[Federal Register Volume 66, Number 130 (Friday, July 6, 2001)]
[Proposed Rules]
[Pages 35576-35580]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 01-16841]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
45 CFR Part 46
RIN 0940-AA03
Protection of Human Research Subjects
AGENCY: Department of Health and Human Services (DHHS).
ACTION: Notice of Proposed Rule Making.
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SUMMARY: The Department of Health and Human Services (DHHS) is
proposing to amend Subpart B of its human subjects protection
regulations published on January 17, 2001. These regulations provide
additional protections for pregnant women and human fetuses involved in
research and pertain to human in vitro fertilization. The rule
continues the special protections for pregnant women and human fetuses
that have existed since 1975. The Department proposes to amend the
regulations by making limited changes in terminology referring to
neonates, clarifying provisions for paternal consent when research is
conducted on fetuses, and clarifying language that applies to research
on newborns of uncertain viability.
DATES: Comments on the proposed regulation must be received on or
before September 4, 2001.
ADDRESSES: Comments must be sent to: Irene Stith-Coleman, Ph.D., Office
of Human Research Protections (OHRP) 200 Independence Avenue, SW., Room
733-E, Washington, DC, 20201. Telephone 202-260-1587. Email
[email protected]. 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: Irene Stith-Coleman, Ph.D., Office of
Human Research Protections (OHRP) 200 Independence Avenue, SW., Room
733-E, Washington, DC, 20201. Telephone 202-260-1587. Interested
persons may obtain a copy of the current regulations for the protection
of human subjects, including Subpart B, at http://ohrp.osophs.dhhs.gov/humansubjects/guidance/45cfr46.htm.
SUPPLEMENTARY INFORMATION:
Background
The Department of Health and Human Services (DHHS) regulates
research involving human subjects conducted or supported by the agency
through regulations codified at Title 45, part 46,
[[Page 35577]]
of the Code of Federal Regulations. Subpart B of 45 CFR part 46,
promulgated on August 8, 1975, pertains to research involving fetuses,
pregnant women, and human in vitro fertilization. The 1975 regulations
were jointly published in the Federal Register with the report and
recommendations of the National Commission for the Protection of Human
Subjects of Biomedical and Behavioral Research, Research on the Fetus
(40 FR 33526). Subsequent changes were incorporated January 11, 1978
(43 FR 1758), November 3, 1978 (43 FR 51559), and June 1, 1994 (59 FR
28276).
On January 17, 2001, the Department published in the Federal
Register a Final Rule, with an effective date of March 19, 2001 (66 FR
3878), intended to amend Subpart B of 45 CFR Part 46. This preamble
refers to that rule as ``the January rule.'' The January rule's
effective date was delayed by 60 days on March 19, 2001, in accordance
with the memorandum of January 20, 2001, from the Assistant to the
President and Chief of Staff, entitled A Regulatory Review Plan,
published in the Federal Register on January 24, 2001. (66 FR 15352).
The effective date of the January rule was further delayed by 180 days
on May 18, 2001 to give the Department an opportunity to obtain comment
on three modifications to the rule. (66 FR 27559).
The Department determined that there was a need to delay the
January rule's effective date to seek public comment on three limited
aspects: (1) Whether paternal consent (when the father is readily
available) should be obtained for participation in federally funded
research that is directed solely at a fetus; (2) whether the definition
of ``fetus'' should be modified so that it describes only the stage
prior to delivery; and (3) whether the rule should be modified to make
clear that fetuses of uncertain viability may be subjected to added
risk only if the research is intended to enhance the probability of
survival of the particular fetus to the point of viability.
First, the Department proposes to require a father's consent (when
the father is readily available) for participating in research that is
directed solely at a fetus and that does not affect a mother's health.
We believe that this approach is the most respectful of the parents'
joint interests in their fetus's health. In this narrow situation, the
January rule allowed the mother alone to consent for the research on
the fetus. The preamble to the January rule explained that consent
requirements for research involving pregnant women were modified to
address cases in which a requirement for the father's consent had been
a barrier to participation in research which held potential benefit for
both pregnant women and their fetuses. We believe that this problem is
addressed by the clarification in this rule that only the mother's
consent is required for participation in research that may benefit both
the pregnant woman and the fetus. In keeping with the January rule, a
father's consent would not be needed for a woman to participate in a
research activity that would benefit her health.
Second, the Department proposes to add to the regulations the term
``neonate'' to describe an infant that has been delivered but for which
a viability determination has not yet been made. The January rule uses
the term ``fetus'' to describe not only infants at the stage prior to
delivery, but also just-delivered newborns. We believe that using the
term ``fetus'' only for those infants that have not been delivered is
preferable because it is more consistent with the ordinary
understanding of that word and because using the term neonate for a
fetus that has been delivered is more appropriate. We propose to use
the term ``neonate'' to describe a newborn for which a viability
determination has not yet been made. This modification will not change
the strong protections the rule gives to pregnant women and fetuses, or
change the regulatory framework that has been established to guide
decisions regarding conduct of federally-supported research.
Third, the Department proposes to clarify the language that governs
decisions regarding conduct of federally-supported research on neonates
of uncertain viability. Some changes in wording were introduced in the
January rule that may have created confusion on this issue. We wish to
make clear that these neonates may be subjected to added risk only if
the research is intended to enhance the particular neonate's
probability of survival to the point of viability.
The Department proposes other minor clarifying and technical
changes that are consistent with these proposed amendments.
Proposed Changes to Subpart B
Title Subpart B--Additional Protections for Pregnant Women and Human
Fetuses Involved in Research, and Pertaining to Human In Vitro
Fertilization
The title is changed to add the word ``neonate.''
Section 46.201 To what do these regulations apply?
Paragraph (a)--There is no substantive change to this paragraph.
The word ``neonate'' is added to reflect that the rule covers neonates.
Paragraphs (b)-(d)--No change.
Section 46.202--Definitions
Paragraph (a)--The definition of ``dead fetus'' is modified by
changing the word ``fetus'' to ``neonate.'' The words ``after
delivery'' are deleted to avoid redundancy.
Paragraph (b)--The definition of ``fetus'' is modified to clarify
that the term refers only to the stage prior to delivery.
Paragraph (c)--No change.
Paragraph (d)--A new paragraph (d) and new definition of
``neonate'' is added.
Paragraph (d)--Paragraph (d) is relabeled paragraph (e). The
definition of ``nonviable fetus'' in new paragraph (e) is modified by
changing the word ``fetus'' to ``neonate.''
Paragraphs (e) and (f) are relabeled paragraphs (f) and (g).
Paragraph (g)--Paragraph (g) is relabeled paragraph (h). The
definition of ``viable'' in new paragraph (h) is modified by changing
the word ``fetus'' to ``neonate'' and deleting the language ``after
delivery.'' Language regarding the application of Subpart D of the
human subjects regulations is clarified.
Section 46.203 Duties of IRBs in connection with research involving
pregnant women, fetuses, and human in vitro fertilization
The title of this section is changed to add the term ``neonate.''
Section 46.204 Research involving pregnant women or fetuses prior to
delivery
The words ``prior to delivery'' are deleted from the title and
introductory text. This description is not needed in light of the
change in the definition of the term ``fetus'' in Section 46.202(b).
Paragraph (b)--The paragraph is clarified to explain that research
involving fetuses may only be conducted when risk is caused solely by
interventions or procedures that hold out the prospect of direct
benefit for the woman or the fetus, or, if there is no such prospect of
benefit, the risk is not greater than minimal and the purpose of the
research is the development of important biomedical knowledge which
cannot be obtained by any other means. This change is consistent with
language in the January rule regarding research involving neonates that
is not greater than minimal risk.
[[Page 35578]]
Paragraph (c)--No change.
Paragraph (d)--The paragraph is modified to clarify that if the
research holds out the prospect of direct benefit to the pregnant
woman, only her consent must be obtained, consistent with provisions of
Subpart A of the human subjects protection regulations. The phrases
``or the consent of her legally authorized representative'' and
``unless altered or waived in accord with Sec. 46.101(i) or
Sec. 46.116(c) or (d)'' are deleted to avoid redundancy, as these
provisions are incorporated by the reference to subpart A.
A new paragraph (e) is added to clarify that if the research holds
out the prospect of direct benefit solely to the fetus, the consent of
the father (when the father is readily available) is required,
consistent with provisions of Subpart A of the human subjects
protection regulations. The father's consent is not required if he is
unable to consent because of unavailability, incompetence, or temporary
incapacity. Consent of the father's legally authorized representative
thus would not be required under this provision. This revision changes
the January rule, which allowed the mother alone to consent to research
involving the fetus. We believe that this revision better recognizes
the joint interests of a mother and father in a fetus's participation
in research in the situation in which the research holds out the
prospect of direct benefit solely to the fetus.
Paragraph (e) is relabeled paragraph (f) and new paragraph (f) is
modified by replacing the language ``the woman or her legally
authorized representative'' with ``the individual(s) providing consent
under paragraph (d) or (e) under this section'' to take into account
new Section 46.204(e).
Paragraphs (f)-(i) are relabeled paragraphs (g)-(j), and in new
paragraph (j) the term ``fetus'' is changed to ``neonate.''
Section 46.205 Research involving fetuses after delivery
The title is modified by changing ``fetus'' to ``neonate'' and by
deleting the words ``after delivery'' which are not needed due to the
new definition of ``neonate'' provided under Section 46.202(d).
Paragraph (a)--The term ``fetus'' is changed to ``neonate''
throughout the paragraph. The words ``after delivery'' are deleted, as
they are not needed due to the new definition of ``neonate'' provided
under Section 46.202(d). The words ``or resultant child'' are deleted
from subparagraph (2) as they are not needed due to clarifications to
Section 46.202(g) described above.
Paragraph (b)--The term ``fetus'' is changed to ``neonate'' and the
words ``after delivery'' are deleted throughout the paragraph. In
subparagraph (1), the word ``that'' replaces ``the,'' and the words
``of the research'' are deleted to clarify that research involving risk
is permitted on fetuses of uncertain viability only when it is intended
to increase the probability of their survival to the point of
viability. This modification is consistent with the January rule, but
clarifies any ambiguity that may have been raised by minor changes to
this section in that rule. In subparagraph (2), the phrase ``unless
altered or waived in accord with Sec. 46.101(i) or Sec. 46.116(c) or
(d)'' is deleted to avoid redundancy, as these provisions are
incorporated by the reference to subpart A.
Paragraph (c)--The term ``fetus'' is changed to ``neonate''
throughout the paragraph.
Paragraph (d)--The term ``fetus'' is changed to ``neonate''
throughout the paragraph. Language regarding the application of Subpart
D of the human subjects regulations is clarified.
Section 46.206 Research involving, after delivery, the placenta, the
dead fetus, or fetal material
The term ``fetus'' is changed to ``neonate'' and the term ``fetal''
is changed to ``neonatal'' in the title.
Paragraph (a)--The term ``fetus'' is changed to ``neonate''
throughout the paragraph, and the term ``fetal is changed to
``neonatal.''
Paragraph (b)--No change.
Section 46.207 Research not otherwise approvable which presents an
opportunity to understand, prevent, or alleviate a serious problem
affecting the health or welfare of pregnant women, or fetuses
The term ``neonates'' is added to the title and throughout the
section and in subparagraph (2)(iii), the phrase ``unless altered or
waived in accord with Sec. 46.101(i) or Sec. 46.116(c) or (d)'' is
deleted to avoid redundancy, as these provisions are included in the
reference to subpart A.
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 an 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, a 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 rule a
``significant regulatory action,'' as defined by Executive Order 12866.
Therefore, the rule was submitted to OIRA for review prior to its
publication in the Federal Register.
Regulatory Flexibility Act
The Regulatory Flexibility Act (5 U.S.C. Chapter 6) requires that
regulatory actions be analyzed to determine whether they create a
significant impact on a substantial number of small entities. This rule
primarily affects individual research subjects and institutions that
receive funding from DHHS for research involving human subjects. It
will not have the effect of imposing significant additional costs on
small research institutions that are within the definition of 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 rule does not contain any new information collection
requirements that 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 45 CFR Part 46
Civil rights, Health--clinical research, Human research subjects,
Infants and children, Medical research, Reporting and recordkeeping
requirements.
Dated: June 13, 2001.
Arthur J. Lawrence,
Acting Principal Deputy Assistant Secretary for Health.
Dated: June 14, 2001.
Tommy G. Thompson,
Secretary of Health and Human Services.
For the 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 part 46 is revised to read as
follows:
Authority: 5 U.S.C. 301; 42 U.S.C. 289(a).
2. Subpart B of part 46 is revised to read as follows:
[[Page 35579]]
Subpart B--Additional Protections for Pregnant Women, Human Fetuses
and Neonates Involved 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, fetuses, neonates, and human in vitro fertilization.
46.204 Research involving pregnant women or fetuses.
46.205 Research involving neonates.
46.206 Research involving, after delivery, the placenta, the dead
neonate, or neonatal material.
46.207 Research not otherwise approvable which presents an
opportunity to understand, prevent, or alleviate a serious problem
affecting the health or welfare of pregnant women, fetuses, or
neonates.
Subpart B--Additional Protections for Pregnant Women, Human Fetuses
and Neonates Involved in Research, and Pertaining to Human In Vitro
Fertilization
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 or human
fetuses or neonates, and to all research involving the in vitro
fertilization of human ova, conducted or supported by the Department of
Health and Human Services (DHHS). This includes all research conducted
in DHHS facilities by any person and all research conducted in any
facility by DHHS employees.
(b) The exemptions at Sec. 46.101(b)(1) through (6) are applicable
to this subpart.
(c) The provisions of 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.
(d) The requirements of this subpart are in addition to those
imposed under the other subparts of this part.
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) Dead neonate means a neonate that exhibits neither heartbeat,
spontaneous respiratory activity, spontaneous movement of voluntary
muscles, nor pulsation of the umbilical cord.
(b) Delivery means complete separation of the fetus from the woman
by expulsion or extraction or any other means.
(c) Fetus means the product of conception from implantation until
delivery.
(d) 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.
(e) Neonate means a newborn.
(f) Nonviable neonate means a neonate after delivery that, although
living, is not viable.
(g) 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.
(h) Secretary means the Secretary of Health and Human Services and
any other officer or employee of the Department of Health and Human
Services to whom authority has been delegated.
(i) Viable, as it pertains to the neonate, means being able, after
delivery, 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 neonate is viable for purposes of this subpart.
If a neonate is viable then it may be included in research only to the
extent permitted and in accordance with the requirements of Subparts A
and D of this part.
Sec. 46.203 Duties of IRBs in connection with research involving
pregnant women, fetuses, neonates, 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;
(b) The risk to the fetus is caused solely by interventions or
procedures that hold out the prospect of direct benefit for the woman
or the fetus; or, if there is no such prospect of benefit, the risk to
the fetus is not greater than minimal and the purpose of the research
is the development of important biomedical knowledge which cannot be
obtained by any other means;
(c) Any risk is the least possible for achieving the objectives of
the research;
(d) If the research holds out the prospect of direct benefit to the
pregnant woman or a direct benefit both to the pregnant woman and the
fetus, her consent is obtained in accord with the informed consent
provisions of subpart A of this part;
(e) If the research holds out the prospect of direct benefit solely
to the fetus, then the consent of the pregnant woman and the father is
obtained in accord with the informed consent provisions of subpart A of
this part, except that the father's consent need not be obtained if he
is unable to consent because of unavailability, incompetence, or
temporary incapacity;
(f) The individual(s) providing consent under paragraph (d) or (e)
of this section is fully informed regarding the reasonably foreseeable
impact of the research on the fetus or neonate;
(g) For children as defined in Sec. 46.402(a) who are pregnant,
assent and permission are obtained in accord with the provisions of
subpart D of this part;
(h) No inducements, monetary or otherwise, will be offered to
terminate a pregnancy;
(i) Individuals engaged in the research will have no part in any
decisions as to the timing, method, or procedures used to terminate a
pregnancy; and
(j) Individuals engaged in the research will have no part in
determining the viability of a neonate.
Sec. 46.205 Research involving neonates.
(a) Neonates may be involved in research if all of the following
conditions are met:
(1) Where scientifically appropriate, preclinical and clinical
studies have been conducted and provide data for assessing potential
risks to neonates.
(2) The individual(s) providing consent under paragraph (b)(2) or
(c)(5) of this section is fully informed regarding the reasonably
foreseeable impact of the research on the neonate.
(3) No inducements, monetary or otherwise, will be offered to
terminate a pregnancy.
(4) Individuals engaged in the research will have no part in any
decisions as to the timing, method, or procedures used to terminate a
pregnancy.
[[Page 35580]]
(5) Individuals engaged in the research will have no part in
determining the viability of a neonate.
(6) The requirements of paragraph (b) or (c) of this section have
been met as applicable.
(b) Neonates of uncertain viability. Until it has been ascertained
whether or not a neonate is viable, a neonate may not be involved in
research covered by this subpart unless the following additional
conditions are met:
(1) The IRB determines that:
(i) The research holds out the prospect of enhancing the
probability of survival of the neonate to the point of viability, and
any risk is the least possible for achieving that objective, or
(ii) The purpose of the research is the development of important
biomedical knowledge which cannot be obtained by other means and there
will be no risk to the neonate resulting from the research; and
(2) The legally effective informed consent of either parent of the
neonate or, if neither parent is able to consent because of
unavailability, incompetence, or temporary incapacity, the legally
effective informed consent of either parent's legally authorized
representative is obtained in accord with subpart A of this part.
(c) Nonviable neonates. After delivery, a nonviable neonate may not
be involved in research covered by this subpart unless all of the
following additional conditions are met:
(1) Vital functions of the neonate will not be artificially
maintained;
(2) The research will not terminate the heartbeat or respiration of
the neonate;
(3) There will be no risk to the neonate resulting from the
research;
(4) The purpose of the research is the development of important
biomedical knowledge that cannot be obtained by other means; and
(5) The legally effective informed consent of both parents of the
neonate is 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 one parent of a nonviable neonate will suffice to meet the
requirements of this paragraph (c)(5). The consent of a legally
authorized representative of either or both of the parents of a
nonviable neonate will not suffice to meet the requirements of this
paragraph (c)(5).
(d) Viable neonates. A neonate, after delivery, that has been
determined to be viable may be included 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
neonate, or neonatal material.
(a) Research involving, after delivery, the placenta; the dead
neonate; macerated neonatal material; or cells, tissue, or organs
excised from a dead neonate, 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 individuals can be identified, directly or through identifiers
linked to those individuals, those individuals are research subjects
and all pertinent subparts of this part are applicable.
Sec. 46.207 Research not otherwise approvable which presents an
opportunity to understand, prevent, or alleviate a serious problem
affecting the health or welfare of pregnant women, fetuses, or
neonates.
The Secretary will conduct or fund research that the IRB does not
believe meets the requirements of Sec. 46.204 only if:
(a) The IRB finds that the research presents a reasonable
opportunity to further the understanding, prevention, or alleviation of
a serious problem affecting the health or welfare of pregnant women,
fetuses or neonates; and
(b) The Secretary, after consultation with a panel of experts in
pertinent disciplines (for example: science, medicine, ethics, law) and
following opportunity for public review and comment, including a public
meeting announced in the Federal Register, has determined either:
(1) That the research in fact satisfies the conditions of
Sec. 46.204, as applicable; or
(2) The following:
(i) The research presents a reasonable opportunity to further the
understanding, prevention, or alleviation of a serious problem
affecting the health or welfare of pregnant women, fetuses or neonates;
(ii) The research will be conducted in accord with sound ethical
principles; and
(iii) Informed consent will be obtained in accord with the informed
consent provisions of subpart A and other applicable subparts of this
part.
[FR Doc. 01-16841 Filed 7-5-01; 8:45 am]
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