[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]
BILLING CODE 4510-28-P