[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
_______________________________________________________________________
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.
[[Page 27800]]
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.
[[Page 27802]]
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
