LAWS RELATED TO THE PROTECTION OF HUMAN SUBJECTS
[Code of Federal Regulations]
[Title 21, Volume 1]
[Revised as of April 1, 2001]
From the U.S. Government Printing Office via GPO Access
TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES
PART 50--PROTECTION OF HUMAN SUBJECTS
50.20 General requirements for informed consent.
50.23 Exception from general requirements.
50.24 Exception from informed consent requirements for emergency
50.25 Elements of informed consent.
50.27 Documentation of informed consent.
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.
Sec. 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, and Cosmetic Act, as well as clinical investigations
that support applications for research or 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 the Federal Food, Drug, and
Cosmetic Act and sections 351 and 354-360F of the Public Health Service
(b) References in this part to regulatory sections of the Code of
Federal Regulations are to chapter I of title 21, unless otherwise
[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]
Sec. 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 Secs. 170.30 and
(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 Sec. 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
(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.
(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,
amending, or repealing a standard for these products, described in part
(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
(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 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 Sec. 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
(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
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
(d) Investigator means an individual who actually conducts a
clinical investigation, i.e., under whose immediate direction the test
article is 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
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]
Source: 46 FR 8951, Jan. 27, 1981, unless otherwise noted.
Sec. 50.20 General requirements for informed consent.
Except as provided in Secs. 50.23 and 50.24, 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 undue influence. The
information that is given to the subject or the representative shall be
in language understandable to the subject or the representative. No
informed consent, whether oral or written, may include any exculpatory
language through which the subject or the representative is made to
waive or appear to waive any of the subject's legal rights, or releases
or appears to release the investigator, the sponsor, the institution, or
its agents from liability for negligence.
[46 FR 8951, Jan. 27, 1981, as amended at 64 FR 10942, Mar. 8, 1999]
Sec. 50.23 Exception from general requirements.
(a) The obtaining of informed consent shall be deemed feasible
unless, before use of the test article (except as provided in paragraph
(b) of this section), both the investigator and a physician who is not
otherwise participating in the clinical investigation certify in writing
all of the following:
(1) The human subject is confronted by a life-threatening situation
necessitating the use of the test article.
(2) Informed consent cannot be obtained from the subject because of
an inability to communicate with, or obtain legally effective consent
from, the subject.
(3) Time is not sufficient to obtain consent from the subject's
(4) There is available no alternative method of approved or
generally recognized therapy that provides an equal or greater
likelihood of saving the life of the subject.
(b) If immediate use of the test article is, in the investigator's
opinion, required to preserve the life of the subject, and time is not
sufficient to obtain the independent determination required in paragraph
(a) of this section in advance of using the test article, the
determinations of the clinical investigator shall be made and, within 5
working days after the use of the article, be reviewed and evaluated in
writing by a physician who is not participating in the clinical
(c) The documentation required in paragraph (a) or (b) of this
section shall be submitted to the IRB within 5 working days after the
use of the test article.
(d)(1) Under 10 U.S.C. 1107(f) the President may waive the prior
consent requirement for the administration of
an investigational new drug to a member of the armed forces in
connection with the member's participation in a particular military
operation. The statute specifies that only the President may waive
informed consent in this connection and the President may grant such a
waiver only if the President determines in writing that obtaining
consent: Is not feasible; is contrary to the best interests of the
military member; or is not in the interests of national security. The
statute further provides that in making a determination to waive prior
informed consent on the ground that it is not feasible or the ground
that it is contrary to the best interests of the military members
involved, the President shall apply the standards and criteria that are
set forth in the relevant FDA regulations for a waiver of the prior
informed consent requirements of section 505(i)(4) of the Federal Food,
Drug, and Cosmetic Act (21 U.S.C. 355(i)(4)). Before such a
determination may be made that obtaining informed consent from military
personnel prior to the use of an investigational drug (including an
antibiotic or biological product) in a specific protocol under an
investigational new drug application (IND) sponsored by the Department
of Defense (DOD) and limited to specific military personnel involved in
a particular military operation is not feasible or is contrary to the
best interests of the military members involved the Secretary of Defense
must first request such a determination from the President, and certify
and document to the President that the following standards and criteria
contained in paragraphs (d)(1) through (d)(4) of this section have been
(i) The extent and strength of evidence of the safety and
effectiveness of the investigational new drug in relation to the medical
risk that could be encountered during the military operation supports
the drug's administration under an IND.
(ii) The military operation presents a substantial risk that
military personnel may be subject to a chemical, biological, nuclear, or
other exposure likely to produce death or serious or life-threatening
injury or illness.
(iii) There is no available satisfactory alternative therapeutic or
preventive treatment in relation to the intended use of the
investigational new drug.
(iv) Conditioning use of the investigational new drug on the
voluntary participation of each member could significantly risk the
safety and health of any individual member who would decline its use,
the safety of other military personnel, and the accomplishment of the
(v) A duly constituted institutional review board (IRB) established
and operated in accordance with the requirements of paragraphs (d)(2)
and (d)(3) of this section, responsible for review of the study, has
reviewed and approved the investigational new drug protocol and the
administration of the investigational new drug without informed consent.
DOD's request is to include the documentation required by
Sec. 56.115(a)(2) of this chapter.
(vi) DOD has explained:
(A) The context in which the investigational drug will be
administered, e.g., the setting or whether it will be self-administered
or it will be administered by a health professional;
(B) The nature of the disease or condition for which the preventive
or therapeutic treatment is intended; and
(C) To the extent there are existing data or information available,
information on conditions that could alter the effects of the
(vii) DOD's recordkeeping system is capable of tracking and will be
used to track the proposed treatment from supplier to the individual
(viii) Each member involved in the military operation will be given,
prior to the administration of the investigational new drug, a specific
written information sheet (including information required by 10 U.S.C.
1107(d)) concerning the investigational new drug, the risks and benefits
of its use, potential side effects, and other pertinent information
about the appropriate use of the product.
(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.
(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
(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
(xvii) DOD is to provide public notice as soon as practicable and
consistent with classification requirements through notice in the
Federal Register describing each waiver of informed consent
determination, a summary of the most updated scientific information on
the products used, and other pertinent information.
(xviii) Use of the investigational drug without informed consent
otherwise conforms with applicable law.
(2) The duly constituted institutional review board, described in
paragraph (d)(1)(v) of this section, must include at least 3
nonaffiliated members who shall not be employees or officers of the
Federal Government (other than for purposes of membership on the IRB)
and shall be required to obtain any necessary security clearances. This
IRB shall review the proposed IND protocol at a convened meeting at
which a majority of the members are present including at least one
member whose primary concerns are in nonscientific areas and, if
feasible, including a majority of the nonaffiliated members. The
information required by Sec. 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
(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
[46 FR 8951, Jan. 27, 1981, as amended at 55 FR 52817, Dec. 21, 1990; 64
FR 399, Jan. 5, 1999; 64 FR 54188, Oct. 5, 1999]
Sec. 50.24 Exception from informed consent requirements for emergency
(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
(1) The human subjects are in a life-threatening situation,
available treatments are unproven or unsatisfactory, and the collection
of valid scientific evidence, which may include evidence obtained
through randomized placebo-controlled investigations, is 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
(iii) There is no reasonable way to identify prospectively the
individuals likely to become eligible for participation in the clinical
(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
(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 Sec. 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
(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 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 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 Sec. 56.115(b) of this
(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 Secs. 312.30 or 812.35 of this chapter.
(e) If an IRB determines that it cannot approve a clinical
investigation because the investigation does not 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 to the sponsor of the clinical investigation. The sponsor of the
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
[61 FR 51528, Oct. 2, 1996]
Sec. 50.25 Elements of informed consent.
(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 identifying the subject will be
maintained and that notes the 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.
(b) Additional elements of informed consent. When appropriate, one
or more of the following elements of information shall also be provided
to each subject:
(1) A statement that the particular treatment or procedure may
involve risks to the subject (or to the embryo or fetus, if the subject
is or may become pregnant) which are currently unforeseeable.
(2) Anticipated circumstances under which the subject's
participation may be terminated by the investigator without regard to
the subject's consent.
(3) Any additional costs to the subject that may result from
participation in the research.
(4) The consequences of a subject's decision to withdraw from the
research and procedures for orderly termination of participation by the
(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.
(6) The approximate number of subjects involved in the study.
(c) 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 for informed consent to
be legally effective.
(d) 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
Sec. 50.27 Documentation of informed consent.
(a) Except as provided in Sec. 56.109(c), informed consent shall be
documented by the use of a written consent form approved by the IRB and
signed and dated by the subject or the subject's legally authorized
representative at the time of consent. A copy shall be given to the
person signing the form.
(b) Except as provided in Sec. 56.109(c), the consent form may be
either of the following:
(1) A written consent document that embodies the elements of
informed consent required by Sec. 50.25. 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.
(2) A short form written consent document stating that the elements
of informed consent required by Sec. 50.25 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 the 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.
[46 FR 8951, Jan. 27, 1981, as amended at 61 FR 57280, Nov. 5, 1996]