On January 19, 1995, the AIDS Task

Force made a series of recommendations

related to women’s participation in the

drug development process, including

the recommendation that women with

reproductive potential not be excluded

from studies of drugs being tested for

use against life-threatening diseases,

particularly HIV- and AIDS-related

diseases. This recommendation was

based, in part, on data provided by the

HIV Law Project of the AIDS Service

Center (Ref. 1). The data demonstrated

that participation of women in AIDS

clinical drug trials was low.1

In the view of members of the AIDS

Task Force, this low rate of participation

raised doubts as to whether a sufficient

number of women were being included

in these clinical trials to provide

clinically meaningful information about

the effects of HIV and AIDS drugs in the

women who would be using them.

These data also raised questions and

concerns among women with HIV

regarding their ability to participate in

trials for promising new experimental

therapies. On December 8, 1995, the

Presidential Advisory Council on HIV/

AIDS adopted the AIDS Task Force’s

recommendation that FDA amend its

regulations to prevent the exclusion of

women who have a life-threatening

disease from any phase of clinical

investigations for that disease because of

their reproductive potential. If adopted,

this proposed rule would implement

that recommendation.

FDA’s policies regarding the

participation of women in clinical

investigations have evolved over time.

The agency now believes it is important

to codify its policies regarding the

participation of women with

reproductive potential in clinical

investigations of drug products intended

to treat life-threatening diseases. The

proposed amendments to the clinical

hold regulations address the exclusion

from clinical trials of members of either

gender who have a life-threatening

disease. The primary intent, however, is

to ensure that women who have a lifethreatening disease are not

automatically excluded from

investigational trials of drug products

for that disease due to a perceived risk

or potential risk of reproductive or

developmental toxicity from the use of

the investigational drug. The proposal

would not apply to clinical studies

conducted: (1) Exclusively in healthy

volunteers; (2) under special

circumstances, such as studies of a

single-gender population (e.g., studies

evaluating the excretion of a drug in

semen or its effects on menstrual

function); or (3) in men, as long as a

study that does not exclude subjects

with reproductive potential has been

planned or is being conducted in

women. For the purposes of this

rulemaking, FDA does not intend the

phrase ‘‘women with reproductive

potential’’ to include pregnant women.

The agency acknowledges the need for

more information on the safety and

effectiveness of drugs and biological

products in pregnant women and is

continuing to explore this complex

issue in other forums.

II. Clinical Hold Regulations

A clinical hold is an order, under

§ 312.42 (21 CFR 312.42), that FDA may

issue to a sponsor to delay a proposed

clinical investigation or to suspend an

ongoing investigation for the

development of a new drug, antibiotic

drug, or biological product. A clinical

hold may apply to one or more of the

investigations under an IND. When FDA

places a proposed study on clinical

hold, subjects in that study may not be

given the investigational drug. When

FDA places an ongoing study on clinical

hold, no new subjects may be recruited

to the study and placed on the

investigational drug; subjects already in

the study should be taken off the

therapy involving the investigational

drug unless FDA specifically permits

continuation of the therapy in the

interest of patient safety.

FDA may place a clinical hold on a

proposed or ongoing phase 1, phase 2,

or phase 3 investigation (§ § 312.42(b)(1)

and (b)(2)), a proposed or ongoing

treatment IND or treatment protocol

(§ 312.42(b)(3)), or any investigation that

is not designed to be adequate and well

controlled (§ 312.42(b)(4)). Generally,

FDA will attempt to discuss and resolve

the matter with the sponsor before

issuing a clinical hold order unless

subjects are exposed to immediate and

serious risk (§ 312.42(c)). When the

deficiency that prompts a clinical hold

is corrected by the sponsor, the

investigation generally may resume

(§ 312.42(e)).

III. Evolution of FDA Policy Regarding

Participation of Women in Clinical

Investigations

Although the proposed amendments

to the clinical hold regulations address

the exclusion from trials for drug

products to treat a life-threatening

disease of members of either gender

who have the disease, the primary

intent of the proposed amendments is to

ensure that women who have a lifethreatening disease are not excluded

from clinical trials solely because of

their reproductive potential. Since 1977,

when FDA first issued guidance on the

participation of women in clinical trials,

women with reproductive potential

often have been excluded from early

clinical trials due to the perceived risk

or potential risk of reproductive or

developmental toxicity. As the

following discussion shows, however,

views on the participation of women, as

well as corresponding FDA guidance

and regulations pertaining to clinical

trials of investigational drugs, reflect a
49948 Federal Register / Vol. 62, No. 185 / Wednesday, September 24, 1997 / Proposed Rules

significant evolution of thought during

the past two decades within the agency

and the scientific community. In

addition, during this period

considerable public attention has been

paid to questions about the participation

of women in general in clinical trials.

The following background information

highlights key FDA statements on the

inclusion of women, especially women

with reproductive potential, in the

clinical drug testing process.

Throughout, the phrase ‘‘reproductive

toxicity’’ refers to toxicities to

reproductive organs, while the term

‘‘developmental toxicity’’ refers to

toxicities to potential offspring.

The agency first provided formal

guidance on the participation of women

with reproductive potential in clinical

trials in a 1977 guideline entitled

‘‘General Considerations for the Clinical

Evaluation of Drugs’’ (the 1977

guideline). Developed within the

protective environment brought on by

the thalidomide experience a decade

earlier, the 1977 guideline stated that

women of childbearing potential should

not be included in phase 1 and early

phase 2 trials because of the potential

for reproductive or developmental

toxicity. Women with childbearing

potential could be included in later

phase 2 and phase 3 studies, as long as

animal teratogenicity and the female

part of animal fertility studies had been

completed and there was some evidence

of effectiveness from earlier studies. The

1977 guideline made an exception to

this recommendation for early trials

involving drug products intended to

treat life-threatening diseases, even in

the absence of adequate reproduction

studies in animals. Despite this

exception, however, the exclusion of

women of reproductive potential from

early trials was in some cases applied to

trials for drug products to treat lifethreatening diseases.

Since the 1977 guideline was issued,

views have evolved about the

participation of women in clinical trials.

Views also have evolved about informed

individuals assuming the risks of

investigational products. Recognition

has increased in the agency and among

the public that patients, especially those

with a life-threatening disease, are

willing to accept considerable risks to

participate in studies that may benefit

them. There is increased public

recognition of ethical issues such as

fairness and an individual patient’s

ability to participate in decisions that

involve personal risk. There is growing

understanding that information about

population subgroups, e.g., subsets

grouped by age, gender, or race, is

needed to evaluate the safety and

effectiveness of therapies and to refine

labeling, patient selection, and dose

selection in those groups. Failure to

obtain such information may limit the

usefulness of a treatment or expose a

segment of the population to risk. These

perspectives have influenced FDA

policy since the early 1980’s.

In the Federal Register of July 22,

1993 (58 FR 39406), FDA issued a

‘‘Guideline for the Study and Evaluation

of Gender Differences in the Clinical

Evaluation of Drugs’’ (the 1993

guideline). That guideline revoked the

1977 guideline’s recommendation

regarding restrictions on the

participation of women with

reproductive potential in early clinical

trials, including clinical pharmacology

studies (e.g., dose tolerance,

bioavailability, and mechanism of

action studies) and early therapeutic

studies. The 1993 guideline left the

determination about whether the risks

and benefits support the participation of

women with reproductive potential to

patients, investigators, sponsors, and

institutional review boards (IRB’s).

Although the 1993 guideline does not

require participation of women in any

particular trial, it sets forth FDA’s

general expectations regarding the

inclusion of both women and men in

drug development, analyses of clinical

data by gender, assessment of potential

pharmacokinetic differences between

genders, and conduct of specific

additional studies in women, where

indicated. The 1993 guideline is

consistent with an earlier guideline,

issued in 1988 and entitled, ‘‘Guideline

for the Format and Content of the

Clinical and Statistical Sections of New

Drug Applications’’ published in the

Federal Register of October 7, 1988 (53

FR 39524), in which FDA advised that

new drug applications (NDA’s) should

include analyses of data for population

subsets, including age, gender, and race,

to identify subgroup differences in

effectiveness and adverse reactions to

investigational drugs. The 1993

guideline notes that participants in

clinical studies should, in general,

reflect the population that will receive

the drug once it is marketed and

encourages the participation of women,

whether or not they have a serious

disease, in early phases of all clinical

trials. It points out that including

women early is particularly important

when a drug is intended for a serious

disease and may become available

rapidly, for example, through

distribution under a treatment IND

(§§ 312.34 and 312.35 (21 CFR 312.34

and 312.35)), or marketing under

subpart E of part 601 (21 CFR part 601)

and consisting of §§ 601.40 through

601.46 or subpart H of part 314 (21 CFR

part 314) and consisting of §§ 314.500

through 314.560. (See section IV.A. of

this document for a description of these

procedures.)

FDA has long recognized the

importance of gender data in evaluating

the safety and efficacy of a drug. This is

reflected in other FDA guidances issued

in 1993 (‘‘New Drug Evaluation

Guidance Document: Refusal to File’’

and ‘‘Center for Biologics Evaluation

and Research (CBER): Refusal to File

(RTF) Guidance for Product License

Applications (PLA’s) and Establishment

License Applications (ELA’s)’’ (58 FR

38770, July 20, 1993). These documents

state that FDA may refuse to file an

application if it contains inadequate

evaluation of the safety and/or

effectiveness of a drug, biological

therapeutic, or vaccine in specific

populations, such as in women,

intended to use the product.

FDA also recently proposed a rule

that would codify expectations

regarding presentation in NDA’s of

safety and effectiveness data by gender

as described in the 1993 guideline.

Although it would not require the

inclusion of women with reproductive

potential in clinical investigations, the

rule would require the presentation in

NDA’s of certain data by specific

population subgroups, including

women, who are likely to receive the

drug once it is marketed (60 FR 46794,

September 8, 1995).

The 1977 guideline never

recommended excluding women with

reproductive potential from trials for

drugs to treat life-threatening diseases.

Moreover, the 1993 guideline

recommended that the exclusion of such

women be removed from all trials.

Nevertheless, a recent limited agency

review of clinical trial protocols dealing

with antiviral drugs revealed that

women with reproductive potential are

still being excluded from some

protocols of some investigational trials

for drug products intended to treat HIV,

a life-threatening disease. The agency

believes that this violates ethical

principles and in some cases could lead

to inadequate data on use in women

prior to wide availability of the drug.

The agency has concluded that women

with reproductive potential who have a

life-threatening disease should no

longer be excluded from investigational

clinical trials for drug products to treat

that disease because of a risk or

potential risk of reproductive or

developmental toxicity from use of the

investigational drug, as long as patient

volunteers are fully informed of the

risks, in compliance with informed
Federal Register / Vol. 62, No. 185 / Wednesday, September 24, 1997 / Proposed Rules 49949

consent regulations in part 50 (21 CFR

part 50).

IV. Rationale for the Proposed Rule

In the past, women with a lifethreatening disease who have

reproductive potential often have been

excluded from early investigational

clinical trials for that disease because of

the potential risk of reproductive or

developmental toxicity. As a result,

although it applies to the exclusion of

either gender, the primary goal of this

proposed rule is to ensure that women

who have a life-threatening disease are

not excluded from investigational drug

studies for that disease because of their

reproductive potential.

In lengthy discussions with

representatives of industry and the

public during the development of this

proposal (Ref. 2), the view was

expressed that many early clinical

studies involving life-threatening

diseases offer the potential for

therapeutic benefit. In some cases, for

example, participation in an early

clinical study is a prerequisite for

enrollment in later studies. Based on

these discussions, FDA has concluded

that all trials involving patients with

life-threatening diseases should, for

purposes of this proposed rule, be

considered to have therapeutic potential

and that this proposal would apply to

studies in any phase of a clinical

investigation that enroll participants

with a life-threatening disease.

In developing this proposal, FDA

focused on four important factors: (1)

FDA is committed to expanding access

to and accelerating approval of new

therapies for life-threatening diseases;

(2) important ethical principles underlie

the belief that neither gender should be

excluded from early clinical trials

involving a life-threatening disease

because of their reproductive potential;

(3) the mechanisms are in place, or are

available, to protect individuals who

participate in clinical trials from

potential risks; and (4) FDA is

committed to expanding the collection

of gender-specific data on

investigational therapies, especially for

those populations who ultimately will

be using the therapies. These four

factors are discussed in detail in the

following sections of this document.

A. Expanding Access and Accelerating

Approval

FDA is committed to expanded

patient access to potentially beneficial

therapies for life-threatening and serious

diseases, such as cancer and AIDS,

through the IND process. Mechanisms

for expanding access include treatment

IND’s (§§ 312.34 and 312.35), parallel

track protocols (57 FR 13250, April 15,

1992), and other open-label protocols

either for groups of patients or for one

patient. Tens of thousands of patients

have received promising

pharmaceuticals under expanded access

mechanisms.

In many cases, the risk-benefit

assessment for investigational drugs for

life-threatening or even serious diseases

differs from that for investigational

drugs for treating diseases not

considered life-threatening or serious. In

establishing procedures for the

investigation of drugs for lifethreatening diseases, FDA has

recognized that physicians and patients

are generally willing to accept greater

risks or side effects from these medical

products than they would accept from

products that treat less serious diseases

(53 FR 41516 at 41518, October 21,

1988).

FDA also is committed to expediting

the approval of investigational drugs for

treatment of life-threatening and serious

diseases. The agency has issued

regulations for the expedited

development of new therapies intended

to treat persons with life-threatening or

severely debilitating diseases (subpart E

of part 312 (21 CFR part 312) procedures

in §§ 312.80 through 312.88), especially

where no satisfactory alternative

therapies exist. In addition, FDA has

issued regulations for the accelerated

approval of certain new drugs (subpart

H of part 314 procedures in §§ 314.500

through 314.560) and biological

products (subpart E of part 601

procedures in §§ 601.40 through 601.46)

for serious or life-threatening diseases.

For instance, accelerated approval can

be based on a surrogate endpoint that

reasonably suggests clinical benefit or

on evidence of the drug’s effect on a

clinical endpoint other than survival or

irreversible morbidity. On March 29,

1996, President Clinton announced a

major initiative undertaken by FDA to

make promising new therapies available

sooner to American cancer patients with

intractable or unresponsive

malignancies. Under this initiative, FDA

proposes, among other things, to shorten

approval times for cancer treatments by

recognizing that tumor shrinkage is

often an early indication of a treatment’s

effectiveness and by basing approval of

investigational drugs for refractory

tumors on evidence of tumor shrinkage.

In view of the agency’s commitment

to provide expanded access to and

accelerated approval of new therapies

for life-threatening and serious diseases,

this proposed rule is intended to ensure

that women with reproductive potential

who have a life-threatening disease are

not excluded from volunteering for and

being included in clinical

investigational trials for drug products

intended to treat their disease. Although

a risk or potential risk of reproductive

or developmental toxicity might exist,

FDA recognizes that the potential

benefits that may be accrued by these

women from participation in a study for

their disease may outweigh such risks

and that the availability of certain

safeguards can reduce these risks. (See

section IV.C. of this document for a

discussion regarding minimizing risks.)

B. Ethical Principles

In developing this proposal, FDA has

carefully considered the evolution of

thought within the agency and the

scientific community and among the

public regarding the participation of

women in clinical trials and the related

risks or potential risks. The agency also

has considered the basic ethical

principles that underlie clinical

research. Current FDA and Department

of Health and Human Services

regulations related to informed consent

and IRB’s are based, in large part, on the

three ethical principles relevant to

human subject research discussed in the

Report of the National Commission for

the Protection of Human Subjects of

Biomedical and Behavioral Research

(the Belmont Report) (44 FR 23192,

April 18, 1979). These principles

include respect for persons,

beneficence, and justice.

The principle of respect for persons

usually is cited within the context of

being certain that individuals are

included in clinical research voluntarily

after being fully informed. The principle

recognizes the ability of autonomous

individuals to make their own decisions

about participating in clinical research.

The principle of beneficence requires

that the risks associated with a clinical

research activity be reasonable in the

light of expected benefits. Beneficence

also requires that the chance for benefits

from participation be maximized, and

the risk of possible harms be minimized,

consistent with sound research design.

In weighing risks and benefits,

beneficence also recognizes the results

of research as a potential benefit, so long

as the rights of research participants are

protected.

The principle of justice requires that

the burdens and benefits of

participation in clinical research be

equitably distributed across the entire

population in the place or region where

the clinical research is conducted. In

general, racial, ethnic, gender, and

economic status should not be used as

a basis for excluding participation in

clinical research. Furthermore, persons

who are eligible for participation in the
49950 Federal Register / Vol. 62, No. 185 / Wednesday, September 24, 1997 / Proposed Rules

clinical research because of their disease

or condition should be provided a

reasonable opportunity to be included

in the research until the research cohort

is fully recruited.

An Institute of Medicine committee

recently examined the issue of women

in health research (Ref. 3). As part of

their deliberations, they highlighted the

ethical principle of justice and

recommended that the scientific

community and the institutions that

support it ensure that scientific

advances in medicine and public health

fairly benefit all people, regardless of

gender, race, ethnicity, or age. The

committee concluded that clinical trials

should be conducted consistent with the

principle that medical research

promotes the health and well-being of

both women and men. This proposed

rule would help achieve that goal by

ensuring that women with a lifethreatening disease are not denied the

opportunity to contribute to the body of

scientific knowledge about their disease

and its manifestations in women.

The proposed rule is consistent with

the three ethical principles in the

Belmont Report and would help to

ensure that women with reproductive

potential who suffer from a lifethreatening disease are no longer

excluded from early clinical research.

C. Informed Consent and Other

Mechanisms for Protecting People With

a Life-Threatening Disease in Early

Clinical Trials

A number of mechanisms are in place

to protect participants in early clinical

trials, including requirements for sound

study design, the use of sound research

procedures, and the proper use of the

informed consent process. In addition to

the sponsors, who have the

responsibility of designing safe clinical

trials, and the investigators, who carry

them out, institutional review boards

(IRB’s) play an important role in

ensuring participant safety in clinical

trials. It is the responsibility of the

involved IRB to determine that specific

criteria for the protection of study

participants are met before approving

research subject to the IND regulations

(§ 56.111(a) (21 CFR 56.111(a))). For

example, the IRB must determine that

risks to study participants are

minimized by the use of procedures

consistent with sound research design

and that risks to study participants are

reasonable in relation to anticipated

benefits (§ 56.111(a)(1) and (a)(2)). The

IRB also is responsible for ensuring that

information given to study participants

as part of the informed consent process

is in accordance with FDA’s regulations

under part 50 (see § 56.111(a)(4)).

Elements of informed consent require

that potential study participants be

adequately informed that the study

involves research (§ 50.25(a)(1)) and of

any foreseeable risks or discomforts

(§ 50.25(a)(2)). In addition, prospective

study participants must be informed,

when appropriate, of certain

unforeseeable risks, including potential

risks to the embryo or fetus, should a

female study participant become

pregnant (§ 50.25(b)(1)). As FDA noted

in the 1993 guideline, if animal

reproductive toxicity studies are

complete, the results and an explanation

of their significance in humans should

be presented as part of the informed

consent process (58 FR 39406 at 39411).

If these studies are not complete, that

fact should be communicated along

with any other pertinent information,

such as a general assessment of

reproductive and fetal toxicity

associated with other drugs that have

related chemical structures or

pharmacological effects. If no relevant

information is available, the informed

consent should explicitly state that fact

and make clear that the potential exists

for reproductive risks and/or

developmental risks to a fetus. If

needed, the IRB should require that a

specific period of time lapse between

when the potential study participants

receive relevant information and when

they must decide whether to participate

in the study. If in the IRB’s judgment,

additional information to that required

by § 50.25 would add meaningfully to

the protection of the rights and welfare

of study participants, the IRB may

require the imparting of that

information to the study participants (21

CFR 56.109(b)).

It is also the responsibility of the IRB

to determine that the study is designed

in such a way as to minimize the risk

of fetal exposure to possibly harmful

agents. Developmental toxicity has been

linked to maternal exposure to certain

drugs. Although a link between paternal

drug exposure and developmental

toxicity has not been conclusively

established, results of some studies

suggest that paternal exposure to certain

drugs might be associated with

developmental toxicity (Ref. 4). In

particular, low-level, chronic genotoxic

exposures that maintain fertility might

lead to fetal developmental

abnormalities, particularly when there

is exposure of post-stem cell stages of

spermatozoal development. Although

the agency has not issued formal

guidance on this issue, in such cases, it

might be prudent to take precautions to

prevent impregnation of women by men

participating in such investigational

studies.

The risk of fetal exposure can be

eliminated by preventing pregnancy

(except in those studies designed to test

a drug’s effect during pregnancy). The

risk of fetal exposure also can be

minimized by sponsors and IRB’s, who

can require the use of pregnancy testing

to detect unsuspected pregnancy prior

to initiation of study treatment or at

intervals during the course of drug

exposure. When the study design

permits, sponsors can minimize

potential developmental risks by shortterm timing of studies to coincide with

the early follicular phase of the

menstrual cycle. Thus, in most of these

short-term studies, the investigational

agent would be eliminated from a

woman’s body prior to conception,

should she inadvertently become

pregnant. When the teratogenic effects

of a drug are well established, the

agency, sponsor, or IRB may require the

use of contraception to prevent

pregnancy in sexually active individuals

of childbearing potential.

Women and men can eliminate the

possibility of pregnancy through

abstinence and reduce the possibility of

pregnancy through the use of

contraception for the duration of drug

exposure (which may exceed the length

of the study). In part because the

cooperation of the individual’s sexual

partner may be needed to ensure that

abstinence occurs, or that appropriate

contraceptive methods are used, it is

important for potential study

participants to be provided with an

opportunity to discuss their

involvement in a clinical trial with their

sexual partner prior to deciding whether

to participate in the study.

The agency believes that, through the

proper use of the informed consent

process and the use of other study

design mechanisms, risks to participants

in early clinical trials can be reduced.

When deciding whether to participate in

a clinical trial for an investigational

drug, potential participants should be

able to weigh, in consultation with their

spouse or partner, their health care

provider, and their researcher, the

potential risks of their participation.

D. Expanding the Collection of GenderSpecific Data

As noted previously, the need for

gender specific data was the subject of

guidances developed by the agency in

1988 and 1993 and was addressed in a

proposed rule issued in 1995. Recently,

medical and scientific issues related to

gender analyses were the subject of an

FDA-sponsored workshop on ‘‘Gender

Studies in Product Development:
Federal Register / Vol. 62, No. 185 / Wednesday, September 24, 1997 / Proposed Rules 49951

Scientific Issues and Approaches’’ held

from November 6 to 7, 1995 (Ref. 5).

Workshop participants, including

representatives from industry,

academia, government agencies,

consumer groups, and patient

communities, concluded that women

should be included in all stages of drug

development to fully characterize the

safety and efficacy profile of the

product. It was noted by numerous

participants that use of gender-specific

data from early trials may improve the

efficiency of phase 3 trials by aiding in

the interpretation of expected variations

among gender groups.

In the 1993 guideline, FDA

acknowledged that although drugs often

behave similarly in demographic (age,

gender, race) and other (concomitant

disease, concomitant drugs) subsets of

the population, there are many

differences within such subsets, for

example, in dose-response, in maximum

size of effect, or in the risk of an adverse

effect (58 FR 39406 at 39409). To

identify such potential differences and

to help refine labeling information,

patient selection, and dose selection, the

agency believes that it is important that

those women who are likely to use an

investigational agent once it is marketed

be included in clinical investigations

that may identify potential gender

differences. In the case of HIV and

AIDS, many of the women who are

affected are young women with

reproductive potential. Therefore, early

participation by these women in clinical

trials for such diseases will help ensure

that needed gender-specific safety and

effectiveness data are available for the

women affected by the disease (Ref. 6).

V. Legal Authority

Section 505(i) (21 U.S.C. 355(i)) of the

Federal Food, Drug, and Cosmetic Act

(the act) confers broad authority upon

the Secretary of Health and Human

Services (the Secretary) (and by

delegation to FDA) to issue regulations

governing the clinical investigation of

new drugs to protect the rights, safety,

and welfare of human subjects

(including through informed consent

provisions) and otherwise to protect the

public health. In addition, section 701

of the act (21 U.S.C. 371) provides that

the Secretary has authority to issue

regulations for the efficient enforcement

of the act (including the drug-related

provisions, such as the misbranding and

approval provisions of sections 502 (21

U.S.C. 352) and 505 of the act.

The proposed amendment to the

clinical hold regulations is intended to

protect human subjects against being

categorically excluded, based on

reproductive potential, from the

opportunity to participate in clinical

trials investigating potentially beneficial

treatments for a life-threatening disease.

In addition, the proposed amendment

would enhance public health protection

by expanding opportunities to generate

data concerning the safety and efficacy

of investigational drugs for the

treatment of life-threatening diseases.

The agency believes that prohibiting

the exclusion of women with

reproductive potential who have a lifethreatening disease from clinical trials

also is consistent with congressional

efforts to prevent unwarranted

discrimination against women. In the

employment context, for example, the

Civil Rights Act of 1964, as amended by

the Pregnancy Discrimination Act (42

U.S.C. 2000e(k), 2000e–2(e)(1)) and as

interpreted by the U.S. Supreme Court

in the landmark case of International

Union, United Automobile, Aerospace

and Agricultural Implement Workers,

UAW v. Johnson Controls, Inc., 111 S.Ct.

1196 (1991), prohibits the exclusion of

women with childbearing capacity from

jobs they are qualified to perform solely

because the working conditions of those

jobs pose potential risks to exposed

fetuses. Although the Court did not

consider or hold that the Civil Rights

Act applies to clinical drug trials, which

are manifestly different in nature and

purpose from private employment, FDA

believes it is appropriate to consider the

Court’s opinion when developing policy

on the eligibility of women with

reproductive potential for participation

in clinical trials for a life-threatening

disease.

VI. Description of the Proposed Rule

Current § 312.42(b)(1) identifies the

grounds for placing a clinical hold on

proposed or ongoing phase 1 studies

under an IND, and current § 312.42(b)(2)

identifies the grounds for placing a

clinical hold on proposed or ongoing

phase 2 or phase 3 studies. FDA is

proposing to amend §§ 312.42(b)(1) and

(b)(2) to provide an additional ground

for placing a phase 1, phase 2, or phase

3 study under an IND on clinical hold.

Under proposed §§ 312.42(b)(1)(v) and

(b)(2)(i), FDA may issue a clinical hold

on any proposed or ongoing clinical

trial for a life-threatening illness or

disease that affects both genders if men

or women with reproductive potential

who have the disease being studied are

excluded from eligibility in any phase of

clinical investigation because of a risk

or potential risk of reproductive toxicity

(i.e., toxicity to reproductive organs) or

developmental toxicity (i.e., toxicity to

potential offspring) from use of the

investigational drug. FDA believes that

such risks would be outweighed by the

potential benefits that may be accrued

by participants in a study for the

treatment of their disease and that fully

informed potential participants should

be able to make their own risk-benefit

determination. FDA also believes that,

in the case of developmental toxicity,

potential risks can be minimized by the

prevention of pregnancy through

contraception or abstinence.

The clinical hold under proposed

§§ 312.42(b)(1)(v) and (b)(2)(i) would

not apply to clinical studies conducted:

(1) Exclusively in healthy volunteers; (2)

under special circumstances, such as

studies of a single-gender population

(e.g., studies evaluating the excretion of

a drug in semen or its effects on

menstrual function); or (3) in men, as

long as a study that does not exclude

subjects with reproductive potential has

been planned or is being conducted in

women.

The phrase ‘‘women with

reproductive potential’’ as used in the

proposed rule does not include pregnant

women. The proposed rule also would

not impose requirements to enroll or

recruit a specific number of men or

women with reproductive potential.

As is true for clinical holds on any

basis, FDA ordinarily would issue a

clinical hold only after attempts to

convince the sponsor to remove an

exclusion had failed (§ 312.42(c)).

Under proposed § 312.42(b)(1)(v),

‘‘life-threatening illnesses or diseases’’

are defined as ‘‘diseases or conditions

where the likelihood of death is high

unless the course of the disease is

interrupted.’’ The proposed definition is

consistent with the definition of ‘‘lifethreatening’’ in the IND regulations

governing drugs intended to treat lifethreatening illnesses (21 CFR

312.81(a)(1)).

The proposed definition of lifethreatening illnesses or diseases is

intended to include those fatal diseases

where death itself may not be imminent,

but where treatment is necessary to

prevent premature death. For example,

an anti-retroviral drug might be found,

on the basis of phase 2 studies, to delay

progression from the asymptomatic state

to the symptomatic state and then to

AIDS when used early after infection

with HIV. Although this progression

ordinarily would take more than 12

months to occur in most patients, this

condition would be within the

definition of life-threatening. Other

examples of life-threatening illnesses

include cancer, certain cardiac

arrhythmias, intracranial hemorrhage, or

amyotrophic lateral sclerosis.

The exclusion of subjects with

reproductive potential addressed by this

proposed rule not only includes explicit
49952 Federal Register / Vol. 62, No. 185 / Wednesday, September 24, 1997 / Proposed Rules

exclusion but also de facto exclusion.

For example, a de facto exclusion might

result from setting study entry criteria

that require sterilization and would

have the effect of precluding enrollment

of participants with reproductive

potential. De facto exclusions also might

result from setting criteria that are

inherently difficult for subjects to meet,

such as weight, or other physical

requirements that generally differ

between women and men.

VII. Environmental Impact

The agency has determined under 21

CFR 25.30(h) that this action is of a type

that does not individually or

cumulatively have a significant effect on

the human environment. Therefore,

neither an environmental assessment

nor an environmental impact statement

is required.

VIII. Paperwork Reduction Act of 1995

This proposed rule does not contain

any information collection provisions

that would be subject to review by the

Office of Management and Budget

(OMB) under the Paperwork Reduction

Act of 1995 (44 U.S.C. 3501–3520).

IX. Analysis of Impacts

FDA has examined the impacts of the

proposed rule under Executive Order

12866 and the Regulatory Flexibility Act

(5 U.S.C. 601–612). Executive Order

12866 directs agencies to assess all costs

and benefits of available regulatory

alternatives and, when regulation is

necessary, to select regulatory

approaches that maximize net benefits

(including potential economic,

environmental, public health and safety,

and other advantages; distributive

impacts; and equity). The Regulatory

Flexibility Act requires agencies to

analyze regulatory options if the

proposed rule is expected to have a

significant impact on a substantial

number of small entities.

The Unfunded Mandates Reform Act

(Pub. L. 104–4) requires that agencies

prepare an assessment of anticipated

costs and benefits before proposing any

rule that may result in an annual

expenditure by State, local, and tribal

governments, in the aggregate, or by the

private sector, of $100,000,000 or more

(adjusted annually for inflation). This

proposed rule does not impose any

mandates on State, local, or tribal

governments, or the private sector that

will result in an annual expenditure of

$100,000,000 or more. The data for the

impacts analysis were developed by

FDA’s Economics Staff, Office of

Management and Systems, Office of

Planning and Evaluation, and their full

report is on file at the Dockets

Management Branch (address above).

A. Costs

Implementation of this proposed rule

could impart additional direct costs to

the industry in one area—the cost

associated with testing for pregnancy in

women with reproductive potential who

volunteer to participate in clinical trials

that would have previously excluded

them.

As fully described in its detailed

study (Ref. 7), FDA estimated the direct

cost in the following manner. Using an

FDA protocol database, the agency

estimated the number of clinical trials

for drug products for life-threatening

diseases from which women with

reproductive potential are being

excluded. The agency then determined

the total number of subjects recruited

for those clinical trials. Using published

information, the agency estimated the

relative incidence among women with

reproductive potential for the specific

life-threatening diseases compared to

the incidence in the general population.

Using the estimates of relative incidence

among women with reproductive

potential for the specific disease, it was

estimated how many women would be

participating in clinical trials for the

specific disease, were they not being

excluded. Finally, using the

approximate length of each phase of

clinical trials (phases 1, 2, and 3), the

agency calculated the number of

pregnancy tests that would be necessary

to test for pregnancy in this

volunteering population subset.

FDA conducted its analysis using data

extracted from the majority of the

clinical trial protocols submitted to four

review divisions in the Center for Drug

Evaluation and Research (CDER) during

a 20-month period between August 1,

1993, and March 31, 1995: CardioRenal; Anti-Viral; Medical Imaging,

Surgical and Dental; and the former

Pilot Drug Evaluation. The protocol data

base includes information on the phase

of the studies (whether they are phase

1, 2, or 3), the planned size of the trials,

and the indications for which the

therapies are being studied. Data from

this data base were analyzed to estimate

how many protocols were submitted to

these four FDA divisions involving lifethreatening illnesses that excluded

women with reproductive potential.

Forty-three protocols involving lifethreatening illnesses and excluding

women with reproductive potential

were identified as having been

submitted to FDA during this 20-month

period.

Projecting the number of submissions

from the four review divisions across

the entire agency required additional

analysis because it could not be

assumed that all review divisions

receive protocols for life-threatening

diseases at the same rate. To adjust for

the difference from division to division,

the agency calculated the number of

NDA approvals that were granted in

each division for drugs to treat lifethreatening and severely debilitating

illnesses under the accelerated approval

procedures of subpart E of part 312.

Using the results of this analysis and the

annualized numbers from the four

analyzed review divisions, it was

possible to calculate approximately how

many protocols for life-threatening

diseases that exclude women are

submitted to individual review

divisions each year. It was projected

that approximately 62 protocols are

submitted to FDA per year for lifethreatening diseases that exclude

women with reproductive potential.

Next it was assumed that, once they

are no longer excluded, women with

reproductive potential would enter

clinical trials in proportion to the

relative incidence of the disease

occurrence in that population at

diagnosis. Using published data on the

relative incidence among women with

reproductive potential at diagnosis of

AIDS, HIV, and coronary heart disease

and the number of protocols submitted

to the four divisions projected across the

entire agency and annualized, the

agency estimated how many women

(ages 13 to 49 years) are excluded per

year from phase 1, phase 2, and phase

3 clinical studies in the United States.

The results showed that approximately

90 women with reproductive potential

are excluded from phase 1 studies, 266

from phase 2 studies, and 40 from phase

3 studies annually in the United States.

If one assumes further that phase 1

studies last approximately 2 weeks,

phase 2 studies approximately 3

months, and phase 3 studies about a

year, the costs for pregnancy testing can

be assessed. During phase 1 studies,

approximately 1 pregnancy test would

be required for each woman with

reproductive potential entering the

study; during phase 2 studies,

approximately 3 tests would be

required; and, during phase 3 studies,

approximately 12 tests would be

required. At a cost of $30 per test, the

annual cost to industry is estimated to

be at most about $41,000. This estimate

is summarized in Table 1.
Federal Register / Vol. 62, No. 185 / Wednesday, September 24, 1997 / Proposed Rules 49953

TABLE 1.—ESTIMATED ANNUAL COSTS OF TESTING FOR PREGNANCY IN WOMEN WITH REPRODUCTIVE POTENTIAL IN U.S.

CLINICAL TRIALS FOR THERAPIES FOR LIFE-THREATENING ILLNESSES

Study Phase Tests Required per

Woman

Estimated Number of

Women Annually Cost per Test Annual Costs

1 1 90 $30 $2,700

2 3 266 $30 $23,940

3 12 40 $30 $14,400

Totals 396 $41,040

The largest cost encountered in the 43

analyzed protocols was a phase 2 trial

from which an estimated 45 women

with reproductive potential were

excluded. The cost of pregnancy testing

for this trial, if women with

reproductive potential had been

included, would have been about

$4,050. Of the 43 protocols analyzed, 6

had estimated costs of pregnancy testing

exceeding $1,000.

The agency is aware of industry’s

concerns about the liability exposure

associated with the inclusion of women

with reproductive potential in clinical

trials, particularly prior to completion of

animal reproductive studies. FDA

believes, however, that the inclusion in

investigational studies of women with

reproductive potential who have a lifethreatening disease and who have given

informed consent is not likely to lead to

increased liability. Informed consent

means that a study participant has

agreed to participate despite recognition

and appreciation of known or potential

risks, an agreement that should

minimize the legal risks associated with

drug development. Careful use of study

design and informed consent is likely to

minimize exposure to liability (Refs. 8

and 9). There is, of course, no way to

guarantee this, but there have been few

instances of liability assessed against

drug manufacturers for the conduct of

clinical trials.

As already stated, if a deficiency

exists in a clinical investigation that

may be grounds for the imposition of a

clinical hold, FDA will generally

attempt to discuss and satisfactorily

resolve the matter with the sponsor

before issuing the clinical hold order

(§ 312.42(c)). An IND would be placed

on clinical hold for specifically

excluding women with reproductive

potential only as a last resort. Only for

those few protocols could there be an

increase in cost, due primarily to a

delay in starting the clinical trials.

The agency believes that the societal

benefits more than outweigh the

potential minimal additional costs

because a considerable patient

population (women with reproductive

potential who have a life-threatening

disease) could receive a potentially

beneficial new therapy.

B. Small Entities

The protocol analysis identified

protocols sponsored by small

businesses. The largest additional

pregnancy testing cost incurred by a

small business in the reviewed

protocols under the proposed rule was

$990. Projected across all CDER/CBER

review divisions and annualized, we

expect no more than nine protocol

submissions per year from small

businesses that might incur additional

costs under the proposed rule. Few

small firms are likely to be affected in

any given year and most of these would

incur no significant additional costs.

Therefore, under the Regulatory

Flexibility Act, the Commissioner of

Food and Drugs certifies that this rule

will not have a significant effect on a

substantial number of small entities.

X. Request for Comments

Interested persons may, on or before

December 23, 1997, submit to the

Dockets Management Branch (address

above) written comments regarding this

proposal. Two copies of any comments

are to be submitted, except that

individuals may submit one copy.

Comments are to be identified with the

docket number found in brackets in the

heading of this document. Received

comments may be seen in the office

above between 9 a.m. and 4 p.m.,

Monday through Friday.

XI. References

Copies of the following references

have been placed on display in the

Dockets Management Branch (address

above) and may be seen by interested

persons between 9 a.m. and 4 p.m.,

Monday through Friday.

1. McGovern, T., ‘‘Proposal to Eliminate

Obstacles Facing Women in the Drug

Development Process: A Recommendation to

the National Task Force on AIDS Drug

Development,’’ HIV Law Project of the AIDS

Service Center, June 30, 1994.

2. Transcript of the meeting of the National

Task Force on AIDS Drug Development,

October 28, 1994 (see discussion on pp. 25

to 70).

3. Mastroianni, A. C., R. Faden, and D.

Federman, editors, Women and Health

Research: Ethical and Legal Issues of

Including Women in Clinical Studies, Vol. 1,

National Academy Press, Washington, pp.

75–83, 1994.

4. DeLap, R. J., J. L. Fourcroy, and G. A.

Fleming, ‘‘Fetal Harm Due to Paternal Drug

Exposure: A Potential Issue in Drug

Development,’’ Drug Information Journal,

30:359–364, 1996.

5. Transcript of the FDA workshop

‘‘Gender Studies in Product Development:

Scientific Issues and Approaches,’’

November 6–7, 1995.

6. Sherman, L. A., R. Temple, and R. B.

Merkatz, ‘‘Women in Clinical Trials: An FDA

Perspective,’’ Science, 269:793–795, 1995.

7. Food and Drug Administration, Office of

Management and Systems, Office of Planning

and Evaluation, Impacts of Not Excluding

Women with Reproductive Potential Who

Have Life-threatening Illnesses from Clinical

Trials, January 10, 1997.

8. Flannery, E., and S. N. Greenberg,

‘‘Liability Exposure for Exclusion and

Inclusion of Women as Subjects in Clinical

Studies,’’ in Women and Health Research:

Ethical and Legal Issues of Including Women

in Clinical Studies, Vol. 2, edited by A. C.

Mastroianni, R. Faden, and D. Federman,

National Academy Press, Washington, pp.

96–97, 1994.

9. Clayton, E. W., ‘‘Liability Exposure

When Offspring Are Injured Because of Their

Parents’ Participation in Clinical Trials,’’ in

Women and Health Research: Ethical and

Legal Issues of Including Women in Clinical

Studies, Vol. 2, edited by A. C. Mastroianni,

R. Faden, and D. Federman, National

Academy Press, Washington, pp. 108–109,

1994.

List of Subjects in 21 CFR Part 312

Drugs, Exports, Imports,

Investigations, Labeling, Medical

research, Reporting and recordkeeping

requirements, Safety.

Therefore, under the Federal Food,

Drug, and Cosmetic Act, the Public

Health Service Act, and under authority

delegated to the Commissioner of Food

and Drugs, it is proposed that 21 CFR

part 312 be amended as follows:

PART 312—INVESTIGATIONAL NEW

DRUG APPLICATION

1. The authority citation for 21 CFR

part 312 continues to read as follows:

Authority: Secs. 201, 301, 501, 502, 503,

505, 506, 507, 701 of the Federal Food, Drug,
49954 Federal Register / Vol. 62, No. 185 / Wednesday, September 24, 1997 / Proposed Rules

and Cosmetic Act (21 U.S.C. 321, 331, 351,

352, 353, 355, 356, 357, 371); sec. 351 of the

Public Health Service Act (42 U.S.C. 262).

2. Section 312.42 is amended by

adding new paragraph (b)(1)(v) and by

revising paragraph (b)(2)(i) to read as

follows:

§ 312.42 Clinical holds and requests for

modification.

* * * * *

(b) * * *

(1) * * *

(v) The IND is for the study of an

investigational drug intended to treat a

life-threatening illness or disease that

affects both genders, and men or women

with reproductive potential who have

the disease being studied are excluded

from eligibility in any phase of clinical

investigation because of a risk or

potential risk of reproductive (i.e.,

toxicities to reproductive organs) or

developmental (i.e., toxicities to

potential offspring) toxicity from use of

the investigational drug. The phrase

‘‘women with reproductive potential’’

does not include pregnant women. For

purposes of this paragraph, ‘‘lifethreatening illnesses or diseases’’ are

defined as ‘‘diseases or conditions

where the likelihood of death is high

unless the course of the disease is

interrupted.’’ The clinical hold would

not apply under this paragraph to

clinical studies conducted:

(A) Under special circumstances, such

as studies of a single-gender population

(e.g., studies evaluating the excretion of

a drug in semen or the effects on

menstrual function); or

(B) In men, as long as a study that

does not exclude subjects with

reproductive potential has been planned

or is being conducted in women.

(2) * * *

(i) Any of the conditions in

paragraphs (b)(1)(i) through (b)(1)(v) of

this section apply; or

* * * * *

Dated: September 16, 1997.

Michael A. Friedman,

Lead Deputy Commissioner for the Food and

Drug Administration.

Donna E. Shalala,

Secretary of Health and Human Services.

[FR Doc. 97–25268 Filed 9-23-97; 8:45 am]

BILLING CODE 4160–01–F

DEPARTMENT OF THE INTERIOR

Fish and Wildlife Service

50 CFR Part 17

RIN 1018–AE30

Endangered and Threatened Wildlife

and Plants; Public Hearing and

Extension of Comment Period on

Proposed Endangered Status for

Keck’s Checker-Mallow

AGENCY: Fish and Wildlife Service,

Interior.

ACTION: Proposed rule; notice of public

hearing and extension of comment

period.

SUMMARY: The Fish and Wildlife Service

(Service), pursuant to the Endangered

Species Act of 1973, as amended (Act),

provides notice of a public hearing and

extension of the comment period on the

proposed endangered status for Sidalcea

keckii (Keck’s checker-mallow). The

comment period is extended to

accommodate a public hearing that was

requested by California Assemblyman

Roy Ashburn, Thirty-Second District.

DATES: The public hearing will be held

on Tuesday, October 21, from 6:00 p.m.

to 8:00 p.m. in Visalia, California. The

comment period closes November 10,

1997.

ADDRESSES: The public hearing will be

held at the Visalia Convention Center,

303 East Acequia Street, Visalia,

California. Comments and materials

concerning this proposal should be sent

to the Field Supervisor, U.S. Fish and

Wildlife Service, Sacramento Fish and

Wildlife Office, 3310 El Camino

Avenue, Suite 130, Sacramento,

California 95821–6340. Comments and

materials received will be available for

public inspection, by appointment,

during normal business hours at the

above address.

FOR FURTHER INFORMATION CONTACT: Ken

Fuller of the Sacramento Fish and

Wildlife Office (see ADDRESSES section)

at (916) 979–2120.

SUPPLEMENTARY INFORMATION:

Background

On July 28, 1997, the Service

published a rule proposing endangered

status for Sidalcea keckii in the Federal

Register (62 FR 40325). The original

comment period was to close on

September 26, 1997. Section 4(b)(5)(E)

of the Act (16 U.S.C. 1531 et seq.)

requires that a public hearing be held if

it is requested within 45 days of the

publication of the proposed rule. In

response to a request for a public

hearing from California Assemblyman

Roy Ashburn, a public hearing will be

held in Visalia, California on October

21, 1997, at the Visalia Convention

Center. Parties wishing to make

statements for the record should bring a

copy of their statements to the hearing.

Oral statements may be limited in

length, if the number of parties present

at the hearing necessitates such a

limitation. There are no limits to the

length of written comments or materials

presented at the hearing or mailed to the

Service. Written comments carry the

same weight as oral comments. The

comments period now closes on

November 10, 1997. Written comments

should be submitted to the Service in

the ADDRESSES section.

Sidalcea keckii is an annual plant that

is known from one population in the

hilly annual grasslands of south-central

Tulare County. The plant is threatened

by agricultural land conversion, urban

development, and naturally occurring

events. Comments from the public

regarding the accuracy of this proposed

rule are sought, especially regarding:

(1) Biological, commercial trade, or

other relevant data concerning any

threat (or lack thereof) to the species

listed above;

(2) The location of any additional

populations of the species and the

reasons why any habitat should or

should not be determined to be critical

habitat as provided by section 4 of the

Act;

(3) Additional information concerning

the range, distribution, and population

sizes of the species; and

(4) Current or planned activities in the

subject area and their possible impacts

on the species.

Author

The primary author of this notice is

Ken Fuller (see ADDRESSES section).

Authority

The authority for this action is the

Endangered Species Act of 1973 (16

U.S.C. 1531 et seq.).

Dated: September 16, 1997.

Cynthia Barry,

Acting Regional Director, Region 1, Portland,

Oregon.

[FR Doc. 97–25061 Filed 9–23–97; 8:45 am]

BILLING CODE 4310–55–P