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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
PART 46-PROTECTION OF HUMAN SUBJECTS
REVISED AS OF MARCH 8, 1983
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45 CFR 46
PART 46-PROTECTION OF
HUMAN
SUBJECTS
Subpart A-Basic HHS Policy for
Protection of Human Research
Subjects
See.
46.101
To what do these regulations apply?
46.102
Definitions.
46.103
Assurances.
46.104
Section reserved.
46.105
Section reserved.
46.106
Section 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.
40.113 Suspension or termination of IRB
approval of research.
$6.114 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.
46.121 Investigational new drug or device
30-day delay requirement.
46.122 Use of federal funds.
40.123 Early termination of research
funding: evaluation of subsequent
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
Sec.
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 towerd 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
Sec.
46.301
Applicability.
46.302
Purpose.
46.303 Definitiona.
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 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 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; sec 474(a), 88
Stat. 352 (42 U.S.C. 289/-3(a)).
Subpart A -Basic HHS Policy for
Protection of Human Research
Subjects
#
Source: 46 FR 8386, January 26, 1981, 48 FR
9269, March 4, 1983.
§ 46.101 To what 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 categories 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
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.
risk of criminal or civil liability or be . obtaining benefits or services under
(4) Research involving the
observation (including observation by
participants) of public behavior.
except where all of the following
conditions exist: (i) observations are
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 Department 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
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, but 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 local laws or regulations.
(h) Each subpart 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 all 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.
§ 46.102 Definitions.
(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) "Department" or "HHS"
means the Department of Health and
Human Services.
(c) "Institution" means any public
or private entity of agency (including
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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(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) "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 part that a
research project or activity involving
human subjects has been reviewed
and approved by the Institutional
Review Board (IRB) in accordance
with the approved assurance on file at
HHS. (Certification is required when
the research is funded by the
Department and not otherwise exempt
in accordance with § 46.101(b)).
§ 46.103 Assurances.
(a) Each 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 IRB provided for in
the assurance, and will be subject to
continuing review by the IRB. 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 the 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
Secretary. 1
(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; (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 1 of
unanticipated problems involving
risks to subjects or others.
(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 these
regulations, and shall be filed in such
form and manner as the Secretary
may prescribe.
(d) The Secretary will evaluate all
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
research activities and the types of
subject populations likely to be
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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.
(c) 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 IRB.
Other institutions shall certity that the
application or proposal has been
approved by the IRB within 30 days
after 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]
§ 46.105 [Reserved]
$ 46.106 [Reserved)
§ 46.107 IRB membership.
(a) Each IRB shall have at least
five members, with varying
backgrounds to promete 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' 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 IRB 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) Each IRB shall include at least
one member whose primary concerns
are in nonscientific areas; for
example: lawyers, ethicists, 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 IRB functions and
operations.
In order to fulfill the requirements
of 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
§ 46.110), 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 concems 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.
(c) Be responsible for reporting to
the appropriate institutional officials
and the Secretary ' any serious or
continuing noncompliance by
investigators with the requirements
and determinations of the IRB.
§ 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 shail 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
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Institutes of Health, Department of Health
and Human Services, Bethesda, Maryland
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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 these regulations 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.
§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 has established,
and published 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, through periodic
republication in the Federal
Register.
(b) An IRB may review some or all
of the research appearing on the list
through an expedited review
procedure, if the research involves no
more than minimal risk. The IRB may
also use the expedited review
procedure to review minor changes in
previously approved research during
the period 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 Secretary may restrict,
suspend, or terminate an institution's
or IRB's use of the expedited review
procedure when necessary to protect
the rights or welfare of subjects.
§46.111 Criteria for IRB
approval of research.
(a) In order to approve research
covered by these regulations 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 long-range effects
of applying knowledge gained in the
rescarch (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.
(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) Where appropriate, the research
plan makes adequate provision for
monitoring the data collected to
insure the safety of subjects.
(7) Where appropriate, there are
adequate provisions to protect the
privacy of subjects and to maintain
the confidentiality of data.
(b) Where some or all of the
subjects are likely to be vulnerable to
coercion or undue influence, such as
persons with acute or severe physical
or mental illness, or persons who are
economically or educationally
disadvantaged. appropriate 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 these
regulations 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.
§ 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 Secretary. 1
' Reports should be filed with the Office
for Protection from Research Risks, National
Institutes of Health, Department of Health
and Human Services, Bethesda, Maryland
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§ 46.114 Cooperative research.
Cooperative research projects are
those projects, normally supported
through grants, contracts, or similar
arrangements, which involve
institutions in addition to the grantee
or prime contractor (such as a
contractor with the grantee, or a
subcontractor with the prime
contractor). In such instances, the
grantee or prime contractor remains
responsible to the Department for
safeguarding the rights and welfare of
human subjects. Also, when
cooperating institutions conduct some
or all of the research involving some
or all of these subjects. each
cooperating institution shall comply
with these regulations as though it
received funds for its participation in
the project directly from the
Department, except that in complying
with these regulations institutions
may use joint review, reliance upon
the review of another qualified IRB,
or similar arrangements aimed at
avoidance of duplication of effort.
§ 46.115 IRB records."
(a) An institution, or where
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 as
required by § 46.103(b)(3).
(6) Written procedures for the IRB
as required by § 46.103(b)(4).
(7) Statements of significant new
findings provided to subjects, as
required by § 46.116(b)(5).
(b) The records required by this
regulation shall be retained for at
least 3 years after completion of the
research, and the records shall be
accessible for inspection and copying
by authorized representatives of the
Department at reasonable times and
in a reasonable manner.
§ 46.116 General requirements
for informed consent.
Except as provided elsewhere in
this or other subparts, no investigator
may involve a human being as a
subject in research covered by these
regulations 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 unduc
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 subjectr.
? (1) A statement that the study
involves research, an explanation of
the 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:
1 (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 ID A
. 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:
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'(1) A statement that the particular
" treatment or procedure may involve
risks to the subject (or to the embryo
For fetus, if the subject is or may
Èbecome pregnant) which are currently
unforeseeable:
#: (2) Anticipated circumstances
å under which the subject's
« participation may be terminated by
¡. she 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
ythe research and procedures for
gorderly 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 3.consent
procedure which does not include; or
which ahera,;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) 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; and
(2) The research could not
practicably be carried out without the
waiver or alteration.
(d) An IRB may approve & consent
procedure which does not include, or
....
which alters, some or all of the
elements of informed consent set
forth above, 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 these regulations are
not intended 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 these regulations 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.
§ 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 "'shon 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 po
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 where the documentation
requirement is waived, the IRB may
require the investigator to provide
subjects with a written statement
regarding the research.
§ 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 the
Department with the knowledge that
subjects may be involved within the
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period of funding, but definite plans
would not normally be set forth in the
application or proposal. These
include activities such as institutional
type grants (including bloc grants)
where selection of specific projects is
the institution's responsibility:
research training grants where 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
described in § 46.10!(b), 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 these regulations, and certification
submitted to the Department.
§ 46.119 Research undertaken
without the intention of involving
human subjects.
In the event research (conducted or
funded by the Department) is
undertaken without the intention of
involving human subjects, but it is
later proposed to use human subjects
in the research, the research shall first
be reviewed and approved by an IRB,
as provided in these regulations, a
certification submitted to the
Department, and final approval given
to the proposed change by the
Department.
§ 46.120 Evaluation and
disposition of applications and
proposals.
(a) The Secretary will evaluate all
applications and proposals involving
human subjects submitted to the
Department through such officers and
employees of the Department and
such experts and consultants as the
Secretary 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 proposed research to
the subjects and others, and the
importance of the knowledge to be
gained.
(b) On the basis of this evaluation,
the Secretary may approve or
disapprove the application or
proposal, or enter into negotiations to
develop an approvable one.
§ 46.121 Investigational new drug
or device 30-day delay requirement.
When an institution is required to
prepare or to submit a certification
with an application or proposal under
these regulations, and the application
or proposal involves an
investigational new drug (within the
meaning of 21 U.S.C. 355(i) or
357(d)) or a significant risk device (as
defined in 21 CFR 812.3(m)), the
institution shall identify the drug or
device in the certification. The
institution shall also state whether the
30-day interval required for
investigational new drugs by 21 CFR
312. 1(a) and for significant risk
devices by 21 CFR 812.30 has
elapsed, or whether the Food and
Drug Administration has waived that
requirement. If the 30-day interval
has expired, the institution shall state
whether the Food and Drug
Administration has requested that the
sponsor continue to withhold or
restrict the use of the drug or device
in human subjects. If the 30-day
interval has not expired, and a waiver
has not been received. the institution
shall send a statement to the
Department upon expiration of the
interval. The Department will not
consider a certification acceptable
until the institution has submitted a
statement that the 30-day interval has
elapsed, and the Food and Drug
Administration has not requested it to
limit the use of the drug or device, or
that the Food and Drug
Administration has waived the 30-day
interval.
§ 46,122 Use of Federal funds.
Federal funds administered by the
Department may not be expended for
research involving human subjects
unless the requirement of these
regulations, including all subparts of
these regulations, have been satisfied.
§ 46.123 Early termination of
research funding; evaluation of
subsequent applications and
proposals.
(a) The Secretary may require that
Department funding for any project
be terminated or suspended in the
manner prescribed in applicable
program requirements, when the
Secretary finds an institution has
materially failed to comply with the
terms of these regulations.
(b) In making decisions about
funding applications or proposals
covered by these regulations the
Secretary 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 paragraph (a) of this
section and whether the applicant or
the person who would direct the
scientific and technical aspects of an
activity has in the judgment of the
Secretary materially failed to
discharge responsibility for the
protection of the rights and welfare of
human subjects (whether or not
Department funds were involved).
$ 46.124 Conditions.
With respect to any research
project or any class of research
projects the Secretary may impose
additional conditions prior to or at the
time of funding when in the
Secretary's judgment 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 11528, Aug. 8. 1975. 43 FR
1758, January 11. 1978. 43 FR
51559, November 3. 1978
$ 46.201 Applicability.
(a) The regulations in this subpart
are applicable to all Department of
Health. Education, and Welfare
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grants and contract supporting
research, development, and related
activities involving: (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, Education, and
Welfare and any other officer or
employee of the Department of
Health, Education, and Welfare 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 explusion or extraction of
the fetus, that it is viable.
(d) "Viable" as it pertains to the
Ictus 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.
§ 46.204 Ethical Advisory
Boards. 1
(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,
Education, and Welfare.
(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 Board and the
Board has rendered advice as to its
acceptability from an ethical
standpoint.
(d) No application or proposal
involving human in vitro fertilization
may be funded by the Department or
any component thereof until the
application or proposal has been
reviewed by the Ethical Advisory
Board and the Board has rendered
advice as to its acceptability from an
ethical standpoint.
§ 46.205 Additional duties of the
Institutionel 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
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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.
§ 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 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
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not reasonably available, or (3) the
pregnancy resulted from rape.
.
§ 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 modification or waiver.
Any such modifications or waivers
will be published as notices in the
FEDERAL REGISTER
Subpart C-Additional Protections
Pertaining to Biomedical and
Behavioral Research Involving
Prisoners as Subjects :
Source: 43 FR 53655. Nov 16. 1978
§ 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, Education, and Welfare
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, Education, and
Welfare and any other officer or
employee of the Department of
Health, Education, and Welfare to
whom authority has been delegated.
(b) "DHEW" means the
Department of Health, Education,
and Welfare.
(c) "Prisoner" means any
ladividual involuntarily confined of
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
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.
§ 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 bis 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
nonprisoner volunteers;
(4) Procedures for the selection of
subjects within the prison are fair to
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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 subjecta 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
paroiç boards will nos jaka 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 rescarch
involving prisoners ..
(a) Biomedical or behavioral
research conducted or supported by
DHEW 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:
(A) 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:
(B) 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;
(C) 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;
of
(D) Research un 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 DHEW
shall not involve prisoners as
subjects.
Subpart D-Additional Protection
for Chlidres Involved as Subjects la
Research.
Source: 48 FR 9818, March 8, 1983
§ 46.401 To what do these
regulations apply?
(B) 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
nonsubstantive, 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 (1), (2), (5) and (6)
as listed in Subpart A at §46.101(b)
are applicable to this subpart.
Exemption (4), research involving
the observation of public behavior,
listed at § 46.101(b), is applicable to
this subpart where the investigator(s)
does not participate in the activities
being observed. Exemption (3),
research involving survey or
interview procedures, listed at
§ 46.101(b) does not apply to research
covered by this subpart.
(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.
§ 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:
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(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
§ 46.406.
#46.405 Research involving greater
thas micheal 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 for the
individual subject, or by a
monitoring procedure that is likely to § 46.407 Research not otherwise
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.
8 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 IRD 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 subjecta'
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.
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
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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 IRD 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 IRE shall determine, in
accordance with and to the extent
that consent is required by's 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 IRD 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.
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45 CFR 46
NOTICES
HUMAN SUBJECTS
Minimum Criteria Identifying the
Viable Fetus
On March 13, 1975. regulations
were published in the FEDERAL
REGISTER (40 FR 11854) relating to the
protection of human subjects in
research, development, and related
activities supported by Department of
Health, Education, and Welfare
grants and contracts. These
regulations are codified at 45 CFR
Part 46.
Elsewhere in this issue of the
FEDERAL REGISTER, the Secretary
is amending 45 CFR Part 46 by,
among other things, adding a new
Subpart B to provide additional
protections pertaining to research.
development, and related activities
involving fetuses, pregnant women,
and in vitro fertilization.
Section 46.203(d) of Subpart B
provides inter alia as follows:
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.
This notice is published in
accordance with $ 46.203(d). For
purposes of Subpart B, the guidelines
indicating that a fetus other than a
dead fetus within the meaning of
§ 46.203(f) is viable include the
following:
an estimated gestational age of 20 weeks of
more and a body weight of 500 grams or
more.
FEDERAL REGISTER, VOL 40,
AUGUST 8, 1975
U.S. GOVERNMENT PRINTING OFFICE : 1983 0 - 406-756
.
4
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PROCEDURE 13.
EXPERIMENTATION ON HUMAN SUBJECTS FOR
INTELLIGENCE PURPOSES
A.
APPLICABILITY
This procedure applies to experimentation on human sub-
jects if such experimentation is conducted by or on behalf of
a DoD intelligence component. This procedure does not apply
to experimentation on animal subjects.
B.
EXPLANATION OF UNDEFINED TERMS
1.
Experimentation in this context means any research or
testing activity involving human subjects that may expose such
subjects to the possibility of permanent or temporary injury
(including physical or psychological damage and damage to the
reputation of such persons) beyond the risks of injury to
which such subjects are ordinarily exposed in their daily
lives.
---
2.
Experimentation is conducted on behalf of a DoD
intelligence component if it is conducted under contract to
that component or to another DoD component for the benefit of
the intelligence component or at the request of such a com-
ponent regardless of the existence of a contractual rela-
tionship.
12-1
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3.
Human subjects in this context includes any person
----
whether or not such person is a United States person.
4
c.
PROCEDURES
1 .
Experimentation on human subjects conducted by or on
behalf of a DoD intelligence component may be undertaken only
with the informed consent of the subject, and in accordance
with guidelines issued by the Department of Health and Human
Services, setting out conditions that safeguard the welfare of
such subjects.
2. DoD intelligence components may not engage in or
contract for experimentation on human subjects without appro-
val of the Secretary or Deputy Secretary of Defense, or the
Secretary or Under Secretary of a Military Department, as
appropriate. [Requests for such approval submitted by Army
.
Intelligence components will be addressed through command
channels to HQDA (DAMI-CIC) , WASH DC 20310. ]
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