1. IRB Review: Beyond the Basics Kevin L. Nellis, M.S., M.T. (A.S.C.P.) Program Analyst Program for Research Integrity Development and Education (PRIDE) March 23, 2011

2. Goal Applying The Belmont Report Common Rule VHA Handbook 1200.05 … to VA IRB Review 2

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4. The Belmont Report Boundaries Between Practice and Research Principles Respect for persons Beneficence Justice 4

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6. Common Rule IRB Approval Criteria 38 CFR 16.111 38 CFR 16.111 criteria must be met before the IRB can grant approval Expedited review Convened initial review Continuing review Amendments 6

7. Common Rule IRB Approval Criteria 38 CFR 16.111 Risks are minimized Risk/benefit balance is reasonable Subject selection is equitable Appropriate informed consent will be sought Informed consent will be appropriately documented Safety will be appropriately monitored Privacy and confidentiality will be protected Additional safeguards included for vulnerable subjects VHA Handbook 1200.05, Paragraph 17 7

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9. Additional Criteria for IRB Approval VHA Handbook 1200.05, Paragraph 17(i-k) Conflicts of interest must be managed or eliminated Investigator must have appropriate background and experience Ensure consistency of Protocol Informed consent form HIPAA authorization When applicable, comply with other VA regulations 9

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11. Home Telemonitoring Case Study Veterans over the age 60 with multiple chronic illnesses and at risk for worsening medical status are randomized: 100 provided with home telemonitoring device 100 placed in a usual care arm Make appointments when problems arise Use the 24 hr nurse hotline and My HealtheVet that is available to all patients at the XYZ VAMC Outcomes are assessed by hospitalizations and ER visits over 1 yr 11

12. Boundaries Between Practice and Research The Belmont Report Research and clinical practice can be blurred when they occur together ‘Practice’ provides diagnosis, preventive treatment or therapy ‘Research’ designates an activity designed to develop or contribute to generalizable knowledge VHA Handbook 1200.05 differentiates usual care from research 12

13. How Are Boundaries Between Practice and Research Applied to IRB Review of Home Telemonitoring Study? IRB ensures Protocol clearly differentiates the usual care (appointments and 24 hr nurse hotline) from the research (home telemonitoring arm) Informed consent defines risks related to the research Risks associated with reliance on telemonitoring (versus the usual care risks from appointments and 24 hr hotline) 13

14. Principle of Respect for Persons The Belmont Report IRB review must ensure Persons are treated in an ethical manner Respect their decisions Protect them from harm Individuals are treated as autonomous agents Provide potential subjects with sufficient information so they are free to make their own decisions 14

15. Principle of Respect for Persons The Belmont Report IRB review must ensure the immature and the incapacitated are respected and protected Some may need to be excluded Others require little protection beyond making sure they undertake activities freely and are aware of possible risks Extent of protection varies based on Person or population Circumstances 15

16. How is the Principle for Respect for Persons Applied to IRB Review? Ensure full disclosure of information Debrief subjects involving incomplete disclosure Manner and context is important Adapt process to subject’s ability to comprehend information May be suitable to give oral or written tests of comprehension 16

17. How is the Principle for Respect for Persons Applied to IRB Review? Ensure that informed consent process is Voluntary Without undue influence Ensure additional protections described for vulnerable populations Required additional findings Provisions for surrogate consent 17

18. How is Respect Applied to IRB Review of Home Telemonitoring Study? IRB should ensure full disclosure of information in the informed consent process IRB may require testing subjects to ensure they understand how to operate home telemonitoring equipment IRB may require investigator to exclude certain populations (e.g., patients with certain diseases, persons who lack decision-making capacity, etc) IRB ensures privacy is maintained 18

19. Principle of Beneficence The Belmont Report Make efforts to secure subjects’ well-being Do not harm - fundamental principle of medical ethics Benefits must outweigh the risks Risks must be justified 19

20. Principle of Beneficence How is This Applied to IRB Review? Ensure that science is valid Ensure protocol and informed consent process distinguish and clarify risks as much as possible Psychological Physical Legal Social Economic 20

21. How is the Principle of Beneficence Applied to IRB Review? IRB cannot permit brutal or inhumane treatment of subjects IRB ensures that benefits and risks are “balanced” and shown to be “in a favorable ratio” IRB ensures justification of Significant risks Appropriateness of involving vulnerable populations IRB can add protections to minimize the significant risks 21

22. How is the Principle of Beneficence Applied to IRB Review? IRB ensures appropriate safety monitoring Privacy Officer and ISO ensure appropriate protections for Privacy Confidentiality Information security 22

23. How is Beneficence Applied to IRB Review of Home Telemonitoring Study? IRB must ensure that the risks are reasonable in relationship to the potential benefits of the research IRB determines whether the subjects are vulnerable and if additional protections are needed Privacy Officer and ISO evaluate protections for privacy, confidentiality, and information security 23

24. A Closer Look at Beneficence Principle of Therapeutic Misconception Principle of Equipoise 24

25. Principle of Therapeutic Misconception Subjects misunderstand the primary purpose of the research as therapeutic Fail to appreciate the difference between research and treatment Underestimate risk Overestimate benefit Undermines informed consent Investigators can be susceptible to believing research offers a direct benefit 25

26. How is Therapeutic Misconception Avoided? IRB should evaluate quality of protocol and informed consent process to ensure they do not promote potential therapeutic misconception In Phase I trials (e.g., first time testing in humans to assess safety and tolerability), IRB should insist on clarity for Proposed dosing strategy How investigators plan to assure that subjects understand the nature of the purpose of the study 26

27. How is Therapeutic Misconception is Avoided in the Home Telemonitoring Study? IRB may ensure that telemonitoring is fully described as a research intervention in the protocol and informed consent IRB may ensure home telemonitoring is not described as a standard clinical intervention for this entity 27

28. Principle of Equipoise Genuine uncertainty as to whether the outcomes of the research will be beneficial If the answer to the research question is known, the research is not “in equipoise” Subjects may participate in a randomized controlled research study only when uncertainty surrounds which arm they should be in 28

29. How is Equipoise applied to IRB Review of Telemonitoring Study? There must be a genuine uncertainty as to whether the outcomes of telemonitoring are different than the outcomes of usual care There are no data demonstrating home telemonitoring is or is not equivalent to usual care 29

30. Principle of Justice The Belmont Report Distribute the burdens and benefits of research equally Ensure subjects are selected for reasons directly related to the problem being studied Do not select subjects because they are Readily availability In a compromised position Easy to manipulate 30

31. Principle of Justice The Belmont Report Advances resulting from research should provide advantages to everyone affected Research should not unduly involve persons from groups unlikely to benefit from the research 31

32. How is the Principle of Justice Applied to IRB Review? Select classes of subjects in an order of preference (e.g., adults before children) Be cognizant of biases Social Racial Sexual Cultural 32

33. How is the Principle of Justice Applied to IRB Review? Ensure that researchers exhibit fairness: Should not offer research to only favored individuals or populations Should not select only "undesirable" persons for risky research Should not focus on vulnerable populations for convenience IRB must consider the individual’s access to research participation and the impact on groups 33

34. How is This Applied to IRB Review of Home Telemonitoring Study? IRB should determine if the right group of subjects are selected for the study Are the inclusion criteria appropriate? Are others appropriately excluded? Is it appropriate to exclude homeless Veterans? Does the recruitment strategy select Veterans at risk for worsening medical status because they are easy to approach in clinics? 34

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36. How are ‘Minimization of Risks’ and ‘Risks and Benefits Analysis’ Applied to IRB Review? IRB needs to understand the research Science can be evaluated by Scientific Review Committee IRB needs to evaluate ALL the risks (psychological, physical, legal, social, economic) of research and ensure that risks are minimized Apply the Belmont principle of beneficence 38 CFR 16.111(a)(1)-(2) 36

37. How does Equitable Selection of Subjects Apply to IRB Review? IRB must take inclusion and exclusion criteria into account, based on Purpose of the research Research setting Vulnerabilities If non-Veterans are to be recruited the must be justification Apply the Belmont principle of justice 38 CFR 16.111(a)(3) 37

38. How does the IRB Evaluate the Informed Consent Process? Ensure that legally effective informed consent is obtained from each prospective subject or the subject’s LAR Ensure that Informed consent form 10-1086 meets all the requirements of VHA Handbook 1200.05 Ensure that information exchanged before the study is appropriate (e.g., recruitment process and advertising) Ensure the process avoids overly optimistic language Provide genetic counseling, access to social worker, referrals, or other support, as appropriate 38 CFR 16.111(a)(4-5) 38 CFR 16.111(a)(4)-(5) 38

39. How Does the IRB Apply Safety Monitoring to IRB Review? Ensures the research plan must make adequate provisions for monitoring the data collected to ensure the safety of subjects, when applicable Research plan may include Establishing a Data Monitoring Committee (DMC) Plan for reporting DMC findings to the IRB and the sponsor IRB can witness the consent process 38 CFR 16.111(a)(6) 39

40. How Does the IRB Ensure Privacy and Confidentiality? The IRB must determine there are adequate provisions to protect privacy of subjects and maintain the confidentiality of data, taking into consideration HIPAA Privacy Rule Privacy Act of 1974 VA Claims Confidentiality Statute Confidentiality of Drug Abuse, Alcoholism and Alcohol Abuse, Infection with Human Immunodeficiency Virus (HIV), and Sickle Cell Anemia Medical Records Confidentiality of Healthcare Quality Assurance Review Records VHA Handbook 1200.05, Paragraph 17(f) 40

41. How Does the IRB Ensure Privacy and Confidentiality? ISO ensures Implementation of applicable VHA and VA information security policies pertaining to research (VA Directive 6500 and its Handbooks) 38 CFR 16.111(a)(7) 41

42. How Does the IRB Ensure Vulnerable Subjects are Protected? Ensure all required determinations are made Ensure additional safeguards outlined in the protocol are appropriate Ensure adequate plans are in place if subjects are likely to Loose decision-making capacity Become pregnant Become incarcerated 38 CFR 16.111(b) 42

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44. Conflict of Interest (COI) VHA Handbook 1200.05, Paragraph 17(i) IRB ensures COI does not undermine credibility of the research IRB ensures all COI is Managed, reduced, or eliminated Financial Role (investigator-patient relationships) Professional Institutional Personal roles 44

45. Conflict of Interest (COI) Considerations IRB ensures disclosure of COI within the 10-1086 is done in an obvious and meaningful manner, when appropriate IRB considers whether the COI impacts Risks of the study Study design or Procedures Monitoring Reporting Data analysis Recruitment or enrollment 45

46. Investigator Qualifications VHA Handbook 1200.05, Paragraph 17(j) Ensure that investigators have the appropriate background and experience to conduct the research NOTE: The IRB is not responsible for confirming that the investigator or other research team members have met current credentialing, privileging, and training requirements 46

47. IRB Must Ensure Consistent Documentation VHA Handbook 1200.05, Paragraph 17(k) IRB ensures the following are consistent with the protocol and IRB application: Informed consent document Waiver (or alteration) of informed consent Waiver of documentation of informed consent HIPAA authorization Waiver of HIPAA authorization 47

48. Key Points The IRB makes specific findings to grant IRB approval in consideration with : The principles of the Belmont Report The Common Rule VHA Handbook 1200.05 and other VA requirements 48

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