PART 46—PROTECTION OF HUMAN SUBJECTS
Subpart A—Basic HHS Policy for Protection
of Human Research Subjects
Sec.
46.101 To what does this policy apply?
46.102 Definitions.
46.103 Assuring compliance with this policy—
research conducted or supported by
any Federal Department or Agency.
46.104–46.106 [Reserved]
46.107 IRB membership.
46.108 IRB functions and operations.
46.109 IRB review of research.
46.110 Expedited review procedures for certain
kinds of research involving no more
than minimal risk, and for minor
changes in approved research.
46.111 Criteria for IRB approval of research.
46.112 Review by institution.
46.113 Suspension or termination of IRB approval
of research.
46.114 Cooperative research.
46.115 IRB records.
46.116 General requirements for informed
consent.
46.117 Documentation of informed consent.
46.118 Applications and proposals lacking
definite plans for involvement of human
subjects.
46.119 Research undertaken without the intention
of involving human subjects.
46.120 Evaluation and disposition of applications
and proposals for research to be
conducted or supported by a Federal Department
or Agency.
46.121 [Reserved]
46.122 Use of Federal funds.
46.123 Early termination of research support:
Evaluation of applications and proposals.
46.124 Conditions.
Subpart B—Additional Protections Pertaining
to Research, Development,
and Related Activities Involving
Fetuses, Pregnant Women, and Human
In Vitro Fertilization
46.201 Applicability.
46.202 Purpose.
46.203 Definitions.
46.204 Ethical Advisory Boards.
46.205 Additional duties of the Institutional
Review Boards in connection with activities
involving fetuses, pregnant women,
or human in vitro fertilization.
46.206 General limitations.
46.207 Activities directed toward pregnant
women as subjects.
46.208 Activities directed toward fetuses in
utero as subjects.
46.209 Activities directed toward fetuses ex
utero, including nonviable fetuses, as
subjects.
46.210 Activities involving the dead fetus,
fetal material, or the placenta.
46.211 Modification or waiver of specific requirements.
Subpart C—Additional Protections Pertaining
to Biomedical and Behavioral
Research Involving Prisoners as Subjects
46.301 Applicability.
46.302 Purpose.
46.303 Definitions.
46.304 Composition of Institutional Review
Boards where prisoners are involved.
46.305 Additional duties of the Institutional
Review Boards where prisoners are involved.
46.306 Permitted research involving prisoners.
Subpart D—Additional Protections for
Children Involved as Subjects in Research
46.401 To what do these regulations apply?
46.402 Definitions.
46.403 IRB duties.
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Department of Health and Human Services § 46.101
46.404 Research not involving greater than
minimal risk.
46.405 Research involving greater than
minimal risk but presenting the prospect
of direct benefit to the individual subjects.
46.406 Research involving greater than
minimal risk and no prospect of direct
benefit to individual subjects, but likely
to yield generalizable knowledge about
the subject’s disorder or condition.
46.407 Research not otherwise approvable
which presents an opportunity to understand,
prevent, or alleviate a serious
problem affecting the health or welfare
of children.
46.408 Requirements for permission by parents
or guardians and for assent by children.
46.409 Wards.
AUTHORITY: 5 U.S.C. 301; 42 U.S.C. 289.
EFFECTIVE DATE NOTE: At 66 FR 3882, Jan.
17, 2001, the authority for part 46 was revised,
effective Mar. 19, 2001. At 66 FR 15352, Mar.
19, 2001, the effective date was delayed until
May 18, 2001, and at 66 FR 27599, May 18, 2001,
the effective date was further delayed until
Nov. 14, 2001. For the convenience of the
user, the revised text is set forth as follows:
AUTHORITY: 5 U.S.C. 301; 42 U.S.C. 289(a).
EDITORIAL NOTE: The Department of
Health and Human Services issued a notice
of waiver regarding the requirements set
forth in part 46, relating to protection of
human subjects, as they pertain to demonstration
projects, approved under section
1115 of the Social Security Act, which test
the use of cost—sharing, such as deductibles,
copayment and coinsurance, in the Medicaid
program. For further information see 47 FR
9208, Mar. 4, 1982.
Subpart A—Basic HHS Policy for
Protection of Human Research
Subjects
AUTHORITY: 5 U.S.C. 301; 42 U.S.C. 289, 42
U.S.C. 300v–1(b).
SOURCE: 56 FR 28012, 28022, June 18, 1991,
unless otherwise noted.
§ 46.101 To what does this policy
apply?
(a) Except as provided in paragraph
(b) of this section, this policy applies
to all research involving human subjects
conducted, supported or otherwise
subject to regulation by any federal department
or agency which takes appropriate
administrative action to make
the policy applicable to such research.
This includes research conducted by
federal civilian employees or military
personnel, except that each department
or agency head may adopt such procedural
modifications as may be appropriate
from an administrative standpoint.
It also includes research conducted,
supported, or otherwise subject
to regulation by the federal government
outside the United States.
(1) Research that is conducted or supported
by a federal department or
agency, whether or not it is regulated
as defined in § 46.102(e), must comply
with all sections of this policy.
(2) Research that is neither conducted
nor supported by a federal department
or agency but is subject to
regulation as defined in § 46.102(e) must
be reviewed and approved, in compliance
with § 46.101, § 46.102, and § 46.107
through § 46.117 of this policy, by an institutional
review board (IRB) that operates
in accordance with the pertinent
requirements of this policy.
(b) Unless otherwise required by department
or agency heads, research activities
in which the only involvement
of human subjects will be in one or
more of the following categories are
exempt from this policy:
(1) Research conducted in established
or commonly accepted educational settings,
involving normal educational
practices, such as (i) research on regular
and special education instructional
strategies, or (ii) research on the
effectiveness of or the comparison
among instructional techniques, curricula,
or classroom management
methods.
(2) Research involving the use of educational
tests (cognitive, diagnostic,
aptitude, achievement), survey procedures,
interview procedures or observation
of public behavior, unless:
(i) Information obtained is recorded
in such a manner that human subjects
can be identified, directly or through
identifiers linked to the subjects; and
(ii) any disclosure of the human subjects’
responses outside the research
could reasonably place the subjects at
risk of criminal or civil liability or be
damaging to the subjects’ financial
standing, employability, or reputation.
(3) Research involving the use of educational
tests (cognitive, diagnostic,
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§ 46.101 45 CFR Subtitle A (10–1–01 Edition)
aptitude, achievement), survey procedures,
interview procedures, or observation
of public behavior that is not
exempt under paragraph (b)(2) of this
section, if:
(i) The human subjects are elected or
appointed public officials or candidates
for public office; or (ii) federal statute(
s) require(s) without exception that
the confidentiality of the personally
identifiable information will be maintained
throughout the research and
thereafter.
(4) Research, involving the collection
or study of existing data, documents,
records, pathological specimens, or diagnostic
specimens, if these sources are
publicly available or if the information
is recorded by the investigator in such
a manner that subjects cannot be identified,
directly or through identifiers
linked to the subjects.
(5) Research and demonstration
projects which are conducted by or subject
to the approval of department or
agency heads, and which are designed
to study, evaluate, or otherwise examine:
(i) Public benefit or service programs;
(ii) procedures for obtaining
benefits or services under those programs;
(iii) possible changes in or alternatives
to those programs or procedures;
or (iv) possible changes in methods
or levels of payment for benefits or
services under those programs.
(6) Taste and food quality evaluation
and consumer acceptance studies, (i) if
wholesome foods without additives are
consumed or (ii) if a food is consumed
that contains a food ingredient at or
below the level and for a use found to
be safe, or agricultural chemical or environmental
contaminant at or below
the level found to be safe, by the Food
and Drug Administration or approved
by the Environmental Protection
Agency or the Food Safety and Inspection
Service of the U.S. Department of
Agriculture.
(c) Department or agency heads retain
final judgment as to whether a
particular activity is covered by this
policy.
(d) Department or agency heads may
require that specific research activities
or classes of research activities conducted,
supported, or otherwise subject
to regulation by the department or
agency but not otherwise covered by
this policy, comply with some or all of
the requirements of this policy.
(e) Compliance with this policy requires
compliance with pertinent federal
laws or regulations which provide
additional protections for human subjects.
(f) This policy does not affect any
state or local laws or regulations which
may otherwise be applicable and which
provide additional protections for
human subjects.
(g) This policy does not affect any
foreign laws or regulations which may
otherwise be applicable and which provide
additional protections to human
subjects of research.
(h) When research covered by this
policy takes place in foreign countries,
procedures normally followed in the
foreign countries to protect human
subjects may differ from those set
forth in this policy. [An example is a
foreign institution which complies
with guidelines consistent with the
World Medical Assembly Declaration
(Declaration of Helsinki amended 1989)
issued either by sovereign states or by
an organization whose function for the
protection of human research subjects
is internationally recognized.] In these
circumstances, if a department or
agency head determines that the procedures
prescribed by the institution afford
protections that are at least
equivalent to those provided in this
policy, the department or agency head
may approve the substitution of the
foreign procedures in lieu of the procedural
requirements provided in this
policy. Except when otherwise required
by statute, Executive Order, or the department
or agency head, notices of
these actions as they occur will be published
in the FEDERAL REGISTER or will
be otherwise published as provided in
department or agency procedures.
(i) Unless otherwise required by law,
department or agency heads may waive
the applicability of some or all of the
provisions of this policy to specific research
activities or classes of research
activities otherwise covered by this
policy. Except when otherwise required
by statute or Executive Order, the department
or agency head shall forward
advance notices of these actions to the
Office for Protection from Research
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Department of Health and Human Services § 46.102
1 Institutions with HHS-approved assurances
on file will abide by provisions of title
45 CFR part 46 subparts A–D. Some of the
other Departments and Agencies have incorporated
all provisions of title 45 CFR part 46
into their policies and procedures as well.
However, the exemptions at 45 CFR 46.101(b)
do not apply to research involving prisoners,
fetuses, pregnant women, or human in vitro
fertilization, subparts B and C. The exemption
at 45 CFR 46.101(b)(2), for research involving
survey or interview procedures or observation
of public behavior, does not apply
to research with children, subpart D, except
for research involving observations of public
behavior when the investigator(s) do not participate
in the activities being observed.
Risks, Department of Health and
Human Services (HHS), and shall also
publish them in the FEDERAL REGISTER
or in such other manner as provided in
department or agency procedures.1
[56 FR 28012, 28022, June 18, 1991; 56 FR 29756,
June 28, 1991]
§ 46.102 Definitions.
(a) Department or agency head means
the head of any federal department or
agency and any other officer or employee
of any department or agency to
whom authority has been delegated.
(b) Institution means any public or
private entity or agency (including federal,
state, and other agencies).
(c) Legally authorized representative
means an individual or judicial or
other body authorized under applicable
law to consent on behalf of a prospective
subject to the subject’s participation
in the procedure(s) involved in the
research.
(d) Research means a systematic investigation,
including research development,
testing and evaluation, designed
to develop or contribute to generalizable
knowledge. Activities which
meet this definition constitute research
for purposes of this policy,
whether or not they are conducted or
supported under a program which is
considered research for other purposes.
For example, some demonstration and
service programs may include research
activities.
(e) Research subject to regulation, and
similar terms are intended to encompass
those research activities for which
a federal department or agency has
specific responsibility for regulating as
a research activity, (for example, Investigational
New Drug requirements
administered by the Food and Drug Administration).
It does not include research
activities which are incidentally
regulated by a federal department
or agency solely as part of the department’s
or agency’s broader responsibility
to regulate certain types of activities
whether research or non-research
in nature (for example, Wage
and Hour requirements administered
by the Department of Labor).
(f) Human subject means a living individual
about whom an investigator
(whether professional or student) conducting
research obtains
(1) Data through intervention or
interaction with the individual, or
(2) Identifiable private information.
Intervention includes both physical procedures
by which data are gathered (for
example, venipuncture) and manipulations
of the subject or the subject’s environment
that are performed for research
purposes. Interaction includes
communication or interpersonal contact
between investigator and subject.
Private information includes information
about behavior that occurs in a
context in which an individual can reasonably
expect that no observation or
recording is taking place, and information
which has been provided for specific
purposes by an individual and
which the individual can reasonably
expect will not be made public (for example,
a medical record). Private information
must be individually identifiable
(i.e., the identity of the subject is
or may readily be ascertained by the
investigator or associated with the information)
in order for obtaining the
information to constitute research involving
human subjects.
(g) IRB means an institutional review
board established in accord with and
for the purposes expressed in this policy.
(h) IRB approval means the determination
of the IRB that the research
has been reviewed and may be conducted
at an institution within the
constraints set forth by the IRB and by
other institutional and federal requirements.
(i) Minimal risk means that the probability
and magnitude of harm or discomfort
anticipated in the research are
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108
§ 46.103 45 CFR Subtitle A (10–1–01 Edition)
not greater in and of themselves than
those ordinarily encountered in daily
life or during the performance of routine
physical or psychological examinations
or tests.
(j) Certification means the official notification
by the institution to the supporting
department or agency, in accordance
with the requirements of this
policy, that a research project or activity
involving human subjects has been
reviewed and approved by an IRB in accordance
with an approved assurance.
§ 46.103 Assuring compliance with this
policy—research conducted or supported
by any Federal Department
or Agency.
(a) Each institution engaged in research
which is covered by this policy
and which is conducted or supported by
a federal department or agency shall
provide written assurance satisfactory
to the department or agency head that
it will comply with the requirements
set forth in this policy. In lieu of requiring
submission of an assurance, individual
department or agency heads
shall accept the existence of a current
assurance, appropriate for the research
in question, on file with the Office for
Protection from Research Risks, HHS,
and approved for federalwide use by
that office. When the existence of an
HHS-approved assurance is accepted in
lieu of requiring submission of an assurance,
reports (except certification)
required by this policy to be made to
department and agency heads shall
also be made to the Office for Protection
from Research Risks, HHS.
(b) Departments and agencies will
conduct or support research covered by
this policy only if the institution has
an assurance approved as provided in
this section, and only if the institution
has certified to the department or
agency head that the research has been
reviewed and approved by an IRB provided
for in the assurance, and will be
subject to continuing review by the
IRB. Assurances applicable to federally
supported or conducted research shall
at a minimum include:
(1) A statement of principles governing
the institution in the discharge
of its responsibilities for protecting the
rights and welfare of human subjects of
research conducted at or sponsored by
the institution, regardless of whether
the research is subject to federal regulation.
This may include an appropriate
existing code, declaration, or
statement of ethical principles, or a
statement formulated by the institution
itself. This requirement does not
preempt provisions of this policy applicable
to department- or agency-supported
or regulated research and need
not be applicable to any research exempted
or waived under § 46.101 (b) or
(i).
(2) Designation of one or more IRBs
established in accordance with the requirements
of this policy, and for
which provisions are made for meeting
space and sufficient staff to support
the IRB’s review and recordkeeping duties.
(3) A list of IRB members identified
by name; earned degrees; representative
capacity; indications of experience
such as board certifications, licenses,
etc., sufficient to describe each member’s
chief anticipated contributions to
IRB deliberations; and any employment
or other relationship between
each member and the institution; for
example: full-time employee, part-time
employee, member of governing panel
or board, stockholder, paid or unpaid
consultant. Changes in IRB membership
shall be reported to the department
or agency head, unless in accord
with § 46.103(a) of this policy, the existence
of an HHS-approved assurance is
accepted. In this case, change in IRB
membership shall be reported to the
Office for Protection from Research
Risks, HHS.
(4) Written procedures which the IRB
will follow (i) for conducting its initial
and continuing review of research and
for reporting its findings and actions to
the investigator and the institution;
(ii) for determining which projects require
review more often than annually
and which projects need verification
from sources other than the investigators
that no material changes have occurred
since previous IRB review; and
(iii) for ensuring prompt reporting to
the IRB of proposed changes in a research
activity, and for ensuring that
such changes in approved research,
during the period for which IRB approval
has already been given, may not
be initiated without IRB review and
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109
Department of Health and Human Services § 46.107
approval except when necessary to
eliminate apparent immediate hazards
to the subject.
(5) Written procedures for ensuring
prompt reporting to the IRB, appropriate
institutional officials, and the
department or agency head of (i) any
unanticipated problems involving risks
to subjects or others or any serious or
continuing noncompliance with this
policy or the requirements or determinations
of the IRB and (ii) any suspension
or termination of IRB approval.
(c) The assurance shall be executed
by an individual authorized to act for
the institution and to assume on behalf
of the institution the obligations imposed
by this policy and shall be filed
in such form and manner as the department
or agency head prescribes.
(d) The department or agency head
will evaluate all assurances submitted
in accordance with this policy through
such officers and employees of the department
or agency and such experts
or consultants engaged for this purpose
as the department or agency head determines
to be appropriate. The department
or agency head’s evaluation will
take into consideration the adequacy
of the proposed IRB in light of the anticipated
scope of the institution’s research
activities and the types of subject
populations likely to be involved,
the appropriateness of the proposed initial
and continuing review procedures
in light of the probable risks, and the
size and complexity of the institution.
(e) On the basis of this evaluation,
the department or agency head may
approve or disapprove the assurance, or
enter into negotiations to develop an
approvable one. The department or
agency head may limit the period during
which any particular approved assurance
or class of approved assurances
shall remain effective or otherwise
condition or restrict approval.
(f) Certification is required when the
research is supported by a federal department
or agency and not otherwise
exempted or waived under § 46.101 (b) or
(i). An institution with an approved assurance
shall certify that each application
or proposal for research covered
by the assurance and by § 46.103 of this
Policy has been reviewed and approved
by the IRB. Such certification must be
submitted with the application or proposal
or by such later date as may be
prescribed by the department or agency
to which the application or proposal
is submitted. Under no condition shall
research covered by § 46.103 of the Policy
be supported prior to receipt of the
certification that the research has been
reviewed and approved by the IRB. Institutions
without an approved assurance
covering the research shall certify
within 30 days after receipt of a request
for such a certification from the department
or agency, that the application
or proposal has been approved by
the IRB. If the certification is not submitted
within these time limits, the
application or proposal may be returned
to the institution.
(Approved by the Office of Management and
Budget under control number 9999–0020)
[56 FR 28012, 28022, June 18, 1991; 56 FR 29756,
June 28, 1991]
§§ 46.104—46.106 [Reserved]
§ 46.107 IRB membership.
(a) Each IRB shall have at least five
members, with varying backgrounds to
promote complete and adequate review
of research activities commonly conducted
by the institution. The IRB
shall be sufficiently qualified through
the experience and expertise of its
members, and the diversity of the
members, including consideration of
race, gender, and cultural backgrounds
and sensitivity to such issues as community
attitudes, to promote respect
for its advice and counsel in safeguarding
the rights and welfare of
human subjects. In addition to possessing
the professional competence
necessary to review specific research
activities, the IRB shall be able to ascertain
the acceptability of proposed
research in terms of institutional commitments
and regulations, applicable
law, and standards of professional conduct
and practice. The IRB shall therefore
include persons knowledgeable in
these areas. If an IRB regularly reviews
research that involves a vulnerable
category of subjects, such as children,
prisoners, pregnant women, or handicapped
or mentally disabled persons,
consideration shall be given to the inclusion
of one or more individuals who
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§ 46.108 45 CFR Subtitle A (10–1–01 Edition)
are knowledgeable about and experienced
in working with these subjects.
(b) Every nondiscriminatory effort
will be made to ensure that no IRB
consists entirely of men or entirely of
women, including the institution’s consideration
of qualified persons of both
sexes, so long as no selection is made
to the IRB on the basis of gender. No
IRB may consist entirely of members
of one profession.
(c) Each IRB shall include at least
one member whose primary concerns
are in scientific areas and at least one
member whose primary concerns are in
nonscientific areas.
(d) Each IRB shall include at least
one member who is not otherwise affiliated
with the institution and who is
not part of the immediate family of a
person who is affiliated with the institution.
(e) No IRB may have a member participate
in the IRB’s initial or continuing
review of any project in which
the member has a conflicting interest,
except to provide information requested
by the IRB.
(f) An IRB may, in its discretion, invite
individuals with competence in
special areas to assist in the review of
issues which require expertise beyond
or in addition to that available on the
IRB. These individuals may not vote
with the IRB.
§ 46.108 IRB functions and operations.
In order to fulfill the requirements of
this policy each IRB shall:
(a) Follow written procedures in the
same detail as described in § 46.103(b)(4)
and, to the extent required by,
§ 46.103(b)(5).
(b) Except when an expedited review
procedure is used (see § 46.110), review
proposed research at convened meetings
at which a majority of the members
of the IRB are present, including
at least one member whose primary
concerns are in nonscientific areas. In
order for the research to be approved,
it shall receive the approval of a majority
of those members present at the
meeting.
§ 46.109 IRB review of research.
(a) An IRB shall review and have authority
to approve, require modifications
in (to secure approval), or disapprove
all research activities covered
by this policy.
(b) An IRB shall require that information
given to subjects as part of informed
consent is in accordance with
§ 46.116. The IRB may require that information,
in addition to that specifically
mentioned in § 46.116, be given to
the subjects when in the IRB’s judgment
the information would meaningfully
add to the protection of the rights
and welfare of subjects.
(c) An IRB shall require documentation
of informed consent or may waive
documentation in accordance with
§ 46.117.
(d) An IRB shall notify investigators
and the institution in writing of its decision
to approve or disapprove the proposed
research activity, or of modifications
required to secure IRB approval
of the research activity. If the IRB decides
to disapprove a research activity,
it shall include in its written notification
a statement of the reasons for its
decision and give the investigator an
opportunity to respond in person or in
writing.
(e) An IRB shall conduct continuing
review of research covered by this policy
at intervals appropriate to the degree
of risk, but not less than once per
year, and shall have authority to observe
or have a third party observe the
consent process and the research.
(Approved by the Office of Management and
Budget under control number 9999–0020)
§ 46.110 Expedited review procedures
for certain kinds of research involving
no more than minimal risk, and
for minor changes in approved research.
(a) The Secretary, HHS, has established,
and published as a Notice in the
FEDERAL REGISTER, a list of categories
of research that may be reviewed by
the IRB through an expedited review
procedure. The list will be amended, as
appropriate after consultation with
other departments and agencies,
through periodic republication by the
Secretary, HHS, in the FEDERAL REGISTER.
A copy of the list is available
from the Office for Protection from Research
Risks, National Institutes of
Health, HHS, Bethesda, Maryland
20892.
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111
Department of Health and Human Services § 46.112
(b) An IRB may use the expedited review
procedure to review either or both
of the following:
(1) Some or all of the research appearing
on the list and found by the reviewer(
s) to involve no more than minimal
risk,
(2) Minor changes in previously approved
research during the period (of
one year or less) for which approval is
authorized.
Under an expedited review procedure,
the review may be carried out by the
IRB chairperson or by one or more experienced
reviewers designated by the
chairperson from among members of
the IRB. In reviewing the research, the
reviewers may exercise all of the authorities
of the IRB except that the reviewers
may not disapprove the research.
A research activity may be disapproved
only after review in accordance
with the non-expedited procedure
set forth in § 46.108(b).
(c) Each IRB which uses an expedited
review procedure shall adopt a method
for keeping all members advised of research
proposals which have been approved
under the procedure.
(d) The department or agency head
may restrict, suspend, terminate, or
choose not to authorize an institution’s
or IRB’s use of the expedited review
procedure.
§ 46.111 Criteria for IRB approval of
research.
(a) In order to approve research covered
by this policy the IRB shall determine
that all of the following requirements
are satisfied:
(1) Risks to subjects are minimized:
(i) By using procedures which are consistent
with sound research design and
which do not unnecessarily expose subjects
to risk, and (ii) whenever appropriate,
by using procedures already
being performed on the subjects for diagnostic
or treatment purposes.
(2) Risks to subjects are reasonable
in relation to anticipated benefits, if
any, to subjects, and the importance of
the knowledge that may reasonably be
expected to result. In evaluating risks
and benefits, the IRB should consider
only those risks and benefits that may
result from the research (as distinguished
from risks and benefits of
therapies subjects would receive even if
not participating in the research). The
IRB should not consider possible longrange
effects of applying knowledge
gained in the research (for example,
the possible effects of the research on
public policy) as among those research
risks that fall within the purview of its
responsibility.
(3) Selection of subjects is equitable.
In making this assessment the IRB
should take into account the purposes
of the research and the setting in
which the research will be conducted
and should be particularly cognizant of
the special problems of research involving
vulnerable populations, such as
children, prisoners, pregnant women,
mentally disabled persons, or economically
or educationally disadvantaged
persons.
(4) Informed consent will be sought
from each prospective subject or the
subject’s legally authorized representative,
in accordance with, and to the extent
required by § 46.116.
(5) Informed consent will be appropriately
documented, in accordance
with, and to the extent required by
§ 46.117.
(6) When appropriate, the research
plan makes adequate provision for
monitoring the data collected to ensure
the safety of subjects.
(7) When appropriate, there are adequate
provisions to protect the privacy
of subjects and to maintain the confidentiality
of data.
(b) When some or all of the subjects
are likely to be vulnerable to coercion
or undue influence, such as children,
prisoners, pregnant women, mentally
disabled persons, or economically or
educationally disadvantaged persons,
additional safeguards have been included
in the study to protect the
rights and welfare of these subjects.
§ 46.112 Review by institution.
Research covered by this policy that
has been approved by an IRB may be
subject to further appropriate review
and approval or disapproval by officials
of the institution. However, those officials
may not approve the research if it
has not been approved by an IRB.
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112
§ 46.113 45 CFR Subtitle A (10–1–01 Edition)
§ 46.113 Suspension or termination of
IRB approval of research.
An IRB shall have authority to suspend
or terminate approval of research
that is not being conducted in accordance
with the IRB’s requirements or
that has been associated with unexpected
serious harm to subjects. Any
suspension or termination of approval
shall include a statement of the reasons
for the IRB’s action and shall be
reported promptly to the investigator,
appropriate institutional officials, and
the department or agency head.
(Approved by the Office of Management and
Budget under control number 9999–0020)
§ 46.114 Cooperative research.
Cooperative research projects are
those projects covered by this policy
which involve more than one institution.
In the conduct of cooperative research
projects, each institution is responsible
for safeguarding the rights
and welfare of human subjects and for
complying with this policy. With the
approval of the department or agency
head, an institution participating in a
cooperative project may enter into a
joint review arrangement, rely upon
the review of another qualified IRB, or
make similar arrangements for avoiding
duplication of effort.
§ 46.115 IRB records.
(a) An institution, or when appropriate
an IRB, shall prepare and maintain
adequate documentation of IRB
activities, including the following:
(1) Copies of all research proposals reviewed,
scientific evaluations, if any,
that accompany the proposals, approved
sample consent documents,
progress reports submitted by investigators,
and reports of injuries to subjects.
(2) Minutes of IRB meetings which
shall be in sufficient detail to show attendance
at the meetings; actions
taken by the IRB; the vote on these actions
including the number of members
voting for, against, and abstaining; the
basis for requiring changes in or disapproving
research; and a written summary
of the discussion of controverted
issues and their resolution.
(3) Records of continuing review activities.
(4) Copies of all correspondence between
the IRB and the investigators.
(5) A list of IRB members in the same
detail as described is § 46.103(b)(3).
(6) Written procedures for the IRB in
the same detail as described in
§ 46.103(b)(4) and § 46.103(b)(5).
(7) Statements of significant new
findings provided to subjects, as required
by § 46.116(b)(5).
(b) The records required by this policy
shall be retained for at least 3
years, and records relating to research
which is conducted shall be retained
for at least 3 years after completion of
the research. All records shall be accessible
for inspection and copying by authorized
representatives of the department
or agency at reasonable times
and in a reasonable manner.
(Approved by the Office of Management and
Budget under control number 9999–0020)
§ 46.116 General requirements for informed
consent.
Except as provided elsewhere in this
policy, no investigator may involve a
human being as a subject in research
covered by this policy unless the investigator
has obtained the legally effective
informed consent of the subject or
the subject’s legally authorized representative.
An investigator shall seek
such consent only under circumstances
that provide the prospective subject or
the representative sufficient opportunity
to consider whether or not to
participate and that minimize the possibility
of coercion or undue influence.
The information that is given to the
subject or the representative shall be
in language understandable to the subject
or the representative. No informed
consent, whether oral or written, may
include any exculpatory language
through which the subject or the representative
is made to waive or appear
to waive any of the subject’s legal
rights, or releases or appears to release
the investigator, the sponsor, the institution
or its agents from liability for
negligence.
(a) Basic elements of informed consent.
Except as provided in paragraph
(c) or (d) of this section, in seeking informed
consent the following information
shall be provided to each subject:
(1) A statement that the study involves
research, an explanation of the
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113
Department of Health and Human Services § 46.116
purposes of the research and the expected
duration of the subject’s participation,
a description of the procedures
to be followed, and identification of
any procedures which are experimental;
(2) A description of any reasonably
foreseeable risks or discomforts to the
subject;
(3) A description of any benefits to
the subject or to others which may reasonably
be expected from the research;
(4) A disclosure of appropriate alternative
procedures or courses of treatment,
if any, that might be advantageous
to the subject;
(5) A statement describing the extent,
if any, to which confidentiality of
records identifying the subject will be
maintained;
(6) For research involving more than
minimal risk, an explanation as to
whether any compensation and an explanation
as to whether any medical
treatments are available if injury occurs
and, if so, what they consist of, or
where further information may be obtained;
(7) An explanation of whom to contact
for answers to pertinent questions
about the research and research subjects’
rights, and whom to contact in
the event of a research-related injury
to the subject; and
(8) A statement that participation is
voluntary, refusal to participate will
involve no penalty or loss of benefits to
which the subject is otherwise entitled,
and the subject may discontinue participation
at any time without penalty
or loss of benefits to which the subject
is otherwise entitled.
(b) Additional elements of informed
consent. When appropriate, one or
more of the following elements of information
shall also be provided to
each subject:
(1) A statement that the particular
treatment or procedure may involve
risks to the subject (or to the embryo
or fetus, if the subject is or may become
pregnant) which are currently
unforeseeable;
(2) Anticipated circumstances under
which the subject’s participation may
be terminated by the investigator
without regard to the subject’s consent;
(3) Any additional costs to the subject
that may result from participation
in the research;
(4) The consequences of a subject’s
decision to withdraw from the research
and procedures for orderly termination
of participation by the subject;
(5) A statement that significant new
findings developed during the course of
the research which may relate to the
subject’s willingness to continue participation
will be provided to the subject;
and
(6) The approximate number of subjects
involved in the study.
(c) An IRB may approve a consent
procedure which does not include, or
which alters, some or all of the elements
of informed consent set forth
above, or waive the requirement to obtain
informed consent provided the IRB
finds and documents that:
(1) The research or demonstration
project is to be conducted by or subject
to the approval of state or local government
officials and is designed to
study, evaluate, or otherwise examine:
(i) Public benefit of service programs;
(ii) procedures for obtaining benefits or
services under those programs; (iii)
possible changes in or alternatives to
those programs or procedures; or (iv)
possible changes in methods or levels
of payment for benefits or services
under those programs; and
(2) The research could not practicably
be carried out without the
waiver or alteration.
(d) An IRB may approve a consent
procedure which does not include, or
which alters, some or all of the elements
of informed consent set forth in
this section, or waive the requirements
to obtain informed consent provided
the IRB finds and documents that:
(1) The research involves no more
than minimal risk to the subjects;
(2) The waiver or alteration will not
adversely affect the rights and welfare
of the subjects;
(3) The research could not practicably
be carried out without the
waiver or alteration; and
(4) Whenever appropriate, the subjects
will be provided with additional
pertinent information after participation.
(e) The informed consent requirements
in this policy are not intended
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114
§ 46.117 45 CFR Subtitle A (10–1–01 Edition)
to preempt any applicable federal,
state, or local laws which require additional
information to be disclosed in
order for informed consent to be legally
effective.
(f) Nothing in this policy is intended
to limit the authority of a physician to
provide emergency medical care, to the
extent the physician is permitted to do
so under applicable federal, state, or
local law.
(Approved by the Office of Management and
Budget under control number 9999–0020)
§ 46.117 Documentation of informed
consent.
(a) Except as provided in paragraph
(c) of this section, informed consent
shall be documented by the use of a
written consent form approved by the
IRB and signed by the subject or the
subject’s legally authorized representative.
A copy shall be given to the person
signing the form.
(b) Except as provided in paragraph
(c) of this section, the consent form
may be either of the following:
(1) A written consent document that
embodies the elements of informed
consent required by § 46.116. This form
may be read to the subject or the subject’s
legally authorized representative,
but in any event, the investigator
shall give either the subject or the representative
adequate opportunity to
read it before it is signed; or
(2) A short form written consent document
stating that the elements of informed
consent required by § 46.116
have been presented orally to the subject
or the subject’s legally authorized
representative. When this method is
used, there shall be a witness to the
oral presentation. Also, the IRB shall
approve a written summary of what is
to be said to the subject or the representative.
Only the short form itself
is to be signed by the subject or the
representative. However, the witness
shall sign both the short form and a
copy of the summary, and the person
actually obtaining consent shall sign a
copy of the summary. A copy of the
summary shall be given to the subject
or the representative, in addition to a
copy of the short form.
(c) An IRB may waive the requirement
for the investigator to obtain a
signed consent form for some or all
subjects if it finds either:
(1) That the only record linking the
subject and the research would be the
consent document and the principal
risk would be potential harm resulting
from a breach of confidentiality. Each
subject will be asked whether the subject
wants documentation linking the
subject with the research, and the subject’s
wishes will govern; or
(2) That the research presents no
more than minimal risk of harm to
subjects and involves no procedures for
which written consent is normally required
outside of the research context.
In cases in which the documentation
requirement is waived, the IRB may require
the investigator to provide subjects
with a written statement regarding
the research.
(Approved by the Office of Management and
Budget under control number 9999–0020)
§ 46.118 Applications and proposals
lacking definite plans for involvement
of human subjects.
Certain types of applications for
grants, cooperative agreements, or contracts
are submitted to departments or
agencies with the knowledge that subjects
may be involved within the period
of support, but definite plans would not
normally be set forth in the application
or proposal. These include activities
such as institutional type grants
when selection of specific projects is
the institution’s responsibility; research
training grants in which the activities
involving subjects remain to be
selected; and projects in which human
subjects’ involvement will depend upon
completion of instruments, prior animal
studies, or purification of compounds.
These applications need not be
reviewed by an IRB before an award
may be made. However, except for research
exempted or waived under
§ 46.101 (b) or (i), no human subjects
may be involved in any project supported
by these awards until the
project has been reviewed and approved
by the IRB, as provided in this policy,
and certification submitted, by the institution,
to the department or agency.
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115
Department of Health and Human Services § 46.201
§ 46.119 Research undertaken without
the intention of involving human
subjects.
In the event research is undertaken
without the intention of involving
human subjects, but it is later proposed
to involve human subjects in the
research, the research shall first be reviewed
and approved by an IRB, as provided
in this policy, a certification submitted,
by the institution, to the department
or agency, and final approval
given to the proposed change by the department
or agency.
§ 46.120 Evaluation and disposition of
applications and proposals for research
to be conducted or supported
by a Federal Department or
Agency.
(a) The department or agency head
will evaluate all applications and proposals
involving human subjects submitted
to the department or agency
through such officers and employees of
the department or agency and such experts
and consultants as the department
or agency head determines to be
appropriate. This evaluation will take
into consideration the risks to the subjects,
the adequacy of protection
against these risks, the potential benefits
of the research to the subjects and
others, and the importance of the
knowledge gained or to be gained.
(b) On the basis of this evaluation,
the department or agency head may
approve or disapprove the application
or proposal, or enter into negotiations
to develop an approvable one.
§ 46.121 [Reserved]
§ 46.122 Use of Federal funds.
Federal funds administered by a department
or agency may not be expended
for research involving human
subjects unless the requirements of
this policy have been satisfied.
§ 46.123 Early termination of research
support: Evaluation of applications
and proposals.
(a) The department or agency head
may require that department or agency
support for any project be terminated
or suspended in the manner prescribed
in applicable program requirements,
when the department or agency head
finds an institution has materially
failed to comply with the terms of this
policy.
(b) In making decisions about supporting
or approving applications or
proposals covered by this policy the department
or agency head may take
into account, in addition to all other
eligibility requirements and program
criteria, factors such as whether the
applicant has been subject to a termination
or suspension under paragarph
(a) of this section and whether the applicant
or the person or persons who
would direct or has have directed the
scientific and technical aspects of an
activity has have, in the judgment of
the department or agency head, materially
failed to discharge responsibility
for the protection of the rights and
welfare of human subjects (whether or
not the research was subject to federal
regulation).
§ 46.124 Conditions.
With respect to any research project
or any class of research projects the department
or agency head may impose
additional conditions prior to or at the
time of approval when in the judgment
of the department or agency head additional
conditions are necessary for the
protection of human subjects.
Subpart B—Additional Protections
Pertaining to Research, Development,
and Related Activities
Involving Fetuses, Pregnant
Women, and Human In
Vitro Fertilization
SOURCE: 40 FR 33528, Aug. 8, 1975, unless
otherwise noted.
EFFECTIVE DATE NOTE: At 66 FR 3882, Jan.
17, 2001, subpart B was revised, effective Mar.
19, 2001. At 66 FR 15352, Mar. 19, 2001, the effective
date was delayed until May 18, 2001,
and at 66 FR 27599, May 18, 2001, the effective
date was further delayed until Nov. 14, 2001.
For the convenience of the user, subpart B
effective Nov. 14, 2001, follows the text of this
subpart B.
§ 46.201 Applicability.
(a) The regulations in this subpart
are applicable to all Department of
Health and Human Services grants and
contracts supporting research, development,
and related activities involving:
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116
§ 46.202 45 CFR Subtitle A (10–1–01 Edition)
(1) The fetus, (2) pregnant women, and
(3) human in vitro fertilization.
(b) Nothing in this subpart shall be
construed as indicating that compliance
with the procedures set forth
herein will in any way render inapplicable
pertinent State or local laws
bearing upon activities covered by this
subpart.
(c) The requirements of this subpart
are in addition to those imposed under
the other subparts of this part.
§ 46.202 Purpose.
It is the purpose of this subpart to
provide additional safeguards in reviewing
activities to which this subpart
is applicable to assure that they
conform to appropriate ethical standards
and relate to important societal
needs.
§ 46.203 Definitions.
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
to whom authority has been delegated.
(b) Pregnancy encompasses the period
of time from confirmation of implantation
(through any of the presumptive
signs of pregnancy, such as missed
menses, or by a medically acceptable
pregnancy test), until expulsion or extraction
of the fetus.
(c) Fetus means the product of conception
from the time of implantation
(as evidenced by any of the presumptive
signs of pregnancy, such as missed
menses, or a medically acceptable
pregnancy test), until a determination
is made, following expulsion or extraction
of the fetus, that it is viable.
(d) Viable as it pertains to the fetus
means being able, after either spontaneous
or induced delivery, to survive
(given the benefit of available medical
therapy) to the point of independently
maintaining heart beat 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 is viable for
purposes of this subpart. If a fetus is
viable after delivery, it is a premature
infant.
(e) Nonviable fetus means a fetus ex
utero which, although living, is not viable.
(f) Dead fetus means a fetus ex utero
which exhibits neither heartbeat, spontaneous
respiratory activity, spontaneous
movement of voluntary muscles,
nor pulsation of the umbilical cord (if
still attached).
(g) 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.
[40 FR 33528, Aug. 8, 1975, as amended at 43
FR 1759, Jan. 11, 1978]
§ 46.204 Ethical Advisory Boards.
(a) One or more Ethical Advisory
Boards shall be established by the Secretary.
Members of these board(s) shall
be so selected that the board(s) will be
competent to deal with medical, legal,
social, ethical, and related issues and
may include, for example, research scientists,
physicians, psychologists, sociologists,
educators, lawyers, and
ethicists, as well as representatives of
the general public. No board member
may be a regular, full-time employee of
the Department of Health and Human
Services.
(b) At the request of the Secretary,
the Ethical Advisory Board shall
render advice consistent with the policies
and requirements of this part as to
ethical issues, involving activities covered
by this subpart, raised by individual
applications or proposals. In addition,
upon request by the Secretary,
the Board shall render advice as to
classes of applications or proposals and
general policies, guidelines, and procedures.
(c) A Board may establish, with the
approval of the Secretary, classes of
applications or proposals which: (1)
Must be submitted to the Board, or (2)
need not be submitted to the Board.
Where the Board so establishes a class
of applications or proposals which
must be submitted, no application or
proposal within the class may be funded
by the Department or any component
thereof until the application or
proposal has been reviewed by the
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117
Department of Health and Human Services § 46.207
Board and the Board has rendered advice
as to its acceptability from an ethical
standpoint.
[40 FR 33528, Aug. 8, 1975, as amended at 43
FR 1759, Jan. 11, 1978; 59 FR 28276, June 1,
1994]
§ 46.205 Additional duties of the Institutional
Review Boards in connection
with activities involving
fetuses, pregnant women, or human
in vitro fertilization.
(a) In addition to the responsibilities
prescribed for Institutional Review
Boards under Subpart A of this part,
the applicant’s or offeror’s Board shall,
with respect to activities covered by
this subpart, carry out the following
additional duties:
(1) Determine that all aspects of the
activity meet the requirements of this
subpart;
(2) Determine that adequate consideration
has been given to the manner
in which potential subjects will be selected,
and adequate provision has been
made by the applicant or offeror for
monitoring the actual informed consent
process (e.g., through such mechanisms,
when appropriate, as participation
by the Institutional Review Board
or subject advocates in: (i) Overseeing
the actual process by which individual
consents required by this subpart are
secured either by approving induction
of each individual into the activity or
verifying, perhaps through sampling,
that approved procedures for induction
of individuals into the activity are
being followed, and (ii) monitoring the
progress of the activity and intervening
as necessary through such steps
as visits to the activity site and continuing
evaluation to determine if any
unanticipated risks have arisen);
(3) Carry out such other responsibilities
as may be assigned by the Secretary.
(b) No award may be issued until the
applicant or offeror has certified to the
Secretary that the Institutional Review
Board has made the determinations
required under paragraph (a) of
this section and the Secretary has approved
these determinations, as provided
in § 46.120 of Subpart A of this
part.
(c) Applicants or offerors seeking
support for activities covered by this
subpart must provide for the designation
of an Institutional Review Board,
subject to approval by the Secretary,
where no such Board has been established
under Subpart A of this part.
[40 FR 33528, Aug. 8, 1975, as amended at 46
FR 8386, Jan. 26, 1981]
§ 46.206 General limitations.
(a) No activity to which this subpart
is applicable may be undertaken unless:
(1) Appropriate studies on animals
and nonpregnant individuals have been
completed;
(2) Except where the purpose of the
activity is to meet the health needs of
the mother or the particular fetus, the
risk to the fetus is minimal and, in all
cases, is the least possible risk for
achieving the objectives of the activity.
(3) Individuals engaged in the activity
will have no part in: (i) Any decisions
as to the timing, method, and
procedures used to terminate the pregnancy,
and (ii) determining the viability
of the fetus at the termination of
the pregnancy; and
(4) No procedural changes which may
cause greater than minimal risk to the
fetus or the pregnant woman will be introduced
into the procedure for terminating
the pregnancy solely in the interest
of the activity.
(b) No inducements, monetary or otherwise,
may be offered to terminate
pregnancy for purposes of the activity.
[40 FR 33528, Aug. 8, 1975, as amended at 40
FR 51638, Nov. 6, 1975]
§ 46.207 Activities directed toward
pregnant women as subjects.
(a) No pregnant woman may be involved
as a subject in an activity covered
by this subpart unless: (1) The
purpose of the activity is to meet the
health needs of the mother and the
fetus will be placed at risk only to the
minimum extent necessary to meet
such needs, or (2) the risk to the fetus
is minimal.
(b) An activity permitted under paragraph
(a) of this section may be conducted
only if the mother and father
are legally competent and have given
their informed consent after having
been fully informed regarding possible
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118
§ 46.208 45 CFR Subtitle A (10–1–01 Edition)
impact on the fetus, except that the father’s
informed consent need not be secured
if: (1) The purpose of the activity
is to meet the health needs of the
mother; (2) his identity or whereabouts
cannot reasonably be ascertained; (3)
he is not reasonably available; or (4)
the pregnancy resulted from rape.
§ 46.208 Activities directed toward
fetuses in utero as subjects.
(a) No fetus in utero may be involved
as a subject in any activity covered by
this subpart unless: (1) The purpose of
the activity is to meet the health needs
of the particular fetus and the fetus
will be placed at risk only to the minimum
extent necessary to meet such
needs, or (2) the risk to the fetus imposed
by the research is minimal and
the purpose of the activity is the development
of important biomedical
knowledge which cannot be obtained
by other means.
(b) An activity permitted under paragraph
(a) of this section may be conducted
only if the mother and father
are legally competent and have given
their informed consent, except that the
father’s consent need not be secured if:
(1) His identity or whereabouts cannot
reasonably be ascertained, (2) he is not
reasonably available, or (3) the pregnancy
resulted from rape.
§ 46.209 Activities directed toward
fetuses ex utero, including nonviable
fetuses, as subjects.
(a) Until it has been ascertained
whether or not a fetus ex utero is viable,
a fetus ex utero may not be involved
as a subject in an activity covered
by this subpart unless:
(1) There will be no added risk to the
fetus resulting from the activity, and
the purpose of the activity is the development
of important biomedical
knowledge which cannot be obtained
by other means, or
(2) The purpose of the activity is to
enhance the possibility of survival of
the particular fetus to the point of viability.
(b) No nonviable fetus may be involved
as a subject in an activity covered
by this subpart unless:
(1) Vital functions of the fetus will
not be artificially maintained,
(2) Experimental activities which of
themselves would terminate the heartbeat
or respiration of the fetus will not
be employed, and
(3) The purpose of the activity is the
development of important biomedical
knowledge which cannot be obtained
by other means.
(c) In the event the fetus ex utero is
found to be viable, it may be included
as a subject in the activity only to the
extent permitted by and in accordance
with the requirements of other subparts
of this part.
(d) An activity permitted under paragraph
(a) or (b) of this section may be
conducted only if the mother and father
are legally competent and have
given their informed consent, except
that the father’s informed consent need
not be secured if: (1) His identity or
whereabouts cannot reasonably be
ascertained, (2) he is not reasonably
available, or (3) the pregnancy resulted
from rape.
[40 FR 33528, Aug. 8, 1975, as amended at 43
FR 1759, Jan. 11, 1978]
§ 46.210 Activities involving the dead
fetus, fetal material, or the placenta.
Activities involving the dead fetus,
mascerated fetal material, or cells, tissue,
or organs excised from a dead fetus
shall be conducted only in accordance
with any applicable State or local laws
regarding such activities.
§ 46.211 Modification or waiver of specific
requirements.
Upon the request of an applicant or
offeror (with the approval of its Institutional
Review Board), the Secretary
may modify or waive specific requirements
of this subpart, with the approval
of the Ethical Advisory Board
after such opportunity for public comment
as the Ethical Advisory Board
considers appropriate in the particular
instance. In making such decisions, the
Secretary will consider whether the
risks to the subject are so outweighed
by the sum of the benefit to the subject
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
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119
Department of Health and Human Services Pt. 46, Subpt. B, Note
modification or waiver. Any such modifications
or waivers will be published
as notices in the FEDERAL REGISTER.
EFFECTIVE DATE NOTE: At 66 FR 3882, Jan.
17, 2001, subpart B was revised, effective Mar.
19, 2001. At 66 FR 15352, Mar. 19, 2001, the effective
date was delayed until May 18, 2001,
and at 66 FR 27599, May 18, 2001, the effective
date was further delayed until Nov. 14, 2001.
For the convenience of the user, the revised
text is set forth as follows:
Subpart B—Additional Protections for
Pregnant Women and Human
Fetuses Involved in Research, and
Pertaining to Human In Vitro Fertilization
§ 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, 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 § 46.101(b)(1) through
(6) are applicable to this subpart.
(c) The provisions of § 46.101(c) through (i)
are applicable to this subpart. Reference to
State or local laws in this subpart and in
§ 46.101(f) is intended to include the laws of
federally recognized American Indian and
Alaska Native Tribal Governments.
(d) The requirements of this subpart are in
addition to those imposed under the other
subparts of this part.
§ 46.202 Definitions.
The definitions in § 46.102 shall be applicable
to this subpart as well. In addition, as
used in this subpart:
(a) Dead fetus means a fetus after delivery
that exhibits neither heartbeat, spontaneous
respiratory activity, spontaneous movement
of voluntary muscles, nor pulsation of the
umbilical cord. Delivery means complete
separation of the fetus from the woman by
expulsion or extraction or any other means.
(b) Fetus means the product of conception
from implantation until a determination is
made after delivery that it is viable.
(c) 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.
(d) Nonviable fetus means a fetus after delivery
that, although living, is not viable.
(e) 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.
(f) 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.
(g) Viable as it pertains to the fetus 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 fetus is viable for purposes of this
subpart. If a fetus after delivery is viable
then it is a child as defined by § 46.402(a), and
subpart D of this part is applicable.
§ 46.203 Duties of IRBs in connection with
research involving pregnant women,
fetuses, and human in vitro fertilization.
In addition to other responsibilities assigned
to IRBs under this part, each IRB
shall review research covered by this subpart
and approve only research which satisfies
the conditions of all applicable sections of
this subpart and the other subparts of this
part.
§ 46.204 Research involving pregnant
women or fetuses prior to delivery.
Pregnant women or fetuses prior to delivery
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 not greater than
minimal, or any risk to the fetus which is
greater than minimal is caused solely by
interventions or procedures that hold out
the prospect of direct benefit for the woman
or the fetus;
(c) Any risk is the least possible for achieving
the objectives of the research;
(d) 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, unless
altered or waived in accord with § 46.101(i) or
§ 46.116(c) or (d);
(e) The woman or her legally authorized
representative, as appropriate, is fully informed
regarding the reasonably foreseeable
impact of the research on the fetus or resultant
child;
(f) For children as defined in 45 CFR
46.402(a) who are pregnant, assent and permission
are obtained in accord with the provisions
of subpart D of this part;

Pt. 46, Subpt. B, Note 45 CFR Subtitle A (10–1–01 Edition)
(g) No inducements, monetary or otherwise,
will be offered to terminate a pregnancy;
(h) 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
(i) Individuals engaged in the research will
have no part in determining the viability of
a fetus.
§ 46.205 Research involving fetuses after delivery.
(a) After delivery, fetuses 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 fetuses.
(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
fetus or resultant child.
(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.
(5) Individuals engaged in the research will
have no part in determining the viability of
a fetus.
(6) The requirements of paragraph (b) or (c)
of this section have been met as applicable.
(b) Fetuses of uncertain viability. After delivery,
and until it has been ascertained
whether or not a fetus is viable, a fetus 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
particular fetus to the point of viability, and
any risk is the least possible for achieving
the objectives of the research, 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 fetus
resulting from the research; and
(2) The legally effective informed consen 
of either parent of the fetus 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, unless altered or waived in accord with § 46.101(i) or § 46.116(c) or (d).

(c) Nonviable fetuses. After delivery, a nonviable fetus may not be involved in research covered by this subpart unless all of the following additional conditions are met:

(1) Vital functions of the fetus will not be artificially maintained;

(2) The research will not terminate the heartbeat or respiration of the fetus;

(3) There will be no risk to the fetus 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 fetus is obtained in accord with subpart A of this part, except that the waiver and alteration provisions of § 46.116(c) and (d) do not apply. However, if either parent is unable to consent because of unavailability, incompetence, or temporary incapacity, the informed consent of one parent of a nonviable fetus will suffice to meet the requirements of this paragraph. The consent of a legally authorized representative of either or both of the parents of a nonviable fetus will not suffice to meet the requirements of this paragraph.

(d) Viable fetuses. A fetus, after delivery, that has been determined to be viable is a child as defined by § 46.402(a) and 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.

§ 46.206 Research involving, after delivery, the placenta, the dead fetus, or fetal material.

(a) Research involving, after delivery, the placenta; the dead fetus; macerated fetal material; or cells, tissue, or organs excised from a dead fetus, 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.

§ 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 Secretary will conduct or fund research that the IRB does not believe meets the requirements of § 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 or fetuses; 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 § 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 or fetuses;

(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, unless altered or waived in accord with § 46.101(i) or § 46.116(c) or (d).

Subpart C—Additional Protections Pertaining to Biomedical and Behavioral Research Involving Prisoners as Subjects

SOURCE: 43 FR 53655, Nov. l6, l978, unless otherwise noted.

§ 46.301 Applicability.

(a) The regulations in this subpart are applicable to all biomedical and behavioral research conducted or supported by the Department of Health and Human Services involving prisoners as subjects.

(b) Nothing in this subpart shall be construed as indicating that compliance with the procedures set forth herein will authorize research involving prisoners as subjects, to the extent such research is limited or barred by applicable State or local law.

(c) The requirements of this subpart are in addition to those imposed under the other subparts of this part.

§ 46.302 Purpose.

Inasmuch as prisoners may be under constraints because of their incarceration which could affect their ability to make a truly voluntary and uncoerced decision whether or not to participate as subjects in research, it is the purpose of this subpart to provide additional safeguards for the protection of prisoners involved in activities to which this subpart is applicable.

§ 46.303 Definitions.

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 to whom authority has been delegated.

(b) DHHS means the Department of Health and Human Services.

(c) Prisoner means any individual involuntarily confined or detained in a penal institution. The term is intended to encompass individuals sentenced to such an institution under a criminal or civil statute, individuals detained in other facilities by virtue of statutes or commitment procedures which provide alternatives to criminal prosecution or incarceration in a penal institution, and individuals detained pending arraignment, trial, or sentencing.

(d) Minimal risk is the probability and magnitude of physical or psychological harm that is normally encountered in the daily lives, or in the routine medical, dental, or psychological examination of healthy persons.

§ 46.304 Composition of Institutional Review Boards where prisoners are involved.

In addition to satisfying the requirements in § 46.107 of this part, an Institutional Review Board, carrying out responsibilities under this part with respect to research covered by this subpart, shall also meet the following specific requirements:

(a) A majority of the Board (exclusive of prisoner members) shall have no association with the prison(s) involved, apart from their membership on the Board.

(b) At least one member of the Board shall be a prisoner, or a prisoner representative with appropriate background and experience to serve in that capacity, except that where a particular research project is reviewed by more than one Board only one Board need satisfy this requirement.

[43 FR 53655, Nov. 16, 1978, as amended at 46 FR 8386, Jan. 26, 1981]

§ 46.305 Additional duties of the Institutional Review Boards where prisoners are involved.

(a) In addition to all other responsibilities prescribed for Institutional Review Boards under this part, the Board shall review research covered by this subpart and approve such research only if it finds that:

(1) The research under review represents one of the categories of research permissible under § 46.306(a)(2);

(2) Any possible advantages accruing to the prisoner through his or her participation in the research, when compared to the general living conditions, medical care, quality of food, amenities and opportunity for earnings in the prison, are not of such a magnitude that his or her ability to weigh the risks of the research against the value of such advantages in the limited choice environment of the prison is impaired;

(3) The risks involved in the research are commensurate with risks that would be accepted by non-prisoner volunteers;

(4) Procedures for the selection of subjects within the prison are fair to all prisoners and immune from arbitrary intervention by prison authorities or prisoners. Unless the principal investigator provides to the Board justification in writing for following some other procedures, control subjects must be selected randomly from the group of available prisoners who meet the characteristics needed for that particular research project;

(5) The information is presented in language which is understandable to the subject population;

(6) Adequate assurance exists that parole boards will not take into account a prisoner’s participation in the research in making decisions regarding parole, and each prisoner is clearly informed in advance that participation in the research will have no effect on his or her parole; and

(7) Where the Board finds there may be a need for follow-up examination or care of participants after the end of their participation, adequate provision has been made for such examination or care, taking into account the varying lengths of individual prisoners’ sentences, and for informing participants of this fact.

(b) The Board shall carry out such other duties as may be assigned by the Secretary.

(c) The institution shall certify to the Secretary, in such form and manner as the Secretary may require, that the duties of the Board under this section have been fulfilled.

§ 46.306 Permitted research involving prisoners.

(a) Biomedical or behavioral research conducted or supported by DHHS may involve prisoners as subjects only if:

(1) The institution responsible for the conduct of the research has certified to the Secretary that the Institutional Review Board has approved the research under § 46.305 of this subpart;

and

(2) In the judgment of the Secretary the proposed research involves solely the following:

(i) Study of the possible causes, effects, and processes of incarceration, and of criminal behavior, provided that the study presents no more than minimal risk and no more than inconvenience to the subjects;

(ii) Study of prisons as institutional structures or of prisoners as incarcerated persons, provided that the study presents no more than minimal risk and no more than inconvenience to the subjects;

(iii) Research on conditions particularly affecting prisoners as a class (for example, vaccine trials and other research on hepatitis which is much more prevalent in prisons than elsewhere; and research on social and psychological problems such as alcoholism, drug addiction and sexual assaults) provided that the study may proceed only after the Secretary has consulted with appropriate experts including experts in penology medicine and ethics, and published notice, in the FEDERAL REGISTER, of his intent to approve such research; or

(iv) Research on practices, both innovative and accepted, which have the intent and reasonable probability of improving the health or well-being of the subject. In cases in which those studies require the assignment of prisoners in a manner consistent with protocols approved by the IRB to control groups which may not benefit from the research, the study may proceed only after the Secretary has consulted with appropriate experts, including experts in penology medicine and ethics, and published notice, in the FEDERAL REGISTER, of his intent to approve such research.

(b) Except as provided in paragraph

(a) of this section, biomedical or behavioral research conducted or supported by DHHS shall not involve prisoners as subjects.

Subpart D—Additional Protections for Children Involved as Subjects in Research

SOURCE: 48 FR 9818, Mar. 8, 1983, unless otherwise noted.

§ 46.401 To what do these regulations apply?

(a) This subpart applies to all research involving children as subjects, conducted or supported by the Department of Health and Human Services.

(1) This includes research conducted by Department employees, except that each head of an Operating Division of the Department may adopt such non-substantive, procedural modifications as may be appropriate from an administrative standpoint.

(2) It also includes research conducted or supported by the Department of Health and Human Services outside the United States, but in appropriate circumstances, the Secretary may, under paragraph (e) of § 46.101 of Subpart A, waive the applicability of some or all of the requirements of these regulations for research of this type.

(b) Exemptions at § 46.101(b)(1) and (b)(3) through (b)(6) are applicable to this subpart. The exemption at § 46.101(b)(2) regarding educational tests is also applicable to this subpart. However, the exemption at § 46.101(b)(2) for research involving survey or interview procedures or observations of public behavior does not apply to research covered by this subpart, except for research involving observation of public behavior when the investigator(s) do not participate in the activities being observed.

(c) The exceptions, additions, and provisions for waiver as they appear in paragraphs (c) through (i) of § 46.101 of Subpart A are applicable to this subpart.

[48 FR 9818, Mar. 8, 1983; 56 FR 28032, June 18, 1991; 56 FR 29757, June 28, 1991]

§ 46.402 Definitions.

The definitions in § 46.102 of Subpart A shall be applicable to this subpart as well. In addition, as used in this subpart:

(a) 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.

(b) Assent means a child’s affirmative agreement to participate in research. Mere failure to object should not, absent affirmative agreement, be construed as assent.

(c) Permission means the agreement of parent(s) or guardian to the participation of their child or ward in research.

(d) Parent means a child’s biological or adoptive parent.

(e) Guardian means an individual who is authorized under applicable State or local law to consent on behalf of a child to general medical care.

§ 46.403 IRB duties.

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.

§ 46.404 Research not involving greater than minimal risk.

HHS will conduct or fund research in which the IRB finds that no greater than minimal risk to children is presented, only if the IRB finds that adequate provisions are made for soliciting the assent of the children and the permission of their parents or guardians, as set forth in § 46.408.

§ 46.405 Research involving greater than minimal risk but presenting the prospect of direct benefit to the individual subjects.

HHS will conduct or fund research in which the IRB finds that more than minimal risk to children is presented by an intervention or procedure that holds out the prospect of direct benefit

§ 46.406 45 CFR Subtitle A (10–1–01 Edition) for the individual subject, or by a monitoring procedure that is likely to contribute to the subject’s well-being, only if the IRB finds that:

(a) The risk is justified by the anticipated benefit to the subjects;

(b) The relation of the anticipated benefit to the risk is at least as favorable to the subjects as that presented by available alternative approaches;

and

(c) Adequate provisions are made for soliciting the assent of the children and permission of their parents or guardians, as set forth in § 46.408.

§ 46.406 Research involving greater than minimal risk and no prospect of direct benefit to individual subjects, but likely to yield generalizable knowledge about the subject’s disorder or condition.

HHS will conduct or fund research in which the IRB finds that more than minimal risk to children is presented by an intervention or procedure that does not hold out the prospect of direct benefit for the individual subject, or by a monitoring procedure which is not likely to contribute to the well-being of the subject, only if the IRB finds that:

(a) The risk represents a minor increase over minimal risk;

(b) The intervention or procedure presents experiences to subjects that are reasonably commensurate with those inherent in their actual or expected medical, dental, psychological, social, or educational situations;

(c) The intervention or procedure is likely to yield generalizable knowledge about the subjects’ disorder or condition which is of vital importance for the understanding or amelioration of the subjects’ disorder or condition;

and

(d) Adequate provisions are made for soliciting assent of the children and permission of their parents or guardians, as set forth in § 46.408.

§ 46.407 Research not otherwise approvable which presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children.

HHS will conduct or fund research that the IRB does not believe meets the requirements of § 46.404, § 46.405, or § 46.406 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 children;

and

(b) The Secretary, after consultation with a panel of experts in pertinent disciplines (for example: science, medicine, education, ethics, law) and following opportunity for public review and comment, has determined either:

(1) That the research in fact satisfies the conditions of § 46.404, § 46.405, or § 46.406, 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 children;

(ii) The research will be conducted in accordance with sound ethical principles; (iii) Adequate provisions are made for soliciting the assent of children and the permission of their parents or guardians, as set forth in § 46.408.

§ 46.408 Requirements for permission by parents or guardians and for assent by children.

(a) In addition to the determinations required under other applicable sections of this subpart, the IRB shall determine that adequate provisions are made for soliciting the assent of the children, when in the judgment of the IRB the children are capable of providing assent. In determining whether children are capable of assenting, the IRB shall take into account the ages, maturity, and psychological state of the children involved. This judgment may be made for all children to be involved in research under a particular protocol, or for each child, as the IRB deems appropriate. If the IRB determines that the capability of some or all of the children is so limited that they cannot reasonably be consulted or that the intervention or procedure involved in the research holds out a prospect of direct benefit that is important to the health or well-being of the children and is available only in the context of the research, the assent of the children is not a necessary condition for proceeding with the research. Even where the IRB determines that the subjects are capable of assenting, the IRB may still waive the assent requirement under circumstances in which consent may be waived in accord with § 46.116 of Subpart A.

(b) In addition to the determinations required under other applicable sections of this subpart, the IRB shall determine, in accordance with and to the extent that consent is required by § 46.116 of Subpart A, that adequate provisions are made for soliciting the permission of each child’s parents or guardian. Where parental permission is to be obtained, the IRB may find that the permission of one parent is sufficient for research to be conducted under § 46.404 or § 46.405. Where research is covered by §§ 46.406 and 46.407 and permission is to be obtained from parents, both parents must give their permission unless one parent is deceased, unknown, incompetent, or not reasonably available, or when only one parent has legal responsibility for the care and custody of the child.

(c) In addition to the provisions for waiver contained in § 46.116 of Subpart A, if the IRB determines that a research protocol is designed for conditions or for a subject population for which parental or guardian permission is not a reasonable requirement to protect the subjects (for example, neglected or abused children), it may waive the consent requirements in Subpart A of this part and paragraph (b) of this section, provided an appropriate mechanism for protecting the children who will participate as subjects in the research is substituted, and provided further that the waiver is not inconsistent with Federal, state or local law. The choice of an appropriate mechanism would depend upon the nature and purpose of the activities described in the protocol, the risk and anticipated benefit to the research subjects, and their age, maturity, status, and condition.

(d) Permission by parents or guardians shall be documented in accordance with and to the extent required by § 46.117 of Subpart A.

(e) When the IRB determines that assent is required, it shall also determine whether and how assent must be documented.

§ 46.409 Wards.

(a) Children who are wards of the state or any other agency, institution, or entity can be included in research approved under § 46.406 or § 46.407 only if such research is:

(1) Related to their status as wards;

or

(2) Conducted in schools, camps, hospitals, institutions, or similar settings in which the majority of children involved as subjects are not wards.

(b) If the research is approved under paragraph (a) of this section, the IRB shall require appointment of an advocate for each child who is a ward, in addition to any other individual acting on behalf of the child as guardian or in loco parentis. One individual may serve as advocate for more than one child. The advocate shall be an individual who has the background and experience to act in, and agrees to act in, the best interests of the child for the duration of the child’s participation in the research and who is not associated in any way (except in the role as advocate or member of the IRB) with the research, the investigator(s), or the guardian organization.