Food and Drug Administration, HHS § 50.3 PART 50—PROTECTION OF HUMAN SUBJECTS Subpart A—General Provisions Sec. 50.1 Scope. 50.3 Definitions. Subpart B—Informed Consent of Human Subjects 50.20 General requirements for informed consent. 50.23 Exception from general requirements. 50.24 Exception from informed consent re- quirements for emergency research. 50.25 Elements of informed consent. 50.27 Documentation of informed consent. Subpart C [Reserved] Subpart D—Additional Safeguards for Children in Clinical Investigations 50.50 IRB duties. 50.51 Clinical investigations not involving greater than minimal risk. 50.52 Clinical investigations involving greater than minimal risk but presenting the prospect of direct benefit to indi- vidual subjects. 50.53 Clinical investigations involving greater than minimal risk and no pros- pect of direct benefit to individual sub- jects, but likely to yield generalizable knowledge about the subjects’ disorder or condition. 50.54 Clinical investigations not otherwise approvable that present an opportunity to understand, prevent, or alleviate a se- rious problem affecting the health or welfare of children. 50.55 Requirements for permission by par- ents or guardians and for assent by chil- dren. 50.56 Wards. AUTHORITY: 21 U.S.C 321, 343, 346, 346a, 348, 350a, 350b, 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 in- vestigations 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 ap- plications for research or marketing permits for products regulated by the Food and Drug Administration, includ- ing foods, including dietary supple- ments, that bear a nutrient content claim or a health claim, infant for- mulas, 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 con- duct for, persons who sponsor or mon- itor clinical investigations involving particular test articles may also be found in other parts (e.g., parts 312 and 812). Compliance with these parts is in- tended to protect the rights and safety of subjects involved in investigations filed with the Food and Drug Adminis- tration pursuant to sections 403, 406, 409, 412, 413, 502, 503, 505, 510, 513–516, 518–520, 721, and 801 of the Federal Food, Drug, and Cosmetic Act and sec- tions 351 and 354–360F of the Public Health Service Act. (b) References in this part to regu- latory 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; 66 FR 20597, Apr. 24, 2001] § 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 mar- keting permit includes: (1) A color additive petition, de- scribed in part 71. (2) A food additive petition, described in parts 171 and 571. (3) Data and information about a sub- stance submitted as part of the proce- dures for establishing that the sub- stance is generally recognized as safe for use that results or may reasonably be expected to result, directly or indi- rectly, 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 proce- dures for food additives permitted to be 283 § 50.3 used on an interim basis pending addi- tional study, described in § 180.1. (5) Data and information about a sub- stance submitted as part of the proce- dures 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 appli- cation, 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, amend- ing, or repealing a bioequivalence re- quirement, 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 sub- mitted 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 li- cense, described in part 601 of this chapter. (13) Data and information about a bi- ological product submitted as part of the procedures for determining that li- censed 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 809. (15) An Application for an Investiga- tional Device Exemption, described in part 812. (16) Data and information about a medical device submitted as part of the procedures for classifying these de- vices, 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 de- vices, described in section 514. 21 CFR Ch. I (4–1–12 Edition) (18) An application for premarket ap- proval of a medical device, described in section 515. (19) A product development protocol for a medical device, described in sec- tion 515. (20) Data and information about an electronic product submitted as part of the procedures for establishing, amend- ing, 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 perform- ance 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 radi- ation safety performance standard, as described in § 1010.5. (23) Data and information about a clinical study of an infant formula when submitted as part of an infant formula notification under section 412(c) of the Federal Food, Drug, and Cosmetic Act. (24) Data and information submitted in a petition for a nutrient content claim, described in § 101.69 of this chap- ter, or for a health claim, described in § 101.70 of this chapter. (25) Data and information from inves- tigations involving children submitted in a new dietary ingredient notifica- tion, described in § 190.6 of this chapter. (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 sub- ject to requirements for prior submis- sion to the Food and Drug Administra- tion under these sections of the act, but the results of which are intended to be submitted later to, or held for in- spection by, the Food and Drug Admin- istration 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. 284 Food and Drug Administration, HHS § 50.3 (d) Investigator means an individual who actually conducts a clinical inves- tigation, i.e., under whose immediate direction the test article is adminis- tered or dispensed to, or used involv- ing, a subject, or, in the event of an in- vestigation conducted by a team of in- dividuals, is the responsible leader of that team. (e) Sponsor means a person who initi- ates a clinical investigation, but who does not actually conduct the inves- tigation, i.e., the test article is admin- istered or dispensed to or used involv- ing, a subject under the immediate di- rection of another individual. A person other than an individual (e.g., corpora- tion or agency) that uses one or more of its own employees to conduct a clin- ical investigation it has initiated is considered to be a sponsor (not a spon- sor-investigator), and the employees are considered to be investigators. (f) Sponsor-investigator means an indi- vidual who both initiates and actually conducts, alone or with others, a clin- ical investigation, i.e., under whose im- mediate direction the test article is ad- ministered or dispensed to, or used in- volving, a subject. The term does not include any person other than an indi- vidual, e.g., corporation or agency. (g) Human subject means an indi- vidual 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 pa- tient. (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 syn- onymous with the term institution for purposes of this part. (i) Institutional revie board (IRB) means any board, committee, or other group formally designated by an insti- tution to review biomedical research involving humans as subjects, to ap- prove the initiation of and conduct periodic review of such research. The term has the same meaning as the phrase institutional revie committee as used in section 520(g) of the act. (j) Test article means any drug (in- cluding 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 prob- ability and magnitude of harm or dis- comfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of rou- tine physical or psychological exami- nations or tests. (l) Legally authorized representative means an individual or judicial or other body authorized under applicable law to consent on behalf of a prospec- tive subject to the subject’s particpation in the procedure(s) in- volved in the research. (m) Family member means any one of the following legally competent per- sons: Spouse; parents; children (includ- ing adopted children); brothers, sisters, and spouses of brothers and sisters; and any individual related by blood or af- finity whose close association with the subject is the equivalent of a family re- lationship. (n) Assent means a child’s affirmative agreement to participate in a clinical investigation. Mere failure to object may not, absent affirmative agree- ment, be construed as assent. (o) Children means persons who have not attained the legal age for consent to treatments or procedures involved in clinical investigations, under the ap- plicable law of the jurisdiction in which the clinical investigation will be conducted. (p) Parent means a child’s biological or adoptive parent. (q) Ward means a child who is placed in the legal custody of the State or other agency, institution, or entity, consistent with applicable Federal, State, or local law. (r) Permission means the agreement of parent(s) or guardian to the participa- tion of their child or ward in a clinical investigation. Permission must be ob- tained in compliance with subpart B of this part and must include the ele- ments of informed consent described in § 50.25. (s) Guardian means an individual who is authorized under applicable State or local law to consent on behalf of a 285 § 50.20 child to general medical care when general medical care includes partici- pation in research. For purposes of sub- part D of this part, a guardian also means an individual who is authorized to consent on behalf of a child to par- ticipate in research. [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; 66 FR 20597, Apr. 24, 2001] Subpart B—Informed Consent of Human Subjects SOURCE: 46 FR 8951, Jan. 27, 1981, unless otherwise noted. § 50.20 General requirements for in- formed consent. Except as provided in §§ 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 sub- ject or the subject’s legally authorized representative. An investigator shall seek such consent only under cir- cumstances that provide the prospec- tive subject or the representative suffi- cient opportunity to consider whether or not to participate and that minimize the possibility of coercion or undue in- fluence. 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 writ- ten, may include any exculpatory lan- guage through which the subject or the representative is made to waive or ap- pear to waive any of the subject’s legal rights, or releases or appears to release the investigator, the sponsor, the insti- tution, or its agents from liability for negligence. [46 FR 8951, Jan. 27, 1981, as amended at 64 FR 10942, Mar. 8, 1999] § 50.23 Exception from general re- quirements. (a) The obtaining of informed consent shall be deemed feasible unless, before use of the test article (except as pro- vided in paragraph (b) of this section), both the investigator and a physician 21 CFR Ch. I (4–1–12 Edition) 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 necessi- tating the use of the test article. (2) Informed consent cannot be ob- tained from the subject because of an inability to communicate with, or ob- tain legally effective consent from, the subject. (3) Time is not sufficient to obtain consent from the subject’s legal rep- resentative. (4) There is available no alternative method of approved or generally recog- nized therapy that provides an equal or greater likelihood of saving the life of the subject. (b) If immediate use of the test arti- cle is, in the investigator’s opinion, re- quired to preserve the life of the sub- ject, and time is not sufficient to ob- tain the independent determination re- quired in paragraph (a) of this section in advance of using the test article, the determinations of the clinical investi- gator shall be made and, within 5 work- ing days after the use of the article, be reviewed and evaluated in writing by a physician who is not participating in the clinical investigation. (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 mem- ber of the armed forces in connection with the member’s participation in a particular military operation. The statute specifies that only the Presi- dent may waive informed consent in this connection and the President may grant such a waiver only if the Presi- dent determines in writing that obtain- ing 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 determina- tion 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 286 Food and Drug Administration, HHS § 50.23 standards and criteria that are set forth in the relevant FDA regulations for a waiver of the prior informed con- sent 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 ob- taining informed consent from mili- tary personnel prior to the use of an in- vestigational drug (including an anti- biotic or biological product) in a spe- cific protocol under an investigational new drug application (IND) sponsored by the Department of Defense (DOD) and limited to specific military per- sonnel involved in a particular mili- tary operation is not feasible or is con- trary to the best interests of the mili- tary members involved the Secretary of Defense must first request such a de- termination from the President, and certify and document to the President that the following standards and cri- teria contained in paragraphs (d)(1) through (d)(4) of this section have been met. (i) The extent and strength of evi- dence of the safety and effectiveness of the investigational new drug in rela- tion to the medical risk that could be encountered during the military oper- ation supports the drug’s administra- tion under an IND. (ii) The military operation presents a substantial risk that military per- sonnel 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 satisfac- tory alternative therapeutic or preven- tive treatment in relation to the in- tended use of the investigational new drug. (iv) Conditioning use of the inves- tigational 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 mili- tary personnel, and the accomplish- ment of the military mission. (v) A duly constituted institutional review board (IRB) established and op- erated in accordance with the require- ments 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 inves- tigational new drug without informed consent. DOD’s request is to include the documentation required by § 56.115(a)(2) of this chapter. (vi) DOD has explained: (A) The context in which the inves- tigational drug will be administered, e.g., the setting or whether it will be self-administered or it will be adminis- tered by a health professional; (B) The nature of the disease or con- dition for which the preventive or therapeutic treatment is intended; and (C) To the extent there are existing data or information available, informa- tion on conditions that could alter the effects of the investigational drug. (vii) DOD’s recordkeeping system is capable of tracking and will be used to track the proposed treatment from supplier to the individual recipient. (viii) Each member involved in the military operation will be given, prior to the administration of the investiga- tional new drug, a specific written in- formation sheet (including information required by 10 U.S.C. 1107(d)) con- cerning the investigational new drug, the risks and benefits of its use, poten- tial side effects, and other pertinent in- formation about the appropriate use of the product. (ix) Medical records of members in- volved 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 in- volved in the military operation will accurately document the receipt by members of any investigational new drugs in accordance with FDA regula- tions including part 312 of this chapter. (xi) DOD will provide adequate fol- lowup to assess whether there are bene- ficial or adverse health consequences that result from the use of the inves- tigational product. (xii) DOD is pursuing drug develop- ment, including a time line, and mar- keting approval with due diligence. (xiii) FDA has concluded that the in- vestigational new drug protocol may proceed subject to a decision by the President on the informed consent waiver request. 287 § 50.23 (xiv) DOD will provide training to the appropriate medical personnel and po- tential recipients on the specific inves- tigational 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 stand- ards and criteria. (xvi) DOD shall have a continuing ob- ligation to report to the FDA and to the President any changed cir- cumstances 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 in- vestigational new drug without in- formed consent. (xvii) DOD is to provide public notice as soon as practicable and consistent with classification requirements through notice in the FEDERAL REG- ISTER describing each waiver of in- formed consent determination, a sum- mary of the most updated scientific in- formation 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 pro- tocol 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 ma- jority of the nonaffiliated members. The information required by § 56.115(a)(2) of this chapter is to be pro- vided 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 dis- seminate information, including dis- 21 CFR Ch. I (4–1–12 Edition) tribution of the information sheet to potential recipients, on the investiga- tional product (e.g., in forms other than written); (iii) The adequacy of the information and plans for its dissemination to health care providers, including poten- tial side effects, contraindications, po- tential interactions, and other perti- nent considerations; and (iv) An informed consent form as re- quired by part 50 of this chapter, in those circumstances in which DOD de- termines that informed consent may be obtained from some or all personnel in- volved. (4) DOD is to submit to FDA sum- maries of institutional review board meetings at which the proposed pro- tocol has been reviewed. (5) Nothing in these criteria or stand- ards is intended to preempt or limit FDA’s and DOD’s authority or obliga- tions under applicable statutes and regulations. (e)(1) Obtaining informed consent for investigational in vitro diagnostic de- vices used to identify chemical, bio- logical, radiological, or nuclear agents will be deemed feasible unless, before use of the test article, both the investi- gator (e.g., clinical laboratory director or other responsible individual) and a physician who is not otherwise partici- pating in the clinical investigation make the determinations and later cer- tify in writing all of the following: (i) The human subject is confronted by a life-threatening situation necessi- tating the use of the investigational in vitro diagnostic device to identify a chemical, biological, radiological, or nuclear agent that would suggest a ter- rorism event or other public health emergency. (ii) Informed consent cannot be ob- tained from the subject because: (A) There was no reasonable way for the person directing that the specimen be collected to know, at the time the specimen was collected, that there would be a need to use the investiga- tional in vitro diagnostic device on that subject’s specimen; and (B) Time is not sufficient to obtain consent from the subject without risk- ing the life of the subject. 288 Food and Drug Administration, HHS § 50.24 (iii) Time is not sufficient to obtain consent from the subject’s legally au- thorized representative. (iv) There is no cleared or approved available alternative method of diag- nosis, to identify the chemical, biologi- cal, radiological, or nuclear agent that provides an equal or greater likelihood of saving the life of the subject. (2) If use of the investigational device is, in the opinion of the investigator (e.g., clinical laboratory director or other responsible person), required to preserve the life of the subject, and time is not sufficient to obtain the independent determination required in paragraph (e)(1) of this section in ad- vance of using the investigational de- vice, the determinations of the investi- gator shall be made and, within 5 work- ing days after the use of the device, be reviewed and evaluated in writing by a physician who is not participating in the clinical investigation. (3) The investigator must submit the written certification of the determina- tions made by the investigator and an independent physician required in paragraph (e)(1) or (e)(2) of this section to the IRB and FDA within 5 working days after the use of the device. (4) An investigator must disclose the investigational status of the in vitro diagnostic device and what is known about the performance characteristics of the device in the report to the sub- ject’s health care provider and in any report to public health authorities. The investigator must provide the IRB with the information required in § 50.25 (ex- cept for the information described in § 50.25(a)(8)) and the procedures that will be used to provide this information to each subject or the subject’s legally authorized representative at the time the test results are provided to the sub- ject’s health care provider and public health authorities. (5) The IRB is responsible for ensur- ing the adequacy of the information re- quired in section 50.25 (except for the information described in § 50.25(a)(8)) and for ensuring that procedures are in place to provide this information to each subject or the subject’s legally au- thorized representative. (6) No State or political subdivision of a State may establish or continue in effect any law, rule, regulation or other requirement that informed con- sent be obtained before an investiga- tional in vitro diagnostic device may be used to identify chemical, biologi- cal, radiological, or nuclear agent in suspected terrorism events and other potential public health emergencies that is different from, or in addition to, the requirements of this regulation. [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; 71 FR 32833, June 7, 2006; 76 FR 36993, June 24, 2011] § 50.24 Exception from informed con- sent requirements for emergency research. (a) The IRB responsible for the re- view, approval, and continuing review of the clinical investigation described in this section may approve that inves- tigation without requiring that in- formed consent of all research subjects be obtained if the IRB (with the con- currence 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 life- threatening situation, available treat- ments 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 effective- ness 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 investiga- tion must be administered before con- sent from the subjects’ legally author- ized representatives is feasible; and (iii) There is no reasonable way to identify prospectively the individuals likely to become eligible for participa- tion 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-threat- ening situation that necessitates inter- vention; 289 § 50.24 (ii) Appropriate animal and other preclinical studies have been con- ducted, and the information derived from those studies and related evidence support the potential for the interven- tion to provide a direct benefit to the individual subjects; and (iii) Risks associated with the inves- tigation are reasonable in relation to what is known about the medical con- dition of the potential class of subjects, the risks and benefits of standard ther- apy, 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 com- mitted to attempting to contact a le- gally authorized representative for each subject within that window of time and, if feasible, to asking the le- gally authorized representative con- tacted for consent within that window rather than proceeding without con- sent. The investigator will summarize efforts made to contact legally author- ized representatives and make this in- formation available to the IRB at the time of continuing review. (6) The IRB has reviewed and ap- proved informed consent procedures and an informed consent document consistent with § 50.25. These proce- dures and the informed consent docu- ment are to be used with subjects or their legally authorized representa- tives 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 investiga- tion 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 ap- propriate, consultation carried out by the IRB) with representatives of the communities in which the clinical in- vestigation will be conducted and from which the subjects will be drawn; 21 CFR Ch. I (4–1–12 Edition) (ii) Public disclosure to the commu- nities in which the clinical investiga- tion will be conducted and from which the subjects will be drawn, prior to ini- tiation of the clinical investigation, of plans for the investigation and its risks and expected benefits; (iii) Public disclosure of sufficient in- formation following completion of the clinical investigation to apprise the community and researchers of the study, including the demographic char- acteristics 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 avail- able, the investigator has committed, if feasible, to attempting to contact within the therapeutic window the sub- ject’s family member who is not a le- gally 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 infor- mation available to the IRB at the time of continuing review. (b) The IRB is responsible for ensur- ing that procedures are in place to in- form, at the earliest feasible oppor- tunity, each subject, or if the subject remains incapacitated, a legally au- thorized representative of the subject, or if such a representative is not rea- sonably available, a family member, of the subject’s inclusion in the clinical investigation, the details of the inves- tigation and other information con- tained in the informed consent docu- ment. The IRB shall also ensure that there is a procedure to inform the sub- ject, or if the subject remains incapaci- tated, a legally authorized representa- tive of the subject, or if such a rep- resentative 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 other- wise entitled. If a legally authorized representative or family member is told about the clinical investigation and the subject’s condition improves, 290 Food and Drug Administration, HHS § 50.25 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 be- fore a legally authorized representative or family member can be contacted, in- formation about the clinical investiga- tion 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 com- pletion of the clinical investigation, and the records shall be accessible for inspection and copying by FDA in ac- cordance with § 56.115(b) of this chap- ter. (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 investiga- tional device exemption (IDE) that clearly identifies such protocols as pro- tocols 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. Applica- tions for investigations under this sec- tion may not be submitted as amend- ments under §§ 312.30 or 812.35 of this chapter. (e) If an IRB determines that it can- not approve a clinical investigation be- cause the investigation does not meet the criteria in the exception provided under paragraph (a) of this section or because of other relevant ethical con- cerns, the IRB must document its find- ings and provide these findings prompt- ly in writing to the clinical investi- gator and to the sponsor of the clinical investigation. The sponsor of the clin- ical investigation must promptly dis- close this information to FDA and to the sponsor’s clinical investigators who are participating or are asked to par- ticipate 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] § 50.25 Elements of informed consent. (a) Basic elements of informed consent. In seeking informed consent, the fol- lowing information shall be provided to each subject: (1) A statement that the study in- volves research, an explanation of the purposes of the research and the ex- pected duration of the subject’s partici- pation, a description of the procedures to be followed, and identification of any procedures which are experi- mental. (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 rea- sonably be expected from the research. (4) A disclosure of appropriate alter- native procedures or courses of treat- ment, if any, that might be advan- tageous to the subject. (5) A statement describing the ex- tent, if any, to which confidentiality of records identifying the subject will be maintained and that notes the possi- bility that the Food and Drug Adminis- tration may inspect the records. (6) For research involving more than minimal risk, an explanation as to whether any compensation and an ex- planation as to whether any medical treatments are available if injury oc- curs and, if so, what they consist of, or where further information may be ob- tained. (7) An explanation of whom to con- tact for answers to pertinent questions about the research and research sub- jects’ 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 bene- fits to which the subject is otherwise entitled, and that the subject may dis- continue participation at any time without penalty or loss of benefits to which the subject is otherwise entitled. (b) Additional elements of informed con- sent. 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 291 § 50.27 or fetus, if the subject is or may be- come 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 con- sent. (3) Any additional costs to the sub- ject 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 par- ticipation will be provided to the sub- ject. (6) The approximate number of sub- jects involved in the study. (c) When seeking informed consent for applicable clinical trials, as defined in 42 U.S.C. 282(j)(1)(A), the following statement shall be provided to each clinical trial subject in informed con- sent documents and processes. This will notify the clinical trial subject that clinical trial information has been or will be submitted for inclusion in the clinical trial registry databank under paragraph (j) of section 402 of the Public Health Service Act. The state- ment is: ‘‘A description of this clinical trial will be available on http:// .ClinicalTrials.gov, as required by U.S. Law. This Web site will not in- clude 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.’’ (d) The informed consent require- ments in these regulations are not in- tended to preempt any applicable Fed- eral, State, or local laws which require additional information to be disclosed for informed consent to be legally ef- fective. (e) Nothing in these regulations is in- tended to limit the authority of a phy- sician to provide emergency medical care to the extent the physician is per- mitted to do so under applicable Fed- eral, State, or local law. [46 FR 8951, Jan. 27, 1981, as amended at 76 FR 270, Jan. 4, 2011] 21 CFR Ch. I (4–1–12 Edition) § 50.27 Documentation of informed consent. (a) Except as provided in § 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 le- gally authorized representative at the time of consent. A copy shall be given to the person signing the form. (b) Except as provided in § 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 § 50.25. This form may be read to the subject or the sub- ject’s legally authorized representa- tive, but, in any event, the investigator shall give either the subject or the rep- resentative adequate opportunity to read it before it is signed. (2) A short form written consent docu- ment stating that the elements of in- formed consent required by § 50.25 have been presented orally to the subject or the subject’s legally authorized rep- resentative. When this method is used, there shall be a witness to the oral presentation. Also, the IRB shall ap- prove a written summary of what is to be said to the subject or the represent- ative. Only the short form itself is to be signed by the subject or the rep- resentative. 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 sum- mary 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] Subpart C [Reserved] Subpart D—Additional Safeguards for Children in Clinical Inves- tigations SOURCE: 66 FR 20598, Apr. 24, 2001, unless otherwise noted. § 50.50 IRB duties. In addition to other responsibilities assigned to IRBs under this part and part 56 of this chapter, each IRB must 292 Food and Drug Administration, HHS § 50.54 review clinical investigations involving children as subjects covered by this subpart D and approve only those clin- ical investigations that satisfy the cri- teria described in § 50.51, § 50.52, or § 50.53 and the conditions of all other applicable sections of this subpart D. § 50.51 Clinical investigations not in- volving 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 and documents that adequate provisions are made for solic- iting the assent of the children and the permission of their parents or guard- ians as set forth in § 50.55. § 50.52 Clinical investigations involv- ing 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 mini- mal 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 moni- toring procedure that is likely to con- tribute to the subject’s well-being, may involve children as subjects only if the IRB finds and documents that: (a) The risk is justified by the antici- pated benefit to the subjects; (b) The relation of the anticipated benefit to the risk is at least as favor- able 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. § 50.53 Clinical investigations involv- ing greater than minimal risk and no prospect of direct benefit to in- dividual 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 mini- mal 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 mon- itoring procedure that is not likely to contribute to the well-being of the sub- ject, may involve children as subjects only if the IRB finds and documents that: (a) The risk represents a minor in- crease over minimal risk; (b) The intervention or procedure presents experiences to subjects that are reasonably commensurate with those inherent in their actual or ex- pected medical, dental, psychological, social, or educational situations; (c) The intervention or procedure is likely to yield generalizable knowledge about the subjects’ disorder or condi- tion 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. § 50.54 Clinical investigations not oth- erwise approvable that present an opportunity to understand, prevent, or alleviate a serious problem af- fecting the health or welfare of chil- dren. If an IRB does not believe that a clin- ical investigation within the scope de- scribed in §§ 50.1 and 56.101 of this chap- ter and involving children as subjects meets the requirements of § 50.51, § 50.52, or § 50.53, the clinical investiga- tion may proceed only if: (a) The IRB finds and documents that the clinical investigation presents a reasonable opportunity to further the understanding, prevention, or allevi- ation 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, deter- mines 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 293 § 50.55 understanding, prevention, or allevi- ation 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. § 50.55 Requirements for permission by parents or guardians and for as- sent by children. (a) In addition to the determinations required under other applicable sec- tions 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 pro- viding 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 in- volved 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 proce- dure involved in the clinical investiga- tion holds out a prospect of direct ben- efit that is important to the health or well-being of the children and is avail- able only in the context of the clinical investigation. (d) Even where the IRB determines that the subjects are capable of assent- ing, the IRB may still waive the assent requirement if it finds and documents that: (1) The clinical investigation in- volves no more than minimal risk to the subjects; (2) The waiver will not adversely af- fect the rights and welfare of the sub- jects; (3) The clinical investigation could not practicably be carried out without the waiver; and 21 CFR Ch. I (4–1–12 Edition) (4) Whenever appropriate, the sub- jects will be provided with additional pertinent information after participa- tion. (e) In addition to the determinations required under other applicable sec- tions of this subpart D, the IRB must determine 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, if consistent with State law, for clin- ical investigations to be conducted under § 50.51 or § 50.52. (2) Where clinical investigations are covered by § 50.53 or § 50.54 and permis- sion is to be obtained from parents, both parents must give their permis- sion unless one parent is deceased, un- known, incompetent, or not reasonably available, or when only one parent has legal responsibility for the care and custody of the child if consistent with State law. (f) Permission by parents or guard- ians must be documented in accordance with and to the extent required by § 50.27. (g) When the IRB determines that as- sent is required, it must also determine whether and how assent must be docu- mented. § 50.56 Wards. (a) Children who are wards of the State or any other agency, institution, or entity can be included in clinical in- vestigations approved under § 50.53 or § 50.54 only if such clinical investiga- tions are: (1) Related to their status as wards; or (2) Conducted in schools, camps, hos- pitals, institutions, or similar settings in which the majority of children in- volved as subjects are not wards. (b) If the clinical investigation is ap- proved under paragraph (a) of this sec- tion, the IRB must require appoint- ment of an advocate for each child who is a ward. (1) The advocate will serve in addi- tion to any other individual acting on behalf of the child as guardian or in loco parentis. (2) One individual may serve as advo- cate for more than one child. 294 Food and Drug Administration, HHS § 54.2 (3) The advocate must be an indi- vidual who has the background and ex- perience 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 associ- ated in any way (except in the role as advocate or member of the IRB) with the clinical investigation, the investi- gator(s), or the guardian organization. PART 54—FINANCIAL DISCLOSURE BY CLINICAL INVESTIGATORS Sec. 54.1 Purpose. 54.2 Definitions. 54.3 Scope. 54.4 Certification and disclosure require- ments. 54.5 Agency evaluation of financial inter- ests. 54.6 Recordkeeping and record retention. AUTHORITY: 21 U.S.C. 321, 331, 351, 352, 353, 355, 360, 360c–360j, 371, 372, 373, 374, 375, 376, 379; 42 U.S.C. 262. SOURCE: 63 FR 5250, Feb. 2, 1998, unless oth- erwise noted. § 54.1 Purpose. (a) The Food and Drug Administra- tion (FDA) evaluates clinical studies submitted in marketing applications, required by law, for new human drugs and biological products and marketing applications and reclassification peti- tions for medical devices. (b) The agency reviews data gen- erated in these clinical studies to de- termine whether the applications are approvable under the statutory re- quirements. FDA may consider clinical studies inadequate and the data inad- equate if, among other things, appro- priate steps have not been taken in the design, conduct, reporting, and anal- ysis of the studies to minimize bias. One potential source of bias in clinical studies is a financial interest of the clinical investigator in the outcome of the study because of the way payment is arranged (e.g., a royalty) or because the investigator has a proprietary in- terest in the product (e.g., a patent) or because the investigator has an equity interest in the sponsor of the covered study. This section and conforming regulations require an applicant whose submission relies in part on clinical data to disclose certain financial ar- rangements between sponsor(s) of the covered studies and the clinical inves- tigators and certain interests of the clinical investigators in the product under study or in the sponsor of the covered studies. FDA will use this in- formation, in conjunction with infor- mation about the design and purpose of the study, as well as information ob- tained through on-site inspections, in the agency’s assessment of the reli- ability of the data. § 54.2 Definitions. For the purposes of this part: (a) Compensation affected by the out- come of clinical studies means compensa- tion that could be higher for a favor- able outcome than for an unfavorable outcome, such as compensation that is explicitly greater for a favorable result or compensation to the investigator in the form of an equity interest in the sponsor of a covered study or in the form of compensation tied to sales of the product, such as a royalty interest. (b) Significant equity interest in the sponsor of a covered study means any ownership interest, stock options, or other financial interest whose value cannot be readily determined through reference to public prices (generally, interests in a nonpublicly traded cor- poration), or any equity interest in a publicly traded corporation that ex- ceeds $50,000 during the time the clin- ical investigator is carrying out the study and for 1 year following comple- tion of the study. (c) Proprietary interest in the tested product means property or other finan- cial interest in the product including, but not limited to, a patent, trade- mark, copyright or licensing agree- ment. (d) Clinical investigator means only a listed or identified investigator or sub- investigator who is directly involved in the treatment or evaluation of re- search subjects. The term also includes the spouse and each dependent child of the investigator. (e) Covered clinical study means any study of a drug or device in humans submitted in a marketing application or reclassification petition subject to 295