1. The Basics of Human Research Protections Office of Research Oversight (ORO) Veterans Health Administration Department of Veterans Affairs February 27, 2004 Thanks to the Office of Human Research Protections for providing some slide text.

2. Outline Ethical Principles Federal Regulations Resources Office of Research Oversight (ORO) 2

3. Ethical Principles Office of Research Oversight (ORO) 3

4. Ethical Principles and Guidelines for the Protection of Human Subjects of Research The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research April 18, 1979 The Belmont Report Office of Research Oversight (ORO) 4

5. Ethical Principles – Belmont Report Respect for Persons –Individual autonomy –Protection of individuals with reduced autonomy Beneficence –Maximize benefits and minimize harms Justice –Equitable distribution of research risks and benefits Office of Research Oversight (ORO) 5

6. Federal Regulations Office of Research Oversight (ORO) 6

7. 45 CFR 46 – Basic HHS Policy for Protection of Human Research Subjects Originally adopted May 1974, Revised January 13, 1981, Revised June 18, 1991 Federal Policy for the Protection of Human Subjects – “The Common Rule” June 18, 1991 Departments of Agriculture, Energy, Commerce, HUD, Justice, Defense, Education, Veterans Affairs, Transportation, and HHS. NSF, NASA, EPA, AID, Social Security Administration, CIA, and the Consumer Product Safety Commission. Federal Regulations and Policy Office of Research Oversight (ORO) 7

8. Federal Regulations and Policy Additional Protections Included in 45 CFR 46: Subpart B – Additional Protections for Pregnant Women, Human Fetuses and Neonates Involved in Research Subpart C – Additional DHHS Protections Pertaining to Biomedical and Behavioral Research Involving Prisoners as Subjects * Subpart D – Additional DHHS Protections for Children Involved as Subjects in Research * * VA follows if waivers from ORD permit inclusion of these populations. Office of Research Oversight (ORO) 8

9. Food and Drug Administration Regulations: Institutional Review Board – 21 CFR 56 Informed Consent – 21 CFR 50 Office of Research Oversight (ORO) 9

10. Differences in VA (38 CFR 16) & FDA (21 CFR Parts 50 & 56) Regulations Basic requirements for IRBs and for Informed Consent are congruent Differences center on differences in applicability –VA regulations based on VA conduct/support of the research –FDA regulations based on use of FDA regulated product: drugs, devices, or biologics Office of Research Oversight (ORO) 10

11. Definitions Research – a systematic investigation designed to develop or contribute to generalizable knowledge. Human Subject – a living individual about whom an investigator conducting research obtains –data through intervention or interaction with the individual, or –identifiable private information (FDA has different definitions) Office of Research Oversight (ORO) 11

12. Exempt Research Some research is “exempt” from federal regulations – six categories of research VHA facilities (not investigators) determine whether proposed research qualifies as “exempt” under VA regulations Office of Research Oversight (ORO) 12

13. Exempt Research Research that is “exempt” includes: Normal educational practices Educational tests, surveys, interviews, or observation of public behavior unless identified and sensitive Research using existing data, documents, records, pathological specimens, or diagnostic specimens, if publicly available or unidentifiable …continued Office of Research Oversight (ORO) 13

14. Exempt Research Research on elected or appointed public officials or candidates for public office Evaluation of public benefit service programs Taste and food quality evaluation and consumer acceptance studies Office of Research Oversight (ORO) 14

15. Basic Protections The regulations contain three basic protections for human subjects: Institutional Assurances Institutional Review Board (IRB) Review Informed Consent Office of Research Oversight (ORO) 15 VA also requires Research and Development Committee review by policy.

16. Institutional Assurances Office of Research Oversight (ORO) 16

17. Assurances Documentation of institutional commitment to comply with the Common Rule for Federally- supported research —OR— ALL human subject research Principal method of compliance oversight Federalwide Assurance Office of Research Oversight (ORO) 17

18. Assurances Required from each VHA facility “engaged” in the research Office of Research Oversight (ORO) 18

19. Engagement Institutions become “engaged” in human subject research whenever their employees or agents –intervene or interact with living individuals for research purposes; or –obtain, release, or access individually identifiable private information for research purposes Awardee institutions are automatically considered to be “engaged” in human subject research even where all activities involving human subjects are carried out by a subcontractor or collaborator Office of Research Oversight (ORO) 19

20. Institutional Review Board Review Office of Research Oversight (ORO) 20

21. IRB Review Institutional Review Board (IRB): A committee charged with the review of human participants research to assure that the rights and welfare of human participants are adequately protected. VA IRBs are subcommittees of the R&D Committee. Why do we need IRB review? –No one can be objective about his/her own work –People underestimate the risks involved in research interventions with which they are quite familiar –People overestimate the benefit of things that are important to them Office of Research Oversight (ORO) 21

22. Institutional Review Board (IRB) Membership: At least five members of varying backgrounds –Sufficiently qualified –Not solely of one profession –Both men and women At least one non-scientist At least one non-affiliated member Expertise on “vulnerable populations” Outside consultants Office of Research Oversight (ORO) 22

23. IRB Responsibilities Review and approve, require modifications, or disapprove all covered research Require that informed consent is in accordance with regulations Require documentation of informed consent or may waive documentation in accordance with regulations Notify investigators in writing of decisions Conduct continuing review of research no less than once per year Office of Research Oversight (ORO) 23

24. IRB Review IRB review and approval must precede initiation of research involving human subjects (Initial Review) * IRB must review and approve changes to the research prior to initiation * In VA, R&D Committee must also approve all research before it commences. Office of Research Oversight (ORO) 24

25. Criteria for IRB Approval Risks to subjects are minimized Risks are reasonable in relation to anticipated benefits Selection of subjects is equitable Informed consent is sought from each subject Informed consent is appropriately documented …continued Office of Research Oversight (ORO) 25

26. Criteria for IRB Approval When appropriate: Data collection is monitored to ensure subject safety Privacy and confidentiality of subjects is protected Additional safeguards are included for vulnerable populations Office of Research Oversight (ORO) 26

27. Full Review Convened meeting – no mail reviews (telephone participation okay under some circumstances) Quorum –Majority of IRB present –At least one non-scientist present –Approval by majority of those present Members with conflict of interest should be absent during discussion and vote Should the quorum fail during a meeting, no further votes can be taken unless the quorum can be restored Office of Research Oversight (ORO) 27

28. Continuing Review Continuing review is to be conducted at intervals appropriate to the degree of risk, but not less than once per year Continuing review must be substantive and meaningful The criteria for IRB approval is the same as for initial review Office of Research Oversight (ORO) 28

29. Expedited Review An IRB may use expedited review for –Research on list of eligible categories IF minimal risk –Minor changes in previously approved research Carried out by IRB chair or one or more experienced IRB members Reviewers can exercise all of the authorities of the IRB except disapproval All IRB members must be informed of research approved under expedited review Office of Research Oversight (ORO) 29

30. Expedited Review Research activities that (1) present no more than minimal risk to human subjects, AND (2) involve only procedures listed in one or more categories published in the expedited review list The categories in the list apply regardless of the age of subjects, except as noted May not be used where identification of the subjects and/or their responses would reasonably place them at risk Office of Research Oversight (ORO) 30

31. Expedited Review May not be used for classified research involving human subjects 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. First seven categories pertain to both initial and continuing IRB review. Office of Research Oversight (ORO) 31

32. Expedited Review Eligible research categories: Clinical studies of drugs and medical devices where IND or IDE not required or device has been approved for marketing and is used as such Collection of blood samples by finger stick, heel stick, ear stick, or venipuncture with restrictions on age, weight, and amount Prospective collection of biological specimens for research purposes by noninvasive means Collection of data through noninvasive procedures routinely employed in clinical practice Office of Research Oversight (ORO) 32

33. Expedited Review Eligible research categories: Research involving materials (data, documents, records, or specimens) that have been collected, or will be collected solely for non- research purposes Collection of data from voice, video, digital, or image recordings made for research purposes Research on individual or group characteristics or behavior or research employing survey, interview, oral history, etc. methodologies Office of Research Oversight (ORO) 33

34. Expedited Review Eligible research categories: Continuing review of research previously approved by the convened IRB with no further direct subject participation Continuing review of research (not under IND or IDE) where 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 Office of Research Oversight (ORO) 34

35. Informed Consent Office of Research Oversight (ORO) 35 Informed Consent

36. Beyond the Consent Form Office of Research Oversight (ORO) 36 CIP

37. The Consent Process Full disclosure of the nature of the research and the subject’s participation Adequate comprehension on the part of the potential subjects, and The subject’s voluntary choice to participate Office of Research Oversight (ORO) 37 Informed consent is not a single event or just a form to be signed – rather, it is an educational process that takes place between the investigator and the prospective or enrolled subject. Necessary elements of the consent process include:

38. Basic Elements 1.Research Purpose Duration Procedures 2.Risks 3.Benefits 4.Alternatives 5.Confidentiality 6.Compensation for Injury 7.Whom to Contact 8.Right to Refuse or Withdraw Office of Research Oversight (ORO) 38

39. Additional Elements 1.Risks related to pregnancy 2.Anticipated reasons for termination from the study 3.Costs 4.Consequences of withdrawal 5.New findings 6.Number of subjects Office of Research Oversight (ORO) 39

40. Comprehension Informed consent is not valid unless the consenter understands the information that has been provided. The investigator must consider the nature of the proposed subject population, the type of information to be conveyed, and the circumstances under which the consent process will take place in determining the appropriate way to present the information. Office of Research Oversight (ORO) 40

41. Voluntary Consent To be valid, consent must be freely given – free from all forms of coercion. In addition to overt coercion, the investigator needs to be sensitive to more subtle forms of coercion, such as social pressure, requests from authority figures, and undue incentives for participation. Office of Research Oversight (ORO) 41

42. Documentation of Consent The consent form is merely the documentation of informed consent and does not, in and of itself, constitute informed consent. The fact that a subject signed a consent form does not mean that s/he understood what was being agreed to or truly gave his/her voluntary consent. Informed consent is a process that is documented by a signed consent form. Office of Research Oversight (ORO) 42 Documentation of “legally effective informed consent” usually involves the use of a written consent form signed by the subject or the subject’s legal representative.

43. IRB Waivers Office of Research Oversight (ORO) 43

44. IRB Waiver – Informed Consent The research involves no more than minimal risk to subjects; The waiver will not adversely affect the rights and welfare of subjects; The research could not practicably be carried out without the waiver; and Whenever appropriate, the subjects will be debriefed – provided with additional pertinent information after they have participated in the study. Office of Research Oversight (ORO) 44 The IRB may approve a waiver of some or all of the consent requirements provided that:

45. IRB Waiver – Documentation of Consent The principal risks are those associated with a breach of confidentiality concerning the subject’s participation in the research; and the consent document is the only record linking the subject with the research; —OR— The research presents no more than minimal risk; and involves procedures that do not require written consent when performed outside of a research setting. Office of Research Oversight (ORO) 45 The IRB may waive the requirement for written documentation of consent in cases where:

46. Vulnerable Populations Office of Research Oversight (ORO) 46

47. Subpart C -- Prisoners HHS issued special protections in 1978 No Exemptions allowed Definition of a “prisoner” Additional duties of the IRB Office of Research Oversight (ORO) 47

48. Subpart D -- Children Definition of a “child” “Permission” “Assent” IRB duties Office of Research Oversight (ORO) 48

49. VHA Handbook 1200.5 Requirements for the Protection of Human Subjects in Research July 15, 2003 Office of Research Oversight (ORO) 49

50. Resources Office of Research Oversight (ORO) 50

51. Electronic Resources OHRP Website: http://ohrp.osophs.dhhs.govhttp://ohrp.osophs.dhhs.gov –IRB Registration & Assurance Filing –Quality Improvement Program –Policy Guidance –Compliance Oversight –Educational Materials/Workshops ORO Website: http://www.va.gov/oro/http://www.va.gov/oro/ –ORO’s Regional Office locations and contact information –ORO’s Central Office contact information ORD Website: http://www.va.gov/resdev/http://www.va.gov/resdev/ –PRIDE’s Website: http://www.va.gov/resdev/fr/PRIDEhttp://www.va.gov/resdev/fr/PRIDE Office of Research Oversight (ORO) 51