`[Federal Register Volume 63, Number 97 (Wednesday, May 20, 1998)]
[Proposed Rules]
[Pages 27794-27804]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-13091]



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Part II





Department of Health and Human Services





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45 CFR Part 46



Protection of Human Research Subjects; Proposed Rule

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

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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.

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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 HHS-wide 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

[[Page 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.

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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 
Sec. 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 Sec. 46.101 of Subpart A of Part 46, to the regulations at Subpart 
B. The provision is identical to Sec. 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 Sec. 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 Sec. 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 Sec. 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 Sec. 46.203 are moved to Sec. 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.

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Section 46.203  Duties of IRBs in Connection With Research Involving 
Pregnant Women, Human Fetuses, Newborns and Human in Vitro 
Fertilization

    Definitions in existing Sec. 46.203 are found in Sec. 46.202 in the 
proposed regulation.
    Definitions in existing Sec. 46.203 are found in Sec. 46.202 in the 
proposed regulation. There is no substantive change to this section; 
the language is more concise. The proposed Sec. 46.203 would replace 
the existing Sec. 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 non-
pregnant 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 life-threatening 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 Sec. 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 Sec. 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 Sec. 46.207). An EAB has not existed within 
the Department since 1980, and Sec. 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 Secs. 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, 
Sec. 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 
Sec. 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 Sec. 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 
Sec. 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 
Sec. 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 
Sec. 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 Sec. 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 Sec. 46.204(e)).
    The existing regulation (Secs. 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.

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    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.
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    \1\ The term ``permission'' as used by the Commission and in 
Subpart D has the same meaning as ``consent'' for the purposes of 
this discussion.
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    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 well-being 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 (Sec. 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 (Sec. 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 
Sec. 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.

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Section 46.205  Research Involving Newborns of Uncertain Viability, 
Nonviable Newborns, and Viable Newborns

    It is proposed that the existing Sec. 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 Sec. 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 Sec. 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 Sec. 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 Sec. 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 Sec. 46.211, is 
parallel to the waiver provisions of Subpart C at Sec. 46.306(a)(2)(C) 
and (D) and Subpart D at Sec. 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.

[[Page 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 Sec. 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.


Sec. 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 Sec. 46.101(b) (1) through (6) are applicable 
to this subpart.
    (c) The additions, exceptions, and provisions for waiver as they 
appear in Sec. 46.101(c) through (i) are applicable to this subpart. 
Reference to State or local laws in this subpart and in Sec. 46.101(f) 
is intended to include the laws of federally recognized American Indian 
and Alaska Native Tribal Governments.


Sec. 46.202  Definitions.

    The definitions in Sec. 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 
Sec. 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.


Sec. 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.


Sec. 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;

[[Page 27804]]

    (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.


Sec. 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 Sec. 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.


Sec. 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.


Sec. 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`