PART 50—PROTECTION OF HUMAN

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SUBJECTS

AUTHORITY: 21 U.S.C. 321, 346, 346a, 348, 352,
353, 355, 360, 360c–360f, 360h–360j, 371, 379e, 381;
42 U.S.C. 216, 241, 262, 263b–263n.
SOURCE: 45 FR 36390, May 30, 1980, unless
otherwise noted.

Subpart A—General Provisions

§ 50.1 Scope.

(a) This part applies to all clinical investigations
regulated by the Food and
Drug Administration under sections
505(i) and 520(g) of the Federal Food,
Drug Drug, and Cosmetic Act, as well as
clinical as clinical investigations that support applications
for research or marketing
permits marketing permits for products regulated by the
Food and Drug Administration, including
food and color additives, drugs for
human use, medical devices for human
use, biological products for human use,
and electronic products. Additional
specific obligations and commitments
of, and standards of conduct for, persons
who sponsor or monitor clinical
investigations involving particular test
articles may also be found in other
parts (e.g., parts 312 and 812). Compliance
with these parts is intended to
protect the rights and safety of subjects
involved in investigations filed
with the Food and Drug Administration
pursuant to sections 406, 409, 502,
503, 505, 510, 513–516, 518–520, 721, and 801
of 801 of the Federal Food, Drug, and Cosmetic
Act Cosmetic Act and sections 351 and 354–360F
of the Public Health Service Act.

(b) References in this part to regulatory
sections of the Code of Federal
Regulations are to chapter I of title 21,
unless otherwise noted.

[45 FR 36390, May 30, 1980; 46 FR 8979, Jan. 27,
1981, as amended at 63 FR 26697, May 13, 1998;
64 FR 399, Jan. 5, 1999]

§ 50.3 Definitions.

As used in this part:

(a) Act means the Federal Food,
Drug, and Cosmetic Act, as amended
(secs. 201—902, 52 Stat. 1040 et seq. as
amended (21 U.S.C. 321—392)).

(b) Application for research or marketing
permit includes:

(1) A color additive petition, described
in part 71.

(2) A food additive petition, described
in parts 171 and 571.

(3) Data and information about a substance
submitted as part of the procedures
for establishing that the substance
is generally recognized as safe
for use that results or may reasonably
be expected to result, directly or indirectly,
in its becoming a component or
otherwise affecting the characteristics
of any food, described in §§ 170.30 and
570.30.

(4) Data and information about a food
additive submitted as part of the procedures
for food additives permitted to be
used on an interim basis pending additional
study, described in § 180.1.

(5) Data and information about a substance
submitted as part of the procedures
for establishing a tolerance for
unavoidable contaminants in food and
food-packaging materials, described in
section 406 of the act.

(6) An investigational new drug application,
described in part 312 of this
chapter.

(7) A new drug application, described
in part 314.

(8) Data and information about the
bioavailability or bioequivalence of
drugs for human use submitted as part
of the procedures for issuing, amending,
or repealing a bioequivalence requirement,
described in part 320.

(9) Data and information about an
over-the-counter drug for human use
submitted as part of the procedures for
classifying these drugs as generally
recognized as safe and effective and not
misbranded, described in part 330.

(10) Data and information about a
prescription drug for human use submitted
as part of the procedures for
classifying these drugs as generally
recognized as safe and effective and not
misbranded, described in this chapter.

(11) [Reserved]

(12) An application for a biologics license,
described in part 601 of this
chapter.

(13) Data and information about a biological
product submitted as part of
the procedures for determining that licensed
biological products are safe and
effective and not misbranded, described
in part 601.

(14) Data and information about an in
vitro diagnostic product submitted as
part of the procedures for establishing,
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§ 50.3 21 CFR Ch. I (4–1–01 Edition)
part of the procedures for establishing, amending, or repealing a standard for
these products, described in part 809.

(15) An Application for an Investigational
Device Exemption, described in
part 812.

(16) Data and information about a
medical device submitted as part of the
procedures for classifying these devices,
described in section 513.

(17) Data and information about a
medical device submitted as part of the
procedures for establishing, amending,
or repealing a standard for these devices,
described in section 514.

(18) An application for premarket pre-market approval
of a medical device, described in
section 515.

(19) A product development protocol
for a medical device, described in section
515.

(20) Data and information about an
electronic product submitted as part of
the procedures for establishing, amending,
or repealing a standard for these
products, described in section 358 of the
Public Health Service Act.

(21) Data and information about an
electronic product submitted as part of
the procedures for obtaining a variance
from any electronic product performance
standard, as described in § 1010.4.

(22) Data and information about an
electronic product submitted as part of
the procedures for granting, amending,
or extending an exemption from a radiation
safety performance standard, as
described in § 1010.5.

(c) Clinical investigation means any
experiment that involves a test article
and one or more human subjects and
that either is subject to requirements
for prior submission to the Food and
Drug Administration under section
505(i) or 520(g) of the act, or is not subject
to subject to requirements for prior submission
to the Food and Drug Administration
under these sections of the act,
but the results of which are intended to
be submitted later to, or held for inspection
by, the Food and Drug Administration
as part of an application for a
research or marketing permit. The
term does not include experiments that
are subject to the provisions of part 58
of this chapter, regarding nonclinical
laboratory studies.

(d) Investigator means an individual
who actually conducts a clinical investigation,
i.e., under whose immediate
direction the test article is administered
or administered or dispensed to, or used involving,
a subject, or, in the event of an investigation
conducted by a team of individuals,
is the responsible leader of
that team.

(e) Sponsor means a person who initiates
a clinical investigation, but who
does not actually conduct the investigation,
i.e., the test article is administered
or dispensed to or used involving,
a subject under the immediate direction
of another individual. A person
other than an individual (e.g., corporation
or agency) that uses one or more
of its own employees to conduct a clinical
investigation it has initiated is
considered to be a sponsor (not a sponsor-
investigator), and the employees
are considered to be investigators.

(f) Sponsor-investigator means an individual
who both initiates and actually
conducts, alone or with others, a clinical
investigation, i.e., under whose immediate
direction the test article is administered
or dispensed to, or used involving,
a subject. The term does not
include any person other than an individual,
e.g., corporation or agency.

(g) Human subject means an individual
who is or becomes a participant
in research, either as a recipient of the
test article or as a control. A subject
may be either a healthy human or a patient.

(h) Institution means any public or
private entity or agency (including
Federal, State, and other agencies).
The word facility as used in section
520(g) of the act is deemed to be synonymous
with the term institution for
purposes of this part.

(i) Institutional review board (IRB)
means any board, committee, or other
group formally designated by an institution
to review biomedical research
involving humans as subjects, to approve
the initiation of and conduct
periodic review of such research. The
term has the same meaning as the
phrase institutional review committee as
used in section 520(g) of the act.

(j) Test article means any drug (including
a biological product for human
use), medical device for human use,
human food additive, color additive,
electronic product, or any other article
subject to regulation under the act or
under sections 351 and 354–360F of the
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Food and Drug Administration, HHS § 50.23
act or under sections 351 and 354–360F of the Public Health Service Act (42 U.S.C. 262
and 263b–263n).

(k) Minimal risk means that the probability
and magnitude of harm or discomfort
anticipated in the research are
not greater in and of themselves than
those ordinarily encountered in daily
life or during the performance of routine
physical or psychological examinations
or tests.

(l) 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
particpation in the procedure(s) involved
in the research.

(m) Family member means any one of
the following legally competent persons:
Spouse; parents; children (including
adopted children); brothers, sisters,
and spouses of brothers and sisters; and
any individual related by blood or affinity
whose close association with the
subject is the equivalent of a family relationship.

[45 FR 36390, May 30, 1980, as amended at 46
FR 8950, Jan. 27, 1981; 54 FR 9038, Mar. 3, 1989;
56 FR 28028, June 18, 1991; 61 FR 51528, Oct. 2,
1996; 62 FR 39440, July 23, 1997; 64 FR 399, Jan.
5, 1999; 64 FR 56448, Oct. 20, 1999]

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(ix) Medical records of members involved in the military operation will accurately document the receipt by members of the notification required by paragraph (d)(1)(viii) of this section.

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(x) Medical records of members involved in the military operation will accurately document the receipt by members of any investigational new drugs in accordance with FDA regulations including part 312 of this chapter.

(xi) DOD will provide adequate followup to assess whether there are beneficial or adverse health consequences that result from the use of the investigational product.

(xii) DOD is pursuing drug development, including a time line, and marketing approval with due diligence.

(xiii) FDA has concluded that the investigational new drug protocol may proceed subject to a decision by the President on the informed consent waiver request.

(xiv) DOD will provide training to the appropriate medical personnel and potential recipients on the specific investigational new drug to be administered prior to its use.

(xv) DOD has stated and justified the time period for which the waiver is needed, not to exceed one year, unless separately renewed under these standards and criteria.

(xvi) DOD shall have a continuing obligation to report to the FDA and to the President any changed circumstances relating to these standards and criteria (including the time period referred to in paragraph (d)(1)(xv) of this section) or that otherwise might affect the determination to use an investigational new drug without informed consent.

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The information required by § 56.115(a)(2) of this chapter is to be provided to the Secretary of Defense for further review.

(3) The duly constituted institutional review board, described in paragraph (d)(1)(v) of this section, must review and approve:

(i) The required information sheet;

(ii) The adequacy of the plan to disseminate information, including distribution of the information sheet to potential recipients, on the investigational product (e.g., in forms other than written);

(iii) The adequacy of the information and plans for its dissemination to health care providers, including potential side effects, contraindications, potential interactions, and other pertinent considerations; and

(iv) An informed consent form as required by part 50 of this chapter, in those circumstances in which DOD determines that informed consent may be obtained from some or all personnel involved.

(4) DOD is to submit to FDA summaries of institutional review board meetings at which the proposed protocol has been reviewed.

(5) Nothing in these criteria or standards is intended to preempt or limit FDA’s and DOD’s authority or obligations under applicable statutes and regulations.

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(a) The IRB responsible for the review,
approval, and continuing review
of the clinical investigation described
in this section may approve that investigation
without requiring that informed
consent of all research subjects
be obtained if the IRB (with the concurrence
of a licensed physician who is
a member of or consultant to the IRB
and who is not otherwise participating
in the clinical investigation) finds and
documents each of the following:

(1) The human subjects are in a lifethreatening
life-threatening situation, available treatments
are unproven or unsatisfactory,
and the collection of valid scientific
evidence, which may include evidence
obtained through randomized placebocontrolled
placebo-controlled investigations, is necessary
to necessary to determine the safety and effectiveness
of particular interventions.

(2) Obtaining informed consent is not
feasible because:

(i) The subjects will not be able to
give their informed consent as a result
of their medical condition;

(ii) The intervention under investigation
must be administered before consent
from the subjects’ legally authorized
representatives is feasible; and

(iii) There is no reasonable way to
identify prospectively the individuals
likely to become eligible for participation
in the clinical investigation.

(3) Participation in the research
holds out the prospect of direct benefit
to the subjects because:

(i) Subjects are facing a life-threatening
situation that necessitates intervention;

(ii) Appropriate animal and other
preclinical studies have been conducted,
and the information derived
from those studies and related evidence
support the potential for the intervention
to provide a direct benefit to the
individual subjects; and

(iii) Risks associated with the investigation
are reasonable in relation to
what is known about the medical condition
of the potential class of subjects,
the risks and benefits of standard therapy,
if any, and what is known about
the risks and benefits of the proposed
intervention or activity.

(4) The clinical investigation could
not practicably be carried out without
the waiver.

(5) The proposed investigational plan
defines the length of the potential
therapeutic window based on scientific
evidence, and the investigator has committed
to attempting to contact a legally
authorized representative for
each subject within that window of
time and, if feasible, to asking the legally
authorized representative contacted
for consent within that window
rather than proceeding without consent.

The investigator will summarize
efforts made to contact legally authorized
representatives and make this information
available to the IRB at the
time of continuing review.

(6) The IRB has reviewed and approved
informed consent procedures
and an informed consent document
consistent with § 50.25. These procedures
and the informed consent document
are to be used with subjects or
their legally authorized representatives
in situations where use of such
procedures and documents is feasible.

The IRB has reviewed and approved
procedures and information to be used
when providing an opportunity for a
family member to object to a subject’s
participation in the clinical investigation
consistent with paragraph (a)(7)(v)
of this section.

(7) Additional protections of the
rights and welfare of the subjects will
be provided, including, at least:

(i) Consultation (including, where appropriate,
consultation carried out by
the IRB) with representatives of the
communities in which the clinical investigation
will be conducted and from
which the subjects will be drawn;
(ii) Public disclosure to the communities
in which the clinical investigation
will be conducted and from which
the subjects will be drawn, prior to initiation
of the clinical investigation, of
plans for the investigation and its risks
and expected benefits;

(iii) Public disclosure of sufficient information
following completion of the
clinical investigation to apprise the
community and researchers of the
study, including the demographic characteristics
of the research population,
and its results;

(iv) Establishment of an independent
data monitoring committee to exercise
oversight of the clinical investigation;
and

(v) If obtaining informed consent is
not feasible and a legally authorized
representative is not reasonably available,
the investigator has committed,
if feasible, to attempting to contact
within the therapeutic window the subject’s
family member who is not a legally
authorized representative, and
asking whether he or she objects to the
subject’s participation in the clinical
investigation. The investigator will
summarize efforts made to contact
family members and make this information
available to the IRB at the
time of continuing review.

(b) The IRB is responsible for ensuring
that procedures are in place to inform,
at the earliest feasible opportunity,
each subject, or if the subject
remains incapacitated, a legally authorized
representative of the subject,
or if such a representative is not reasonably
available, a family member, of
the of the subject’s inclusion in the clinical
investigation, the details of the investigation
and other information contained
in the informed consent document.

The IRB shall also ensure that
there is a procedure to inform the subject,
or if the subject remains incapacitated,
a legally authorized representative
of the subject, or if such a representative
is not reasonably available,
a family member, that he or she may
discontinue the subject’s participation
at any time without penalty or loss of
benefits to which the subject is otherwise
entitled. If a legally authorized
representative or family member is
told about the clinical investigation
and the subject’s condition improves,
the  the subject is also to be informed as
soon as feasible. If a subject is entered
into a clinical investigation with
waived consent and the subject dies before
a legally authorized representative
or family member can be contacted, information
about the clinical investigation
is to be provided to the subject’s
legally authorized representative or
family member, if feasible.

(c) The IRB determinations required
by paragraph (a) of this section and the
documentation required by paragraph

(e) of this section are to be retained by
the IRB for at least 3 years after completion
of the clinical investigation,
and the records shall be accessible for
inspection and copying by FDA in accordance
with § 56.115(b) of this chapter.

(d) Protocols involving an exception
to the informed consent requirement
under this section must be performed
under a separate investigational new
drug application (IND) or investigational
device exemption (IDE) that
clearly identifies such protocols as protocols
that may include subjects who
are unable to consent. The submission
of those protocols in a separate IND/
IDE is required even if an IND for the
same drug product or an IDE for the
same device already exists. Applications
for investigations under this section
may not be submitted as amendments
under §§ 312.30 or 812.35 of this
chapter.

(e) If an IRB determines that it cannot
approve cannot approve a clinical investigation because
the because the investigation does not meet
the meet the criteria in the exception provided
under paragraph (a) of this section or
because of other relevant ethical concerns,
the IRB must document its findings
and provide these findings promptly
in writing to the clinical investigator
and investigator and to the sponsor of the clinical
investigation. The sponsor of the clinical
investigation clinical investigation must promptly disclose
this information to FDA and to
the sponsor’s clinical investigators who
are participating or are asked to participate
in this or a substantially
equivalent clinical investigation of the
sponsor, and to other IRB’s that have
been, or are, asked to review this or a
substantially equivalent investigation
by that sponsor.

[61 FR 51528, Oct. 2, 1996]

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(a) Basic elements of informed consent.
In seeking informed consent, the following
information shall be provided to
each subject:

(1) A statement that the study involves
research, an explanation of the
purposes of the research and the expected
duration of the subject’s participation,
a description of the procedures
to be followed, and identification of
any procedures which are experimental.

(2) A description of any reasonably
foreseeable risks or discomforts to the
subject.

(3) A description of any benefits to
the subject or to others which may reasonably
be expected from the research.

(4) A disclosure of appropriate alternative
procedures or courses of treatment,
if any, that might be advantageous
to the subject.

(5) A statement describing the extent,
if any, to which confidentiality of
records of records identifying the subject will be
maintained be maintained and that notes the possibility
that possibility that the Food and Drug Administration
may inspect the records.

(6) For research involving more than
minimal risk, an explanation as to
whether any compensation and an explanation
as to whether any medical
treatments are available if injury occurs
and, if so, what they consist of, or
where further information may be obtained.

(7) An explanation of whom to contact
for answers to pertinent questions
about the research and research subjects’
rights, and whom to contact in
the event of a research-related injury
to the subject.

(8) A statement that participation is
voluntary, that refusal to participate
will involve no penalty or loss of benefits
to which the subject is otherwise
entitled, and that the subject may discontinue
participation at any time
without penalty or loss of benefits to
which the subject is otherwise entitled.

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