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CODE OF FEDERAL REGULATIONS
TITLE 45
PUBLIC WELFARE
DEPARTMENT OF HEALTH AND HUMAN SERVICES
NATIONAL INSTITUTES OF HEALTH
OFFICE FOR PROTECTION FROM RESEARCH RISKS
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PART 46—PROTECTION OF HUMAN SUBJECTS
REVISED AS OF MARCH 8, 1983
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45 CFR46
PART 4&--PROTECTION OF
HUMAN
SUBJECTS
Subpart A-—Basse HHS Policy for
Projection of Human Research
Subjects
Sec.
101
To what do these regulations apply?
46.J02
Definitions.
46.103
Assurances.
46 104
Section reserved.
46.105
Section reserved.
1 06
Section reserved
46.107
IRB membership.
46.108
1KB functions and operations.
46. 109
IRB review of research.
46.1 10
Expedited review procedures for
certain kinds of research involving no
more than minimal risk, and for minor
changes in approved research.
46.
Criteria for IRB approval of
research.
46 It?
Review by institution.
46,
1 13
Suspension or termination of IRB
approval of research.
*6.114
Cooperative research.
46.115
IRB records.
46 116
Genera! requirements Ioj informed
consent.
1 17
Documentation of informed
consent.
1 18
Applications and proposals lacking
definite plans for involvement of human
subjects.
46.
1)
Research undertaken without the
intention of involving human subjects.
46. 120
Evaluation and disposition of
applications and proposals.
46.121
Investsgaitonal new drug or device
30-day delay requirement.
*6 122
Use of federal funds.
46.123
Early termination of research
funding; evaluation of subsequent
applications and proposals.
124
Conditions.
Suhpart B—Additional Protections
Pertaining to Research,
Development, and Related
Activities Involving Fetuses,
Pregnant Women, and Human
In Vitro Fertilization
Sec
46.201
Applicability.
46 202
Purpose
46.203
Definitions.
46. 204
Ethical Advisory Boards.
46 205
Additional duties of the Institutional
Review Board! in connection with
activities involving fetuses, pregnant
women, or human in vitro fertiliration.
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 ea
utero, including nonviable fetuses, as
subjects.
46.210
Activities involving the dead fetus,
fetal material, or the placenta.
46.21
Modification or waiver of specific
requirements,
Subpart C—Additional Protections
Pertaining to Biomedical and
Behavioral Research Involving
Prisoners as Subjects
Sec.
46.301
Applicability.
46.302
Purpose.
46.303
Definitions.
46.304
Composition of Institutional Review
Boards where prisoners are involved.
4b. 305
Additional duties of the Institutional
Review Boards where prisoners are
involved.
46.306
Permitted activities involving
prisoners.
Subpart D— Additional Protections
for Children Involved as Subjects in
Research
Sec.
46.401
To what do these regulations apply?
46.402
Definitions.
46.403
IRB duties.
46.404
Research not involving greater than
minimal
risk,
46.405
Research involving greater than
minimal risk but presenting the prospect
of ditect 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 gcncralizoble knowledge about the
subject’# disorder or condition.
46.407
Research not otherwise approvaWe
which presents on opportunity to
understand, prevent, or alleviate s 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; sec
474(a), 88
Stat. 352 (42 U.S.C. 289/-3U)).
Subpart A— Basic HHS Policy for
Protection of Human Research
Subjects
Source; 46 FR 8386, January 26, 1981, 48 FR
9269. March 4, 1983.
5 46.101
To whit do these
regulations apply?
(a) Except as provided in
paragraph (b) of this section, this
subpart applies to all research
involving human subjects conducted
by the Department of Health and
Human Services or funded in whole
or in part by a Department grant,
contract, cooperative agreement or
fellowship.
(
1 ) This includes research
conducted by Department employees,
except each Principal Operating
Component head may adopt such
nonsubstantive, procedural
modifications as may be appropriate
from an administrative standpoint.
(2)
It also includes research
conducted or funded by the
Department of Health and Human
Services outside the United States,
but in appropriate circumstances, the
Secretary may, under paragraph (e) of
this section waive the applicability of
some or all of the requirements of
these regulations for research of this
type.
(b) Research activities in which the
only involvement of human subjects
will be in one or more of the
following^ategories are exempt from
these regulations unless the research
is covered by other subparts of this
part;
(
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),
if
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information taken from these sources
is recorded in such a manner that
subjects cannot be identified, directly
or through identifiers linked to the
subjects,
(3)
Research involving survey or
interview procedures, except where
all of the following conditions exist:
(i) responses are recorded in such a
manner that the human subjects can
be identified, directly or through
identifiers linked to the subjects,
(ii)
the subject’s responses,
if they
became known outside the research,
could reasonably place the subject at
risk of criminal or civil liability or be
damaging to the subject’s financial
standing or employability, and
(iii)
the research deals with sensitive
aspects of the subject's own behavior,
such as illegal conduct, drug use,
sexual behavior, or use of alcohol.
All research involving survey or
interview procedures
is exempt,
without exception, when the
respondents are elected or appointed
public officials or candidates for
public office.
(4) Research involving the
observation (including observation by
participants) of public behavior,
except where
all of the following
conditions exist:
(i) observations
arc-
recorded
in such a manner that the
human subjects can be identified,
directly or through identifiers linked
to the subjects,
(ii) the observations
recorded about the individual,
if they
became known outside the research,
could reasonably place the subject
at
risk of criminal or civil
liability or be
damaging
to the subject's financial
standing or employability, and
(iii)
the research deals with sensitive
aspects of the subject's own behavior
such as illegal conduct, drug use.
sexual behavior, or use of alcohol,
(5) 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.
(6)
Unless specifically required by
statute (and except to the extent
specified in paragraph (i)>, research
and demonstration projects which
are conducted by or subject to the
approval of the Depar tment of
Health and Human Services, and
which are designed to study,
evaluate, or otherwise examine: (i)
programs under the Social Security
Act, or other 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.
<c) The Secretary has final
authority to determine whether
a
particular activity
is covered by these
regulations.
(d) The Secretary may require that
specific research activities or classes
of research activities conducted or
funded by the Department, hut not
otherwise covered by these
regulations, comply with some or all
of these regulations.
(e) The Secretary may also waive
applicability of these regulations to
specific research activities or classes
of research activities, otherwise
covered by these regulations. Notices
of these actions will be published
in
the Federal Register as they occur.
(f) No individual may receive
Department funding for research
covered by these regulations unless
the individual
is affiliated with or
sponsored by an institution which
assumes responsibility for the
research under an assurance Satisfying
the requirements of this part, or the
individual makes other arrangements
with the Department,
(g) Compliance with these
regulations
will
in no way render
inapplicable pertinent federal,
state,
or locai laws or regulations.
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(h) Each subpan of these
regulations contains a separate
section describing to what the subpart
applies. Research which
is covered
by more than one subpart shall
comply with
ail applicable subparts.
(i) If, following review of
proposed research activities that are
exempt from these regulations under
paragraph (b)(6), the Secretary
determines that a research or
demonstration project presents a
danger to the physical, mental, or
emotional well-being of a participant
or subject of the research or
demonstration project, then federal
funds may not be expended for such
a project without the written,
informed consent of each participant
or subject.
S 46.102
Definitions.
(a)
“Secretary” means the
Secretary of Health arid Human
Services and any other officer or
employee of (he Department of
Health and Human Services to whom
authority has been delegated.
( b> "Department” or "HHS”
means the Department of Health and
Human Services.
{ e ). *i fmttu riot)
’
* jrnesms
ppgl ic
or private entify^6'fTgeicy
1; (irtc!umng
federal, state, and other agencies).
(d)
‘‘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
(e> “Research’* means a
systematic investigation designed to
develop or contribute to generalizable
knowledge. Activities which meet
this definition constitute ‘‘research"
for purposes of these regulations,
whether or not they are supported or
funded under a program which
is
considered research for other
purposes. For example, some
“demonstration” and “service”
programs may include research
activities.
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(0 “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
(r 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) '“Minimal risk
means that the
risks -of harm anticipated in the
-
proposed research are not greater,
considering probability and
magnitude, than those ordinarily
encountered in daily life or during the
performance of routine physical or
psychological examinations or tests.
<h) “Certification?’ means the
official notification by the institution
to the Department in accordance with
the requirements of this pan that a
research project or activity involving
human subjects has been reviewed
and approved by dic^nftilu tioaal
.Reyiew JJoartl ft$8) in accordance
with the approved assurance on
f ile at
MKS.' (Certification
is required when
the research
is funded by the
Department and not otherwise exempt
in accordance with
§ 46.101(b)).
9 46.103
Assurances.
(a) Bach institution engaged in
research covered by these regulations
shall provide written assurance
satisfactory to the Secretary that
it
will comply with the requirements set
forth
in these regulations.
(b) The Department will conduct or
fund research covered by these
regulations only
if the institution has
an assurance approved as provided in
this section, and only
if the institution
has certified to the Secretary that the
research has been reviewed and
approved by an 1RB provided for in
the assurance, and will he subject to
continuing review by the 1RB. This
assurance 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 source of funding. 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 these regulations
applicable to Department-funded
research and
is not applicable to any
research
in an exempt category
listed
in
§ 46, 101
(2) Designation of one or more
IRBs established in accordance with
the requirements of this subpart, 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 ‘he IRB members
identified by name: earned degrees;
representative capacity; indications of
experience such as board
certifications, licenses, etc.,
sufficient So 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
Secretary.
(4)
Written procedures which the
IRB will follow (i) for conducting
its
initial and continuing review of
research ami 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;
(iii) for insuring prompt
reporting to the IRB of proposed
changes in a research activity, and for
insuring that changes in approved
research, during the period for which
IRB approval has already been given,
may not be initiated without IRB
review and approval except where
necessary to eliminate apparent
immediate hazards to the subject: and
(iv) for insuring prompt reporting to
the IRB and to the Secretary
! of
unanticipated problems involving
risks to subjects or others.
(c) The assuiance shall be executed
by an individual authorized to act for
the institution and to assume on
behalf of the institution the
obligations imposed by these
regulations, and shall be filed in such
form and manner as the Secretary
may prescribe.
(d) The Secretary will evaluate ail
assurances submitted in accordance
with these regulations through such
officers and employees of the
Department and such experts or
consultants engaged for this purpose
as the Secretary determines to be
appropriate. The Secretary's
evaluation, will take into
consideration the adequacy of the
proposed IRB
in light of the
anticipated scope of the institution’s
researefi activities and the types of
subject populations likely to be
1 Repons should be filed with the Office
for Protection from Research Risks, National
Institutes of Health, Department of Health
ami Human Services, Bcthesda, Maryland
20105
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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 Secretary may approve or
disapprove the assurance, or enter
into negotiations to develop an
approvable one. The Secretary 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) Within 60 days after the date of
submission to HHS of an application
or proposal, an institution with an
approved assurance covering the
proposed research shall certify that
the application or proposal has been
reviewed and approved by the 1RB.
Other institutions shall certify that the
application or proposal has been
approved by the IRB within 30 days
afier receipt of a request for such a
certification from the Department.
If
the certification
is not submitted
within these time limits, the
application or proposal may be
returned to the institution.
§ 46.104
[Reserved]
4 46.105
[Reserved]
§ 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, sad the diversity of the
members’ backgrounds including
consideration of the racial and
cultural backgrounds of members 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,
including but not limited to subjects
covered by other subparts of this part,
the IRES shall include one or more
individuals who are primarily
concerned with the welfare of these
subjects.
(b) No IRB may consist entirely of
men or entirely of women, or entirely
of members of one profession.
(c) bach IRB shall include at least
one member whose primary concerns
are in nonscientific areas; for
example; lawyers, cthicists, members
of the clergy.
(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
participating 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
complex issues which require
expertise beyond or in addition to that
available on the IRB. These
individuals may not vote with the
IRB.
§ 46,108
IMIS functions and
operations.
In order to fulfill the requirements
ot these regulations each IRB
shall;
(a) Follow written procedures as
provided in
§ 46. 103(b)(4).
(b) Except when an expedited
review procedure is used (see
§ 46.
1 10), 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 ai the
meeting.
(c) Be responsible for reporting to
the appropriate institutional officials
and the Secretary
1 any serious or
continuing noncompliance by
investigators with the requirements
and determinations of the IRB.
8 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 these regulations.
<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
1 Reports should he Died with the Office
for Protection from Research Sisks. National
Institutes of Health, Department of Health
and Human Services, Bethesda, Maryland
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