21 CFR Part 50

Question 1

What is 21 CFR Part 50?

Answer 1

Protection of Human Subjects

Question 2

What is Subpart A?

Answer 2

General Provisions - Scope and definitions

Question 3

What is 50.1?

Answer 3

Scope: All clinical investigations regulated by the FDA under the Act (see CFR for more details)

Question 4

What is 50.3?

Answer 4

Definitions: see 21 CFR Part 50 Definitions deck

Question 5

What is Subpart B?

Answer 5

Informed Consent of Human Subjects

Question 6

What is 50.20?

Answer 6

General requirements for informed consent: Except as provided in §§ 50.22, 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.

Question 7

What is 50.22?

Answer 7

Exception from informed consent requirements for minimal risk clinical investigations

Question 8

What are the criteria for exception from informed consent requirements under 50.22?

Answer 8

(a) The clinical investigation involves no more than minimal risk to the subjects;
(b) The clinical investigation could not practicably be carried out without the requested waiver or alteration;
(c) If the CI involves using identifiable PI or identifiable biospecimens, the CI could not practicably be carried out without using such in an identifiable format;
(d) The waiver or alteration will not adversely affect the rights and welfare of the subjects; and
(e) Whenever appropriate, the subjects or LARs will be provided with additional pertinent information after participation.

Question 9

What is 50.23?

Answer 9

Exception from general (informed consent) requirements

Question 10

What are the exceptions from general (informed consent) requirements under 50.23?

Answer 10

(a) Human subject is in life-threatening situation necessitating use of test article & informed consent cannot be obtained from the subject because of inability to communicate with or obtain effective consent from subject & insufficient time to obtain consent from LAR & no available alternative method of approved or generally recognized therapy with = or > likelihood of saving subject’s life;
(b) Clinical investigator will make determination which will be reviewed and evaluated within 5 working days after use of article by a physician not participating in the investigation;
(c) Documentation submitted to IRB within 5 days after use of test article;
(d) U.S. President may waive prior consent requirement for armed forces in connection with participation in a particular military operation (see CFR for more details), the IRB must include at least 3 non affiliated members who are not employees or officers of the Federal government (see CFR for more details), the IRB must review and approve items listed here in CFR, DOD will submit to FDA summaries of IRB meetings at which the proposed protocol has been reviewed; AND
(e) see CFR for details

Question 11

What is 50.24?

Answer 11

Exception from informed consent requirements for emergency research

Question 12

What are the exceptions from informed consent requirements for emergency research?

Answer 12

(a) The IRB responsible may approve without requiring informed consent if: The human subjects are in a life-threatening situation, available treatments are unproven or unsatisfactory, and collection of scientific evidence is necessary to determine safety and effectiveness of an intervention; obtaining consent is not feasible (see CFR for more details); participation in the research has prospect of direct benefit to subjects (see CFR for more details); the investigation could not practicably be carried out without the waiver; there is an IRB approved ICF available to be used where feasible; additional protections of the rights and welfare of the subjects will be provided (see CFR for more details);
(b) The IRB is responsible for ensuring procedures are in place to inform as soon as possible each subject or LAR about the clinical investigation (see CFR for more details);
(c) IRB determinations are to be retained for at least 3 years after completion of the investigation;
(d) Protocols with exceptions to ICF requirements must be under a separate IND/IDE clearly identifying exceptions even if an IND/IDE for the same article exists;
(e) If IRB does not approve exception, it must document findings and provide them to investigators and sponsor

Question 13

What is 50.25?

Answer 13

Elements of informed consent

Question 14

What are the basic elements of informed consent in 50.25(a)?

Answer 14

(1) A statement that the study involves research, explanation of purpose of research, expected duration of participation, description of procedures, identification of which procedures are experimental.
(2) A description of any reasonably foreseeable risks/discomforts to the subject.
(3) A description of any benefits to the subject or 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 FDA may inspect the records.
(6) For research involving more than minimal risk, an explanation as to whether any compensation and medical treatments are available if injury occurs, what they consist of, and where to obtain further information.
(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.

Question 15

What are the additional elements of informed consent in 50.25(b)?

Answer 15

(1) A statement that a particular treatment or procedure may involve risks to the subject (or to the embryo/fetus if subject is or may become pregnant) which are currently unforeseeable.
(2) Anticipated circumstances under which the subject’s participation may be terminated by the investigator without regard to the subject’s consent.
(3) Any additional costs to the subject that may result from participation in the research.
(4) The consequences of a subject’s decision to withdraw from the research and procedures for orderly termination of participation by the subject.
(5) A statement that significant new findings developed during the course of the research which may relate to the subject’s willingness to continue participation will be provided to the subject.
(6) The approximate number of subjects involved in the study.

Question 16

What is 50.25(c)?

Answer 16

Requirement to include the following statement: “A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by US Law. This Web site will not include information that can identify you. At most, the Web site will include a summary of the results. You can search this Web site at any time.”

Question 17

What is 50.27?

Answer 17

Documentation of informed consent

Question 18

What is Subpart D?

Answer 18

Additional safeguards for children in Clinical Investigations

Question 19

What is 50.50?

Answer 19

In addition to other responsibilities assigned to IRBs under this part and part 56 of this chapter, each IRB must review clinical investigations involving children as subjects covered by this subpart D and approve only those clinical investigations that satisfy the criteria described in § 50.51, § 50.52, or § 50.53 and the conditions of all other applicable sections of this subpart D.

Question 20

What is 50.51?

Answer 20

Clinical investigations not involving greater than minimal risk: Any clinical investigation within the scope described in §§ 50.1 and 56.101 of this chapter in which no greater than minimal risk to children is presented may involve children as subjects only if the IRB finds that:
(a) No greater than minimal risk to children is presented; and
(b) Adequate provisions are made for soliciting the assent of the children and the permission of their parents or guardians as set forth in § 50.55.

Question 21

What is 50.52?

Answer 21

Clinical investigations involving greater than minimal risk but presenting the prospect of direct benefit to individual subjects: Any clinical investigation within the scope described in §§ 50.1 and 56.101 of this chapter in which 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 contribute to the subject’s well-being, may involve children as subjects 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 § 50.55.

Question 22

What is 50.53?

Answer 22

Clinical investigations involving greater than minimal risk and no prospect of direct benefit to individual subjects, but likely to yield generalizable knowledge about the subjects’ disorder or condition: Any clinical investigation within the scope described in §§ 50.1 and 56.101 of this chapter in which 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 that is not likely to contribute to the well-being of the subject, may involve children as subjects only if the IRB finds that:
(a) The risk represents a minor increase over minimal risk;
(b) The intervention or procedure presents experiences to subjects that are reasonably commensurate with those inherent in their actual or expected medical, dental, psychological, social, or educational situations;
(c) The intervention or procedure is likely to yield generalizable knowledge about the subjects’ disorder or condition that is of vital importance for the understanding or amelioration of the subjects’ disorder or condition; and
(d) Adequate provisions are made for soliciting the assent of the children and permission of their parents or guardians as set forth in § 50.55.

Question 23

What is 50.54?

Answer 23

Clinical investigations not otherwise approvable that present an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children: If an IRB does not believe that a clinical investigation within the scope described in §§ 50.1 and 56.101 of this chapter and involving children as subjects meets the requirements of § 50.51, § 50.52, or § 50.53, the clinical investigation may proceed only if:
(a) The IRB finds that the clinical investigation 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 Commissioner of Food and Drugs, 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, determines either:
(1) That the clinical investigation in fact satisfies the conditions of § 50.51, § 50.52, or § 50.53, as applicable, or
(2) That the following conditions are met:
(i) The clinical investigation presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children;
(ii) The clinical investigation will be conducted in accordance with sound ethical principles; and
(iii) Adequate provisions are made for soliciting the assent of children and the permission of their parents or guardians as set forth in § 50.55.

Question 24

What is 50.55?

Answer 24

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 D, the IRB must 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.

(b) In determining whether children are capable of providing assent, the IRB must take into account the ages, maturity, and psychological state of the children involved. This judgment may be made for all children to be involved in clinical investigations under a particular protocol, or for each child, as the IRB deems appropriate.

(c) The assent of the children is not a necessary condition for proceeding with the clinical investigation if the IRB determines:

(1) That the capability of some or all of the children is so limited that they cannot reasonably be consulted, or

(2) That the intervention or procedure involved in the clinical investigation 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 clinical investigation.

(d) Even where the IRB determines that the subjects are capable of assenting, the IRB may still waive the assent requirement if it finds and documents that:

(1) The clinical investigation involves no more than minimal risk to the subjects;

(2) The waiver will not adversely affect the rights and welfare of the subjects;

(3) The clinical investigation could not practicably be carried out without the waiver; and

(4) Whenever appropriate, the subjects will be provided with additional pertinent information after participation.

(e) In addition to the determinations required under other applicable sections of this subpart D, the IRB must determine, in accordance with and to the extent that consent is required under part 50, that the permission of each child’s parents or guardian is granted.

(1) Where parental permission is to be obtained, the IRB may find that the permission of one parent is sufficient for clinical investigations to be conducted under § 50.51 or § 50.52.

(2) Where clinical investigations are covered by § 50.53 or § 50.54 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.

(f) Permission by parents or guardians must be documented in accordance with and to the extent required by § 50.27.

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

Question 25

What is 50.56?

Answer 25

Wards.

(a) Children who are wards of the State or any other agency, institution, or entity can be included in clinical investigations approved under § 50.53 or § 50.54 only if such clinical investigations are:

(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 clinical investigation is approved under paragraph (a) of this section, the IRB must require appointment of an advocate for each child who is a ward.

(1) The advocate will serve in addition to any other individual acting on behalf of the child as guardian or in loco parentis.

(2) One individual may serve as advocate for more than one child.

(3) The advocate must be an individual who has the background and experience to act in, and agrees to act in, the best interest of the child for the duration of the child’s participation in the clinical investigation.

(4) The advocate must not be associated in any way (except in the role as advocate or member of the IRB) with the clinical investigation, the investigator(s), or the guardian organization.

Question 26

What is 50.23(d)?

Answer 26

Conditions under which 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.

Question 27

Who 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?

Answer 27

Only the President

Question 28

On what grounds may the President 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 under 50.23(d)?

Answer 28

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.

Question 29

What standards and criteria will the President apply in making the 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?

Answer 29

Those 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)).

Question 30

What is the first criteria (50.23(d)(i)) the Secretary of Defense must certify to the President that prior informed consent should be waived?

Answer 30

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.

Question 31

What is the second criteria (50.23(d)(II)) the Secretary of Defense must certify to the President that prior informed consent should be waived?

Answer 31

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.