Guidance for IRBs: Protecting Human Subjects in Clinical Investigations

1. Guidance for IRBsBarbara D. WrightBioresearch Monitoring SpecialistNew Orleans DistrictBaton Rouge Resident Post

2. Objectives • Define key IRB terms • Define IRB Exempt Studies • Identify research eligible for Expedited Review • Define IND, IDE and Expanded Access • Identify the Categories of Expanded Access • Identify the Types of Regulatory Submissions for Expanded Access

3. Objectives • Identify the Responsibilities of Investigators, Sponsors and IRB with Regard to Expanded Access to Investigational Drugs • Identify the IRB’s Responsibilities in Regard to IND or IDE Exempt Research • Informed Consent Waivers

4. 21 CFR 56Institutional Review Boards Objective: To protect the rights and welfare of human subjects involved in clinical investigations.

5. FDA Authority: 21 CFR 56.101 • IND & IDE research [FD&C Act 505(i) & 520(g)] • Investigations submitted in support of research or marketing applications This may include foods that bear a nutrient content or health claim (including dietary supplements), infant formulas, food & color additives, drugs or biologicals for human use, medical devices for human use and electronic products.

6. Definitions Institutional Review Board – any board, committee, or other group formally designated by an institution to review, to approve the initiation of, and to conduct periodic review of, biomedical research involving human subjects. Human Subject – an individual who is or becomes a participant in research, either as a recipient of the test article or control. A subject may be either a healthyindividual or a patient.

7. Definitions Test article – any drug for human use, 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 FD&C Act or under sections 351 or 354-360F of the PHS Act.

8. Definitions Minimal Risk – 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.

9. Definitions Emergency use – the use of a test article on a human subject in a life-threatening situation in which no standard acceptable treatment is available, and in which there is not sufficient time to obtain IRB approval.

10. Definitions IND – Investigational New Drug application • required to legally ship an unapproved new drug in interstate commerce • establishes conditions for use IDE – Investigational Device Exemption • required to legally ship an investigational medical device

11. IRB Review Exemptions - 21 CFR 56.104 • (a) Any investigation which commenced before July 27, 1981 and was subject to requirements for IRB review under FDA regulations before that date, provided that the investigation remains subject to review of an IRB which meets the FDA requirements in effect before July 27, 1981. • (b) Any investigation commenced before July 27, 1981 and was not otherwise subject to requirements for IRB review under Food and Drug Administration regulations before that date.

12. IRB Review Exemptions - 21 CFR 56.104 • (c) Emergency use of a test article, provided that such emergency use is reported to the IRB within 5 working days. Any subsequent use of the test article at the institution is subject to IRB review. • (d) Taste & food quality evaluations and consumer acceptance studies, if wholesome foods without additives are consumed or if a food is consumed that contains a food ingredient at or below the level and for a use found to be safe, or agricultural, chemical, or environmental contaminant at or below the level found to be safe, by FDA or approved by the EPA or FSIS/USDA

13. Categories of Research Eligible for Expedited Review (A) Research activites that (1) present no more than mimimal risk to human subjects, and (2) involve only procedures listed in one or more of the following categories, may be reviewed by the IRB through the expedited review procedure authorized by 45 CFR 46.110 and 21 CFR 56.110. The activities listed should not be deemed to be of minimal risk simply because they are included on this list. Inclusion on this list merely means that the activity is eligible for review through the expedited review procedure when the specific circumstances of the proposed research involve no more than minimal risk to human subjects.

14. Categories of Research Eligible for Expedited Review (B) The categories in this list apply regardless of the age of subjects, except as noted. (C) The expedited review procedure may not be used where identification of the subjects and/or their responses would reasonably place them at risk of criminal or civil liability or be damaging to the subjects’ financial standing,employability, insurability, reputation, or be stigmatizing, unless reasonable and appropriate protections will be implemented so that risks related to invasion of privacy and breach of confidentiality are no greater than minimal.

15. Categories of Research Eligible for Expedited Review (D) The expedited review procedure may not be used for classified research involving human subjects. (E) IRBs are reminded that the standard requirements for informed consent (or its waiver, alteration, or exception) apply regardless of the type of review—expedited or convened— utilized by the IRB. (F) Categories one (1) through seven (7) pertain to both initial and continuing IRB review.

16. Categories of Research Eligible for Expedited Review (1) Clinical studies of drugs and medical devices only when condition (a) or (b) is met. (a) Research on drugs for which an investigational new drug application (21 CFR Part 312) is not required. (b) Research on medical devices for which (i) an investigational device exemption application (21 CFR Part 812) is not required; or (ii) the medical device is cleared/approved for marketing and the medical device is being used in accordance with its cleared/approved labeling.

17. Categories of Research Eligible for Expedited Review (2) Collection of blood samples by finger stick, heel stick, ear stick, or venipuncture as follows: • From healthy, non-pregnant adults who weigh at least 110 pounds. Amounts drawn NTE 550 ml/8 weeks and no more frequently than 2 times/week; or • (b) from other adults and children, considering the age, weight, and health of the subjects, the collection procedure, the amount of blood to be collected, the frequency with which it will be collected. Amounts drawn NTE the lesser of 50 ml or 3 ml per kg/8 weeks and no more frequently than 2 times/week.

18. Categories of Research Eligible for Expedited Review (3) Prospective collection of biological specimens for research purposes by noninvasive means. (4) Collection of data through noninvasive procedures (not involving general anesthesia or sedation) routinely employed in clinical practice, excluding procedures involving x-rays or microwaves. Where medical devices are employed, they must be cleared/approved for marketing. (Studies intended to evaluate the safety and effectiveness of the medical device are not generally eligible for expedited review, including studies of cleared medical devices for new indications.)

19. Categories of Research Eligible for Expedited Review (5) Research involving materials (data, documents, records, or specimens) that have been collected or will be collected solely for nonresearch purposes (such as medical treatment or diagnosis). (6) Collection of data from voice, video, digital, or image recordings made for research purposes.

20. Categories of Research Eligible for Expedited Review (7) Research on individual or group characteristics or behavior (including, but not limited to, research on perception, cognition, motivation, identity, language, communication, cultural beliefs or practices, and social behavior) or research employing survey, interview, oral history, focus group, program evaluation, human factors evaluation, or quality assurance methodologies.

21. Categories of Research Eligible for Expedited Review (8) Continuing review of research previously approved by the convened IRB as follows: • Where (i) the research is permanently closed to the enrollment of new subjects; (ii) all subjects have completed all research-related interventions; and (iii) the research remains active only for long-term follow-up of subjects; or (b) Where no subjects have been enrolled and no additional risks have been identified; or (c) Where the remaining research activities are limited to data analysis.

22. Categories of Research Eligible for Expedited Review (9) Continuing review of research, not conducted under an investigational new drug application or investigational device exemption where categories two (2) through eight (8) do not apply but the IRB has determined and documented at a convened meeting that the research involves no greater than minimal risk and no additional risks have been identified. [Federal Register Vol. 63, No. 216 Monday, November 9, 1998 pp 60353-60356]

23. More Definitions – Drug Research Expanded Access vs. Access vs. Treatment Use Use of an investigational drug when the primary purpose is to diagnose, monitor or treat a patient’s disease or condition.

24. Expanded Access for Treatment Use FDA has had rules in place since 1987 that have allowed patients to have access to investigational drugs under certain circumstances, even though the safety and effectiveness of the drug has not been fully established. Treatment use is not primarily intended to obtain safety or effectiveness data.

25. Changes to Federal Regulations On August 12, 2009, FDA announced changes to the rules to make them broader and clearer for the patient and the treating physician, while still preserving the integrity of clinical trials designed to find out whether a drug has a desired effect on some disease or condition.

26. Expanded Access Rule In order to permit treatment of a patient with an investigational drug under an expanded access program, FDA generally must be satisfied that: • The patient’s disease or condition has no satisfactory approved therapy. An example of this is a rare type of cancer that has no known or approved treatment. Or, it may be the case that the available treatments did not work for the patient. [21 CFR 312.305(a)]

27. Expanded Access Rule • The potential benefit for the patient justifies the potential risks. An example of this is the potential for longer survival with a disease or condition. • The expanded availability of the untested drug will not interfere with that product’s development. For example, access to an investigational drug shouldn’t interfere with enrollment in clinical trials needed to demonstrate the drug's safety and effectiveness. [21 CFR 312.305(a)]

28. The Expanded Access Rule: • Explains the several different kinds of access that are possible, including access for individual patients, for small numbers of patients, and for large numbers of patients in what are called “treatment protocols” • Ensures safeguards to protect patients • Preserves the ability to develop meaningful data on the drugs available under expanded access

29. Categories of Expanded Access • Access for Individual Patients, including for Emergency Use (21 CFR 312.310) • Access for Intermediate-Size Patient Populations (21 CFR 312.315) • Access for Large Patient Populations under a Treatment IND or Treatment Protocol (21 CFR 312.320)

30. Types of Regulatory Submissions Access Protocol • submitted as an amendment to an existing IND • preferred method when an existing IND is in effect New IND (Access IND/Treatment IND) • for treatment use only • when there is no existing IND in effect or the current sponsor declines to sponsor the treatment access Submissions under an existing IND may be made by either the sponsor or a licensed physician.

31. Content of Submissions The different types of submissions have some differences in content requirements. All must contain information required by 21 CFR 312.305(b). However, • Additional requirements for Individual patient and Emergency submissions are outlined in 21 CFR 312.310(b); • Requirements for Intermediate-size patient populations are in 21 CFR 312.315(c); and • Treatment IND/protocols are addressed in 21 CFR 312.320(b).

32. Role of the Physician • Determine that the probable risk to the patient from the investigational drug is not greater than the probable risk from the disease or condition [21 CFR 312.310(a)] • The decision should be based on the physician’s knowledge of the patient’s clinical situation and based on available information regarding the drug.

33. Role of FDA • Determine that the potential benefit justifies the risks of treatment use and that those risks are not unreasonable in the context of the disease or condition [21 CFR 312.305(a)(2)] • Determine that the patient has a serious or life-threatening disease or condition and no other comparable/satisfactory therapeutic options exist [21 CFR 312.305(a)(1)]

34. Role of FDA • Determine that providing access will not interfere with development of the drug for the expanded access use [21 CFR 312.305(a)(3)] • Determine that the patient may not obtain the drug under another IND or protocol (e.g., in a clinical study) [21 CFR 312.310(a)(2)]

35. Role of the IRB Full board approval is required for all expanded access uses, including individual patient access uses. [21 CFR 312.305(c)(4)]

36. Emergency Authorizations[21 CFR 312.310(d)] • FDA may authorize expanded access for an individual patient without a written submission if there is “an emergency that requires the patient to be treated before a written submission can be made.”(e.g., treatment is needed within a very limited # of hours/days) • The licensed physician/sponsor must agree to submit an expanded access IND or protocol within 15 working days • Reporting to IRB within 5 days [21 CFR 56.104(c)]

37. IND Exempt Research What are the IRB’s responsibilities with respect to verifying the determination of whether an IND is required for an FDA-regulated investigation? The IRB should ask the clinical investigator whether the sponsor determined that an IND is or is not required and the basis for the determination. The IRB may request supporting documentation (e.g., letter from sponsor or FDA).

38. IND Exemptions [21 CFR 312.2(b)] (1) The clinical investigation of a drug product that is lawfully marketed in the United States is exempt from the requirements of this part if all the following apply: • (i) The investigation is not intended to be reported to FDA as a well-controlled study in support of a new indication for use nor intended to be used to support any other significant change in the labeling for the drug;

39. IND Exemptions [21 CFR 312.2(b)] • (ii) If the drug that is undergoing investigation is lawfully marketed as a prescription drug product, the investigation is not intended to support a significant change in the advertising for the product; • (iii) The investigation does not involve a route of administration or dosage level or use in a patient population or other factor that significantly increases the risks (or decreases the acceptability of the risks) associated with the use of the drug product;

40. IND Exemptions [21 CFR 312.2(b)] • (iv) The investigation is conducted in compliance with the requirements for institutional review set forth in part 56 and with the requirements for informed consent set forth in part 50; and • (v) The investigation is conducted in compliance with the requirements of 312.7 (promotion). (2)(i) A clinical investigation involving an in vitro diagnostic biological product listed in paragraph (b)(2)(ii) of this section is exempt from the requirements of this part if

41. IND Exemptions [21 CFR 312.2(b)] (a ) it is intended to be used in a diagnostic procedure that confirms the diagnosis made by another, medically established, diagnostic product or procedure and (b ) it is shipped in compliance with 312.160. (ii) In accordance with paragraph (b)(2)(i) of this section, the following products are exempt from the requirements of this part: (a ) blood grouping serum; (b ) reagent red blood cells; and (c ) anti-human globulin.

42. IND Exemptions [21 CFR 312.2(b)] (3) A drug intended solely for tests in vitro or in laboratory research animals is exempt from the requirements of this part if shipped in accordance with 312.160. (4) FDA will not accept an application for an investigation that is exempt under the provisions of paragraph (b)(1) of this section.

43. IND Exemptions [21 CFR 312.2(b)] (5) A clinical investigation involving use of a placebo is exempt from the requirements of this part if the investigation does not otherwise require submission of an IND. (6) A clinical investigation involving an exception from informed consent under 50.24 of this chapter (i.e., emergency research) is not exempt from the requirements of this part.

44. When in IND Doubt If the Sponsor is uncertain whether an IND is required, the Sponsor should contact the appropriate review division within FDA. If the review division is not known, contact CDER at: Office of Communications, Division of Drug Information, Center for Drug Evaluation and Research, Food and Drug Administration 10001 New Hampshire Avenue, 4th Floor Silver Spring, MD 20993 (301) 796-3400

45. When in IND Doubt Contact CBER at: Office of Communication, Outreach and Development Center for Biologics Evaluation and Research Food and Drug Administration 1401 Rockville Pike, Suite 200N Rockville, MD 20852-1448 (800) 835-4709 or (301) 827-1800

46. Investigational Drug Charging Rule The charging rule permits drug manufacturers to charge patients for an investigational drug in clinical trials or that's being made available for expanded access. Charging in clinical trials will be allowed under very limited circumstances, but will be permitted for most expanded access uses.

47. Expanded Access Mechanisms for Medical Devices • Compassionate Use – IDE Supplement (deviation/change in the investigation) • Emergency Use – IDE Supplement (Notification within 5 days) • Treatment IDE (must be for the same use as an approved IDE) • Continued Access Policy / Extended Investigations – IDE Supplement (does not require life-threatening or serious condition)

49. Expanded Access Mechanisms for Unapproved Devices

50. Expanded Access Mechanisms for Unapproved Devices