27794 Federal Register / Vol. 63, No. 97 /Wednesday, May 20, 1998 / Proposed Rules

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

45 CFR Part 46

RIN 0925–AA14

Protection of Human Research

Subjects

AGENCY: Department of Health and

Human Services (HHS).

ACTION: Notice of Proposed rulemaking.

SUMMARY: The Department of Health and

Human Services (HHS) is proposing to

amend its human subjects protection

regulations applicable to research

conducted or supported by HHS, by

replacing the existing Subpart B of the

regulations entitled ‘‘Additional DHHS

Protections Pertaining to Research,

Development, and Related Activities

Involving Fetuses, Pregnant Women,

and Human In Vitro Fertilization’’ with

new regulations entitled ‘‘Additional

DHHS Protections for Pregnant Women,

Human Fetuses, and Newborns Involved

as Subjects in Research, and Pertaining

to Human In Vitro Fertilization.’’ This

revision continues the Department’s

recognition of the need to provide

special protections for the human fetus

and newborn in research, while

eliminating unnecessary barriers to

consent to research that can benefit

fetuses or newborns.

Additionally, consistent with recent

practices and statutory changes, this

proposed regulation provides a

mechanism for special ethical reviews

on an ad hoc basis as may be deemed

appropriate by the Secretary, HHS.

DATES: Comments on the proposed

regulation must be received on or before

August 18, 1998.

ADDRESSES: Comments must be mailed

to: Carol Wigglesworth, Senior Policy

Analyst, Office for Protection from

Research Risks, 6100 Executive

Boulevard, Suite 3B01, MSC–7507,

Rockville, MD 20892–7507. The

Department invites written comments

on the proposed regulations and

requests that comments identify the

specific regulatory provisions to which

they relate.

FOR FURTHER INFORMATION CONTACT:

Carol Wigglesworth, Senior Policy

Analyst, Office for Protection from

Research Risks, 6100 Executive

Boulevard, Suite 3B01, MSC–7507,

Rockville, MD 20892–7507, (301) 402–

5913 (not a toll-free number). Interested

persons may obtain a fax copy of the

current regulations for the protection of

human research subjects (45 CFR 46),

including Subpart B as well as Subparts

A, C, and D, by telephoning (301) 594–

0464 (not a toll free number) and

requesting document number 1004.

SUPPLEMENTARY INFORMATION:

Background

On August 8, 1975, The Department

of Health and Human Services (HHS)

[then the Department of Health,

Education, and Welfare (HEW)]

published regulations pertaining to

research involving fetuses, pregnant

women, and human in vitro

fertilization. Those regulations were

consistent with the recommendations of

the National Commission for the

Protection of Human Subjects of

Biomedical and Behavioral Research

(National Commission) and were

codified at Subpart B of Title 45, Part

46, of the Code of Federal Regulations.

Along with subsequent secondary

changes, incorporated on January 11,

1978 and June 1, 1994, these regulations

remain in force today. Both the 1975

Report of the National Commission and

the 1975 regulations were published in

the Federal Register on August 8, 1975

(40 FR 33526 (1975)).

During the last four years, the

following pertinent events involving

research covered by the 1975

regulations occurred:

• The enactment on June 10, 1993 of

the ‘‘National Institutes of Health (NIH)

Revitalization Act of 1993’’ (Pub. L.

103–43) nullifying the HHS regulatory

requirement for Ethical Advisory Board

review of research involving in vitro

fertilization of human ova at 45 CFR

46.204(d) (59 FR 28276 (1994)).

• The 1994 recommendations of the

Institute of Medicine Committee on the

Ethical and Legal Issues Relating to the

Inclusion of Women in Clinical Studies

urging the Office for Protection from

Research Risks (OPRR), HHS, to ‘‘* * *

revise and reissue subpart B * * *’’ of

the human subject protection

regulations consistent with the

Committee’s recommendations for

enhanced inclusion of women in

research studies (Women and Health

Research: Ethical and Legal Issues of

Including Women in Clinical Studies,

National Academy Press, 1994).

• The issuance of a Food and Drug

Administration ‘‘Guideline for the

Study and Evaluation of Gender

Differences in the Clinical Evaluation of

Drugs’’ on July 22, 1993 (58 FR 39406

(1993)), the issuance of NIH ‘‘Guidelines

on the Inclusion of Women and

Minorities as Subjects in Clinical

Research’’ on March 28, 1994 (59 FR

14508 (1994)), and the issuance of a

Centers for Disease Control and

Prevention and Agency for Toxic

Substances and Disease Registry ‘‘Policy

on the Inclusion of Women and Racial

and Ethic Minorities in Externally

Awarded Research’’ on September 15,

1995 (60 FR 47947 (1995)), each

designed, in part, to improve the

opportunity for women to be included

as human subjects in research.

• The enactment on September 30,

1996, of the ‘‘Omnibus Consolidated

Fiscal Year 1997 Appropriations Act’’

(Pub. L. 104–208) prohibiting HHS from

using funds appropriated by the act for

(i) the creation of a human embryo or

embryos for research purposes, or (ii)

research in which a human embryo or

embryos are destroyed, discarded, or

knowingly subjected to risk of injury or

death greater than that allowed for

research on fetuses in utero under 45

CFR 46.208(a)(2) and section 498(b) of

the Public Health Service Act (42 U.S.C.

289g(b)). On January 26, 1996, identical

language pertinent to FY 1996 funds

had been enacted in Pub. L. 104–99.

The impact of these events on

research involving pregnant women,

fetuses, and in vitro fertilization and the

fact that there had been no major review

of the regulations applicable to these

subjects for nearly two decades,

presented a forceful argument for a

contemporaneous review of these

regulations.

The OPRR, located at NIH, has HHSwide responsibility for the

development, implementation, and

compliance oversight of these

regulations. The Director, OPRR,

convened the Public Health Service

Human Subject Regulation Drafting

Committee, a committee of

representatives of the heads of the

pertinent operating components within

the Public Health Service, to evaluate

Subpart B of 45 CFR Part 46 and to

consider if revisions were in order.

Beginning in May 1994, this committee

met twice monthly over the next 14

months to review the regulations and to

make recommendations for any needed

revisions.

The Drafting Committee found that

the regulations provide adequate

protections for women and fetuses. In

light of the IOM Report and the NIH

guidelines on the Inclusion of Women

and Minorities as subjects in Clinical

Research, the Drafting Committee

concluded that women ought not be

unnecessarily excluded from research

on the basis of pregnancy.

Accordingly, this proposed rule

institutes a policy of presumed

opportunity for inclusion of pregnant

women in research in place of one of

presumed exclusion. Similarly, the

proposed rule modifies the consent

requirements for fetal research to

remove potential barriers to therapeutic

research that might provide medical
Federal Register / Vol. 63, No. 97 /Wednesday, May 20, 1998 / Proposed Rules 27795

benefit to a fetus. The Drafting

Committee also found that

nonsubstantive technical, formatting,

and clarifying changes are in order.

In the midst of the Drafting

Committee’s evaluation and discussion,

the National Task Force on AIDS Drug

Development, chaired by the Assistant

Secretary for Health, recommended that

the regulations applicable to pregnant

subjects of research be amended to

remove any requirement that permission

or consent of the father of the fetus be

obtained before the woman could

become a research subject. The Drafting

Committee carefully reviewed the issue

of a ‘‘paternal consent’’ requirement for

participation of pregnant women and

has incorporated into this proposed rule

changes which are responsive to the

recommendation of the Task Force. The

Presidential Advisory Council on HIV/

AIDS subsequently addressed the matter

of paternal consent during their

December 1995 meeting, and

recommended that the Secretary, HHS

publish for public comment proposed

regulations regarding participation of

pregnant women in clinical trials, with

a revision which will provide that the

lack of a written consent from the father

of the fetus will not disqualify a

pregnant woman from participation in a

federally funded clinical trial.

The Drafting Committee approved a

proposed rule and recommended that

the Assistant Secretary for Health and

the Secretary, HHS, publish the

proposal for public comment. The

notice of proposed rulemaking fulfills

that recommendation.

Proposed Changes to Subpart B

See Figure 1 and Table 1.

BILLING CODE 4140–01–P
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BILLING CODE 4140–01–C

Section 46.201 To what do these

regulations apply?

Paragraph (a)—There is no

substantive change to this paragraph.

Consistent with recent revisions of other

subparts of Part 46, references to grants

and contracts are deleted to demonstrate

that these regulations apply to all

activities, intramural and extramural,

which are conducted or supported by

the Department.

Paragraph (b)—It is now proposed

that the exemptions at § 46.101(b)(1)–(6)

of Subpart A be applicable to Subpart B.

These exemptions were proposed,

discussed, and promulgated subsequent

to the last substantive revision of

Subpart B. The proposals, discussions,

and promulgations of these exemptions

were published in the Federal Register

on: August 14, 1979 (exemptions first

proposed, 44 FR 47688); January 26,

1981 (exemptions first promulgated, 46

FR 8366); March 22, 1982 (new

exemption proposed, 47 FR 12276);

March 4, 1993 (new exemption

promulgated, 48 FR 9276); March 8,

1983 (exemptions added to Subpart D of

45 CFR 46, 48 FR 9814); June 3, 1986

(exemptions proposed for proposed

Model Federal Policy for the Protection

of Human Subjects, 51 FR 20204);

November 10, 1988 (exemptions

proposed in revised proposed Federal

Policy for the Protection of Human

Subjects, 53 FR 45661); and June 18,

1991 (exemptions revised in

promulgation of Federal Policy for the

Protection of Human Subjects, 56 FR

28003). The Department is particularly

interested in comment on the inclusion

of these exemptions.

Paragraph (c)—This provision extends

the additions, exceptions, and

provisions for waiver, as set forth in

paragraphs (c) through (i) of § 46.101 of

Subpart A of Part 46, to the regulations

at Subpart B. The provision is identical

to § 46.401(c) of the regulations

providing additional protection for

research involving children. It does not

appear in the existing Subpart B only

because the additions, exceptions, and

provisions for waiver were not included

in Subpart A at the time Subpart B was

promulgated.

Paragraphs (c) through (i) of § 46.101

address: the authority of Department

and Agency heads to determine the

applicability of the regulations to

specific research activities or classes of

research activities (paragraphs (c), (d),

and (i)); the relationship of the

regulations to any Federal laws or

regulations providing additional

protection for human subjects

(paragraph (e)); the relationship of the

regulations to any state or local laws or

regulations which provide additional

protection for human subjects

(paragraph (f)); the relationship of the

regulations to foreign laws or

regulations which provide additional

protection for human subjects

(paragraph (g)); and the authority of

Department and Agency heads to

determine the applicability of foreign

procedures for the protection of human

subjects which differ from the

requirements of the regulations

(paragraph (h)). Note that the proposed

§ 46.201(c) clarifies that the reference to

State or local laws is intended to

include the laws of federally recognized

American Indian and Alaska Native

Tribal Governments.

The authority for determinations by

Department and Agency heads under

those provisions and the recognition of

Federal, State, local, and foreign laws

and regulations that provide additional

protection for human subjects can and

should be applied to the research

covered by Subpart B in the same

manner as they apply to other research

involving human subjects.

Section 46.202 Definitions

The text of the existing § 46.202,

‘‘Purpose,’’ is unnecessary because it

does not provide any substantive

guidance. It is deleted in the proposed

regulation. The absence of a ‘‘purpose’’

section is consistent with Subparts A

and D of 45 CFR Part 46.

Definitions in existing § 46.203 are

moved to § 46.202 in the proposed

regulation. The definitions in the

proposed regulation are substantively

the same as those in the existing

regulation; some language has been

clarified or simplified and definitions of

‘‘newborn’’ and ‘‘children’’ are

provided.

Paragraph (a) ‘‘Secretary’’—no change

Paragraph (b) ‘‘Pregnancy’’—The

definition conforms with the standard

medical definition of pregnancy. The

phrase ‘‘expulsion or extraction of the

fetus’’ has been replaced by the

commonly used term ‘‘delivery’’ here

and throughout Subpart B. The word

‘‘confirmation’’ of implantation has

been deleted as unnecessary. (If a

woman shows any presumptive sign of

pregnancy, such as missed menses, she

is considered pregnant until the results

of a pregnancy test are negative or until

delivery.)

Paragraph (c) Fetus—the definition

has been simplified by adding the

phrase ‘‘during pregnancy’’ and deleting

reference to ex utero.

Paragraph (d) Newborn—the

definition is new and equates to a fetus

after delivery.

Paragraph (e) Nonviable fetus or

nonviable newborn—the definition

replaces the current definition of

‘‘nonviable fetus’’ which refers to

fetuses ex utero. Both terms (fetus and

newborn) are provided because some

persons may prefer one term to the other

depending on the length of the

gestational period. No substantive

change is intended.

Paragraph (f) Dead fetus or dead

newborn—the definition replaces the

definition of dead fetus which pertains

to a fetus ex utero. Both terms (fetus and

newborn) are provided because some

persons may prefer one term to the other

depending on the length of the

gestational period. No substantive

change is intended.

Paragraph (g) Viable fetus or viable

newborn—the definition refers to

fetuses after delivery and replaces the

current definition which refers to

fetuses ex utero. A viable fetus or a

viable newborn is a child. Both terms

(fetus and newborn) are provided

because some persons may prefer one

term to the other depending on the

length of the gestational period. The

meaning of viability is unchanged, and

a reference to Subpart D is added.

Paragraph (h) ‘‘Children’’—the

definition in Subpart D is repeated in

this subpart for ease of reference.

Paragraph (i) ‘‘In vitro fertilization’’—

no change.
27800 Federal Register / Vol. 63, No. 97 /Wednesday, May 20, 1998 / Proposed Rules

Section 46.203 Duties of IRBs in

Connection With Research Involving

Pregnant Women, Human Fetuses,

Newborns and Human in Vitro

Fertilization

Definitions in existing § 46.203 are

found in § 46.202 in the proposed

regulation.

Definitions in existing § 46.203 are

found in § 46.202 in the proposed

regulation. There is no substantive

change to this section; the language is

more concise. The proposed § 46.203

would replace the existing § 46.205

regarding IRB duties, which is

duplicative of language in Subpart A.

In assessing research involving

pregnant women, IRBs must be attentive

to the Department’s objective that

research it supports include pregnant

women unless there are compelling

reasons to exclude them. In other words,

the presumption is one of inclusion, not

exclusion.

Pregnant women are not a vulnerable

population solely by virtue of

pregnancy. IRBs should consider if

proposed research has the potential to

diminish or interfere with this

population’s ability to make a decision.

That is, in its review, the IRB should

note that the intent of ‘‘vulnerable’’ in

Subpart A, section 46.111(a)(3) and (b)

of these regulations, when applied to

pregnant women, is not that pregnant

women have less capacity to make

autonomous decisions than men or nonpregnant women, but that sometimes

the medical management of pregnancy

has the potential to apply coercion to a

woman due to her concerns for the

health of the fetus. This may be

particularly relevant in the case where

a researcher views a planned research

activity as potentially highly beneficial

to a pregnant woman with a lifethreatening illness or to a fetus and,

therefore, the researcher believes that

the potential benefit of the planned

research should override the autonomy

of a pregnant woman. The 1978 report

of the National Commission for the

Protection of Human Subjects of

Biomedical and Behavioral Research

(the Belmont Report), and the resulting

regulations in 45 CFR 46, stand in direct

contrast to that position. The Belmont

Report shall guide the interpretation of

the regulations in section 46.203 so that

a pregnant woman’s decisionmaking

autonomy is always preeminent.

Section 46.204 Research Involving

Pregnant Women or Fetuses

The existing § 46.204 entitled ‘‘Ethical

Advisory Boards’’ calls for the

establishment of one or more standing

EABs by the Secretary, HHS. These

EABs were to have had broad expertise

and advise the Secretary with regard to

ethical issues raised by research

activities covered by Subpart B. This

proposed regulation deletes the text of

existing § 46.204 (a)–(c) and proposes a

provision for convening an ad hoc panel

of expert consultants to review

proposals for modification or waiver of

the regulation which are raised by

individual research proposals. (See

proposed § 46.207). An EAB has not

existed within the Department since

1980, and § 46.204(d), which required

EAB review prior to HHS funding of

human in vitro fertilization, was

nullified June 10, 1993, by the NIH

Revitalization Act of 1993, Pub. L. 103–

43.

The obligations and requirements in

existing §§ 46.206 (General limitations),

46.207 (Activities directed toward

pregnant women as subjects) and 46.208

(Activities directed toward fetuses in

utero as subjects), are combined into a

single section in the proposed rule,

§ 46.204, for ease of reference.

From the standpoint of risk to mother

or fetus, it is irrelevant whether research

is ‘‘directed toward’’ the woman or

directed toward the fetus, because

research on either affects both. Thus, if

a pregnant woman and her fetus are

involved in research, regardless of

whether she or her fetus is the object of

the research, the protections should be

essentially identical. Accordingly, the

proposed regulation combines all

relevant protections for pregnant

women and fetuses into a single section

and deletes any reference to the object

of the research.

The proposed rule adds specificity to

the current requirement for preclinical

studies on animals and nonpregnant

individuals, by calling for

‘‘scientifically’’ appropriate studies,

including studies on pregnant animals,

that provide data to assess potential

risks (proposed § 46.204(a)).

The proposed risk threshold is

unchanged. Pregnant women or fetuses

may not be involved in research unless

the risk to the fetus is not greater than

minimal, except when the risk to the

fetus is caused solely by research

designed to meet the health needs of the

mother or the fetus (proposed

§ 46.204(b)). The existing requirement

that any risk be the least possible risk

for achieving the objectives of the

research is also unchanged in the

proposed regulation.

The proposed regulation includes a

reminder (proposed § 46.204(f)) that

research involving pregnant children is

subject to the requirements for research

involving children in 45 CFR Part 46,

Subpart D, Additional DHHS

Protections for Children Involved as

Subjects in Research.

The existing prohibition on the

involvement of research personnel in

decisions regarding the timing, method,

or procedures to terminate a pregnancy,

and in determinations of viability is

unchanged (proposed § 46.204(g)). The

phrase ‘‘terminate the pregnancy’’ is

replaced by ‘‘abort’’ in the proposed

rule. The existing prohibition on

inducements to terminate pregnancy is

strengthened by deleting the phrase ‘‘for

purposes of the activity’’ (i.e., research),

thus barring any inducement to abortion

regardless of the purpose (proposed

§ 46.204(h)).

The proposed regulation strengthens

the existing requirements for informed

consent by requiring that the pregnant

woman be informed of the reasonably

foreseeable impact on the fetus,

irrespective of the focus of the research

(proposed § 46.204(d)).

Current regulations require, in most

instances, that both parents consent and

be legally competent. The Department

concurs with recent recommendations

of the Presidential Advisory Council on

HIV/AIDS and the National Task Force

on AIDS Drug Development regarding

paternal consent and finds that the fetus

is best served by eliminating

unnecessary barriers to consent for

research that has the possibility of

benefitting the fetus. Therefore, the

proposed regulation modifies the

parental consent requirements by

permitting research based on the

consent of the mother or her legally

authorized representative (proposed

§ 46.204(e)).

The existing regulation (§§ 46.207(b)

and 46.208(b)) permits research

involving pregnant women and fetuses

only if the mother and father are legally

competent and have given their

informed consent. The father’s consent

is not required under certain

circumstances: if his identity or

whereabouts cannot reasonably be

ascertained, if he is not reasonably

available, or if the pregnancy resulted

from rape. Nor is the father’s consent

required if the purpose of the research

is to meet the health needs of the

mother.

When research is directed toward the

health needs of the fetus, there is

currently no exception to the paternal

consent requirement equivalent to the

one for the health needs of the mother.

Thus, under the existing regulation,

there are instances in which research

intended to benefit the fetus may not

occur because one parent refuses, or

because one parent is not legally

competent.
Federal Register / Vol. 63, No. 97 /Wednesday, May 20, 1998 / Proposed Rules 27801

1The term ‘‘permission’’ as used by the

Commission and in Subpart D has the same

meaning as ‘‘consent’’ for the purposes of this

discussion.

The parental consent rules in the

existing regulation are based in part on

the studies and recommendations of the

National Commission for the Protection

of Human Subjects of Biomedical and

Behavioral Research. The history of the

Commission’s consideration of the issue

and the resulting regulation is pertinent

to the proposed modification. In its

Research on the Fetus: Report and

Recommendations (May 1975), the

Commission proposed that: (1) only the

woman’s consent be required when the

research was directed toward her health

needs; and (2) in the other kinds of

research, the woman’s consent be

required and be sufficient if the father

does not object (page 73). The final rule

published on August 8, 1975 as 45 CFR

Part 46, Subpart B, Additional DHHS

Protections Pertaining to Research,

Development, and Related Activities

Involving Fetuses, Pregnant Women,

and Human In Vitro Fertilization (the

existing rule) incorporated the first part

of this recommendation, but with

respect to research not directed toward

the mother’s needs it went beyond the

recommendation by requiring explicit

consent from the father (with the

exceptions described above). The

rationale was one of practical

implementation: the most effective way

of determining that the father did not

object was to request his consent (40 FR

33526–33527 (1975)).

The Commission looked again at the

role of parental consent in its 1976

report, Research Involving Children:

Report and Recommendations. It

recommended that: (1) the permission 1

of only one parent be required for

research involving children that either

was not greater than minimal risk, or

presented the prospect of direct benefit

to the child; and (2) the permission of

both parents be required for any other,

more problematic, research (pages 12–

14). This recommendation was

incorporated into 45 CFR Part 46,

Subpart D, Additional DHHS

Protections for Children Involved as

Subjects in Research.

The Commission’s recommendations

regarding parental consent differ for

fetuses and for children despite the

similarities when they are subjects of

research. The similarities are striking:

neither the fetus nor the child

(especially an infant) can give consent;

the fetus and the child are both

vulnerable; both the mother and father

have an interest in and legal

responsibility for their fetus or their

child. Yet the existing requirements for

parental consent, based largely on the

Commission’s recommendations, treat

children and fetuses differently. The

Commission did not examine or explain

the inconsistency. It acknowledged that

its report about the fetus was hurried,

was its first task, and was done out of

sequence (before first examining

research in general) (page 61).

In actual experience, one approach to

parental consent has presented no

problems, the other several problems.

Since the regulation for research on

children (Subpart D) was issued in

1983, there has been no reported abuse

resulting from the policy of requiring

only one parent’s permission for a

child’s participation in research that

presents no greater than minimal risk or

may be of direct benefit to the child or

infant. Although both parents have an

interest in and responsibility for their

child, no parent has been reported to

object that research may be conducted

with only one parent’s permission.

Since the regulation governing research

on the fetus (Subpart B) was issued in

1975, however, the required consent of

both parents for fetal research has posed

some difficulties. For example, in the

recent trial of the drug zidovudine

(AZT) in pregnant women with HIV

infection (showing that the drug

reduced the percentage of newborns

infected with HIV), the requirement to

obtain the father’s consent was an

obstacle to the participation of some

women. Some fathers, while ‘‘available’’

in some literal sense, did not wish to be

involved with the woman or her

pregnancy in any way. In some

situations, asking for the father’s

consent introduced the possibility of

retaliation against the pregnant woman

by the father. The result in some

instances was that fetuses who could

benefit from participating in research

were excluded when the paternal

consent required by the existing

regulation could not be obtained.

The barriers to participation posed by

the requirement that both parents

consent, and the experience with

consent by one parent under the

regulation for research on children,

suggest that accepting consent by one

parent provides effective protection for

the interests of the fetus and enhances

the opportunities for the fetus to benefit

from research. In light of the physical

realities of pregnancy, any research

involving or directed toward the fetus

necessarily involves the pregnant

woman, and her consent must be

sought. Absent her consent, the research

could not take place even if the father

did consent. Thus, if the consent of one

parent is to be sufficient, that parent

must be the mother.

The Department recognizes the

father’s likely interest in and

responsibility for the fetus and strongly

encourages paternal involvement in

decision-making with respect to

offspring. The father can normally be

assumed to have as much interest,

feeling, and concern for the future wellbeing of the fetus as the mother.

The basic requirements for consent to

research in Subpart A offer a framework

for participation of the father. Consent

may be sought only under

circumstances that provide sufficient

opportunity to consider whether or not

to participate (§ 46.116). In considering

whether to participate, many women

would wish to consult with the father.

In other situations, to seek the consent

of the father could be detrimental to the

mother or could be an obstacle to a

potential therapy for a fetus. The

pregnant woman is in the best situation

to determine whether she should

consult with the father.

Thus, the Department proposes to

modify the regulation to accept consent

from the mother alone as a sufficient

basis for participation of the fetus in the

limited classes of research permitted

under this subpart, i.e., minimal risk

research or research designed to meet

the health needs of the mother or her

fetus.

A similar barrier to participation is

created by the requirement that both

parents be legally competent before

their consent can be accepted for a fetus

to participate in research. Under the

other subparts of 45 CFR Part 46

(including the provisions governing

research on children (§ 46.408(b)))

consent from a legally authorized

representative is adequate for

participation in research. Thus, it is

proposed that consent from a legally

authorized representative of the mother

could be used as a substitute for the

mother’s consent (proposed § 46.204(e)).

This permits participation in research,

including research directed towards the

health needs of the pregnant woman or

her fetus, even though the pregnant

woman is a minor but not emancipated

under state law, or is legally

incompetent for other reasons. The

authorized representative could in many

instances be the father.

The proposed changes would

establish a consent process that has

choice about the best interests of the

fetus as its principal objective. The

rights and responsibilities of parents

and families are recognized by requiring

appropriate review and parental

involvement.
27802 Federal Register / Vol. 63, No. 97 /Wednesday, May 20, 1998 / Proposed Rules

Section 46.205 Research Involving

Newborns of Uncertain Viability,

Nonviable Newborns, and Viable

Newborns

It is proposed that the existing

§ 46.209 be replaced by this section. A

number of clarifications are made and

the consent requirement is modified to

remove barriers to potentially

therapeutic research. The proposed title

refers to newborns, rather than ‘‘fetuses

ex utero,’’ and reflects more clearly the

three types of situations that may arise

after delivery: (a) Viability of the

newborn may not be known, (b) the

newborn may be known to be nonviable,

or (c) the newborn may be known to be

viable. The term ‘‘activity’’ is changed to

‘‘research’’ for consistency with other

portions of the subpart and to reflect

that the regulation addresses risks

associated with research activities in

contrast to those associated with

therapeutic activities that are part of the

accepted standard of care.

a. Proposed § 46.205(a) acknowledges

that there is sometimes a period of

uncertainty about the viability of a

newborn. In accordance with section

498 of the Public Health Service Act, 42

U.S.C. 289g, the proposed section limits

research during this period to either

research that evaluates activities

designed to enhance the probability of

survival of that particular newborn to

viability or risk free research, the

purpose of which is the development of

important biomedical knowledge which

cannot be obtained by other means. As

has been the case under the existing

regulations, the application of this

condition will permit research activities

that, in and of themselves, pose no risk

to the newborn, such as observational

research using monitors or other devices

that are already in place as part of

normal therapeutic practice, if the

purpose of the research is the

development of important biomedical

knowledge which cannot be obtained by

other means.

It is proposed that the consent

requirement for research activities on

newborns of uncertain viability be

changed from the consent of both

parents to the consent of either parent,

and that the competency requirement

for mother and father, in the existing

§ 46.209(d), be deleted. It is further

proposed that if neither parent is able to

consent for the reasons given, then the

consent of a legally authorized

representative of either is sufficient.

This less restrictive consent requirement

is appropriate for the limited scope of

research activities that either must

enhance the possibility of survival to

viability or pose no risk and be directed

toward the development of important

biomedical knowledge that cannot be

obtained by other means.

The existing regulation, while

generally requiring consent from both

parents, also recognizes that there may

be circumstances when it is not

reasonable to require the father’s

consent; in those circumstances, it

allows consent from only one parent,

the mother. For research involving the

fetus, the mother must clearly be the

one to consent. After delivery, however,

if consent is to be required from only

one parent, HHS proposes that it is

appropriate to allow for consent from

either the mother or the father. In

formulating the new requirement, it is

recognized that there may also be

circumstances when it is not possible to

obtain the mother’s consent, (e.g., the

mother is under general anesthesia as a

result of a surgical delivery). Because of

the critical nature of life-saving

interventions performed on newborns of

uncertain viability, and the limited time

available to make decisions regarding

participation in potentially beneficial

research to enhance the possibility of

their survival, the proposed regulation

also allows for consent by a legally

authorized representative, if needed.

b. With regard to research on

nonviable newborns, the proposed

regulation is more restrictive. It does not

permit a legally authorized

representative to consent, and the

provisions for IRB waiver of informed

consent in Subpart A of 45 CFR Part 46

are not authorized. Research involving

nonviable newborns will continue to be

strictly limited (i.e., the proposed

regulation retains the requirement that

the proposed research poses no added

risk to the fetus of suffering injury or

death and the purpose of the research

activity be the ‘‘development of

important biomedical knowledge that

cannot be obtained by other means,’’

and the prohibition against the use of

artificial life support or research that

would terminate heartbeat or

respiration).

In the existing regulation, the consent

of both parents is required for research

on the nonviable newborn unless, for

the reasons given, consent of the father

cannot reasonably be obtained then the

mother’s consent will suffice. In the

proposed regulation, the consent of both

parents is also required, but if either

parent is unable to consent, then the

legally effective consent of the other

parent will suffice.

The requirement in the existing

regulation that both parents be legally

competent is replaced by a requirement

that at least one parent be competent

and provide consent. If neither parent is

able to give consent, whether it is

because of incompetence or because of

some other reason, the research will not

be allowed.

c. No substantive changes are

proposed to the existing provisions

addressing research involving viable

newborns. A reference to Subpart D is

included.

Section 46.206 Research Involving,

After Delivery, the Placenta, the Dead

Newborn, or Fetal Material

It is proposed that the existing

§ 46.210 be replaced by this section. No

substantive changes are proposed to the

current provisions. The intent of the

existing regulation, that all placentas

after delivery are covered by this

section, is clarified.

The Department notes that for cultural

reasons, many ascribe special value and

significance to the placenta. Further,

State, local, or tribal jurisdictions that

have laws or regulations concerning

research involving the placenta do not

necessarily distinguish between the

placentas of living or dead fetuses or

newborns.

Paragraph (b) of § 46.206 is proposed

as a reminder that if, in the course of

using the placenta, the dead newborn,

or fetal material, a living person (e.g.,

the mother) is identified in the research,

then that living person (e.g., the mother)

is a research subject (see definition of

human subject at 45 CFR 46.102(f)). In

that case, the other subparts of 45 CFR

Part 46 are applicable and the researcher

is responsible for obtaining any

necessary review, assurance, approval,

and informed consent.

Section 46.207 Modification or Waiver

of Specific Requirements

This proposed section, to replace the

existing § 46.211, is parallel to the

waiver provisions of Subpart C at

§ 46.306(a)(2)(C) and (D) and Subpart D

at § 46.407. This provision allows the

Secretary, HHS, to modify or waive

requirements after consultation with

appropriate experts and opportunity for

public review and comment. In making

such a decision, the Secretary must

consider whether the risks to the

subjects are so outweighed by the sum

of the benefits to the subjects and the

importance of the knowledge to be

gained as to warrant the modification or

waiver.

The proposed rule removes the

requirement for an EAB, consistent with

the NIH Revitalization Act of 1993

(Public Law 103–43).

The following statements are

provided for the information of the

public.
Federal Register / Vol. 63, No. 97 /Wednesday, May 20, 1998 / Proposed Rules 27803

Executive Order 12866

Executive Order 12866 requires that

all regulatory actions reflect

consideration of the costs and benefits

they generate, and that they meet certain

standards, such as avoiding the

imposition of unnecessary burdens on

the affected public. If a regulatory action

is deemed to fall within the scope of the

definition of the term ‘‘significant

regulatory action’’ contained in § 3 (f) of

the Order, pre-publication review by the

Office of Management and Budget’s

(OMB’s) Office of Information and

Regulatory Affairs (OIRA) is necessary.

OMB deemed this proposed rule a

‘‘significant regulatory action,’’ as

defined under Executive order 12866.

Therefore, the proposed rule was

submitted to OIRA for review prior to its

publication in the Federal Register.

Regulatory Flexibility Act

This proposed rule primarily affects

individual persons. None of the changes

proposed will have the effect of

imposing costs on universities, other

research institutions, or other small

entities. Therefore, the Secretary

certifies that this rule will not have

significant impact on a substantial

number of small entities and that

preparation of an initial regulatory

flexibility analysis is not required.

Paperwork Reduction Act

This proposed rule does not contain

any new information collection

requirements which are subject to Office

of Management and Budget (OMB)

approval under the Paperwork

Reduction Act of 1995 (44 U.S.C.

Chapter 35).

List of Subjects in 42 CFR Part 46

Health—clinical research, Medical

research.

Dated: April 3, 1997.

Harold E. Varmus,

Director, National Institutes of Health.

Approved: September 16, 1997.

Donna E. Shalala,

Secretary.

Editorial Note: This document was

received at the Office of The Federal Register

May 13, 1998.

For reasons presented in the

preamble, it is proposed to amend part

46 of title 45 of the Code of Federal

Regulations as set forth below.

PART 46—PROTECTION OF HUMAN

SUBJECTS

1. The authority citation for 45 CFR

part 46 would be revised to read as

follows:

Authority: 5 U.S.C. 301; 42 U.S.C. 289(a).

2. Subpart B of 45 CFR part 46 would

be revised to read as follows:

Subpart B—Additional DHHS

Protections for Pregnant Women,

Human Fetuses, and Newborns

Involved as Subjects in Research, and

Pertaining to Human In Vitro

Fertilization

Sec.

46.201 To what do these regulations apply?

46.202 Definitions.

46.203 Duties of IRBs in connection with

research involving pregnant women,

human fetuses, newborns, and human in

vitro fertilization.

46.204 Research involving pregnant women

or fetuses.

46.205 Research involving newborns of

uncertain viability, nonviable newborns,

and viable newborns.

46.206 Research involving after delivery,

the placenta, the dead newborn, or fetal

material.

46.207 Modification or waiver of specific

requirements.

§ 46.201 To what do these regulations

apply?

(a) Except as provided in paragraph

(b) of this section, this subpart applies

to all research involving pregnant

women, human fetuses, and newborns

as subjects, and to all research involving

the in vitro fertilization of human ova,

conducted or supported by the

Department of Health and Human

Services. This includes all research

conducted in Department facilities by

any person and all research conducted

in any facility by Department

employees.

(b) The exemptions at § 46.101(b) (1)

through (6) are applicable to this

subpart.

(c) The additions, exceptions, and

provisions for waiver as they appear in

§ 46.101(c) through (i) are applicable to

this subpart. Reference to State or local

laws in this subpart and in § 46.101(f) is

intended to include the laws of federally

recognized American Indian and Alaska

Native Tribal Governments.

§ 46.202 Definitions.

The definitions in § 46.102 shall be

applicable to this subpart as well. In

addition, as used in this subpart:

(a) Secretary means the Secretary of

Health and Human Services and any

other officer or employee of the

Department of Health and Human

Services (DHHS) to whom authority has

been delegated.

(b) Pregnancy encompasses the period

of time from implantation until

delivery. A woman shall be assumed to

be pregnant if she exhibits any of the

pertinent presumptive signs of

pregnancy, such as missed menses, until

the results of a pregnancy test are

negative or until delivery.

(c) Fetus means the product of

conception during pregnancy until a

determination is made after delivery

that it is viable.

(d) Newborn is a fetus after delivery.

(e) Nonviable fetus or nonviable

newborn means a newborn or fetus after

delivery that, although living, is not

viable.

(f) Dead fetus or dead newborn means

a newborn or fetus after delivery which

exhibits neither heartbeat, spontaneous

respiratory activity, spontaneous

movement of voluntary muscles, nor

pulsation of the umbilical cord (if still

attached).

(g) Viable fetus or viable newborn

means a newborn that is able to survive

(given the benefit of available medical

therapy) to the point of independently

maintaining heartbeat and respiration.

The Secretary may from time to time,

taking into account medical advances,

publish in the Federal Register

guidelines to assist in determining

whether a fetus or newborn is viable for

purposes of this subpart. If a newborn

is viable then it is a child, and subpart

D of this part is applicable.

(h) Children are persons who have not

attained the legal age for consent to

treatments or procedures involved in

the research, under the applicable law

of the jurisdiction in which the research

will be conducted. (See definition of

‘‘viable fetus’’ or ‘‘viable newborn’’ at

§ 46.202 (g)).

(i) In vitro fertilization means any

fertilization of human ova which occurs

outside the body of a female, either

through admixture of donor human

sperm and ova or by any other means.

§ 46.203 Duties of IRBs in connection with

research involving pregnant women, human

fetuses, newborns, and human in vitro

fertilization.

In addition to other responsibilities

assigned to IRBs under this part, each

IRB shall review research covered by

this subpart and approve only research

which satisfies the conditions of all

applicable sections of this subpart and

the other subparts of this part.

§ 46.204 Research involving pregnant

women or fetuses.

Pregnant women or fetuses may be

involved in research if all of the

following conditions are met:

(a) Where scientifically appropriate,

preclinical studies, including studies on

pregnant animals, and clinical studies,

including studies on nonpregnant

women, have been conducted and

provide data for assessing potential risks

to pregnant women and fetuses;
27804 Federal Register / Vol. 63, No. 97 /Wednesday, May 20, 1998 / Proposed Rules

(b) The risk to the fetus is not greater

than minimal, or any risk to the fetus

which is greater than minimal is caused

solely by activities designed to meet the

health needs of the mother or her fetus;

(c) Any risk is the least possible for

achieving the objectives of the research.

(d) The woman is fully informed

regarding the reasonably foreseeable

impact of the research on the fetus (or

a resultant child);

(e) The woman’s consent or the

consent of her legally authorized

representative is obtained in accord

with the informed consent provisions of

subpart A of this part;

(f) For pregnant children, assent and

permission are obtained in accord with

the provisions of subpart D of this part;

(g) Individuals engaged in the

research will have no part in:

(1) Any decisions as to the timing,

method, or procedures used to abort a

pregnancy, or

(2) Determining the viability of a

newborn; and

(h) No inducements, monetary or

otherwise, will be offered to abort a

pregnancy.

§ 46.205 Research involving newborns of

uncertain viability, nonviable newborns,

and viable newborns.

(a) Newborns of uncertain viability.

After delivery and until it has been

ascertained whether or not a newborn is

viable, a newborn may not be involved

as a subject in research covered by this

subpart unless both of the conditions in

paragraphs (a)(1) and (2) of this section

are met:

(1) The purpose of the research is:

(i) To enhance the possibility of

survival of the particular newborn to the

point of viability, or

(ii) The development of important

biomedical knowledge which cannot be

obtained by other means and there will

be no risk to the newborn resulting from

the research, and

(2) The legally effective informed

consent of the mother or the father of

the newborn or, if neither parent is able

to consent because of unavailability,

incompetence, or temporary incapacity,

the legally effective informed consent of

the mother’s or the father’s legally

authorized representative is obtained in

accord with Subpart A of this part.

(b) Nonviable newborns. After

delivery, a nonviable newborn may not

be involved as a subject in research

covered by this subpart unless all of the

following conditions are met:

(1) Vital functions of the newborn will

not be artificially maintained;

(2) The research will not terminate the

heartbeat or respiration of the newborn;

(3) There will be no added risk to the

fetus of suffering injury or death

resulting from the research and the

purpose of the research is the

development of important biomedical

knowledge that cannot be obtained by

other means; and

(4) The legally effective informed

consents of both the mother and the

father of the newborn are obtained in

accord with subpart A of this part,

except that the waiver and alteration

provisions of § 46.116 (c) and (d) do not

apply. However, if either parent is

unable to consent because of

unavailability, incompetence, or

temporary incapacity, the informed

consent of the other parent of a

nonviable newborn will suffice to meet

the informed consent requirement of

this paragraph (b)(4). The consent of a

legally authorized representative of

either or both of the parents of a

nonviable newborn will not suffice to

meet the requirements of this paragraph

(b)(4).

(c) Viable newborns. A viable

newborn is a child and may be included

as a subject in research only to the

extent permitted by and in accord with

the requirements of Subparts A and D of

this part.

§ 46.206 Research involving, after delivery,

the placenta, the dead newborn, or fetal

material.

(a) Research involving, after delivery,

the placenta; the dead newborn;

macerated fetal material; or cells, tissue,

or organs excised from a dead newborn

shall be conducted only in accord with

any applicable Federal, State or local

laws and regulations regarding such

activities.

(b) If information associated with

material described in paragraph (a) of

this section is recorded for research

purposes in a manner that living

persons can be identified, directly or

through identifiers linked to those

persons, those persons are research

subjects and all pertinent subparts of

this part are applicable.

§ 46.207 Modification or waiver of specific

requirements.

The Secretary may modify or waive

specific requirements of this subpart for

specific research projects or classes of

research, after consultation with a panel

of experts in pertinent disciplines and

after opportunity for public review and

comment, including a public meeting.

In making a decision to modify or

waive, the Secretary will consider

whether the risks to the subjects are so

outweighed by the sum of the benefits

to the subjects and the importance of the

knowledge to be gained as to warrant

such modification or waiver and that

such benefits cannot be gained except

through a modification or waiver. Any

such modifications or waivers will be

published as notices in the Federal

Register.

[FR Doc. 98–13091 Filed 5–19–98; 8:45 am]

BILLING CODE 4140–01–P