IRB review and assessment of risks / benefits

1. IRB review andassessment of risks / benefits Bernard Lo, M.D. July 31, 2008

2. Why do we have IRBs? • Why do we have federal research regulations?

3. Nazi “experiments” • Unacceptable risk • No consent • Use of vulnerable subjects

4. Tuskegee study 1932 Study started 1936 Journal told that local MDs asked not to treat subjects 1940 Subjects not treated in military 1947 USPHS Rapid Treatment Centers

5. Tuskegee study 1968 Whistleblower Peter Buxtun 1969 CDC local chapters of AMA and NMA reaffirm support, 1970 News coverage

6. Tuskegee study 1974 DHEW issues regulations on funded research 1974 Tuskegee Benefit Program

7. Fundamental tension in research • Primary goal is generalizable knowledge, benefit to society • Participants face risks but benefit to others

8. Ethical violations in Tuskegee • Inappropriate risk / benefit ratio • Lack of informed and voluntary consent • Targeting of vulnerable population

9. Regulations respond to Tuskegee • Beneficence • Risks must be acceptable • Risks must be minimized • Respect for persons • Informed and voluntary consent

10. Regulations respond to Tuskegee • Justice • Equitable selection of subjects • Protections for vulnerable subjects

11. Federal requirements for research • Review by IRB • Independent of investigators • Risks / benefits acceptable • Risks must be minimized • Must understand science • Include psychosocial risks • Confidentiality

12. Federal requirements for research • Informed and voluntary consent • Concerns about undue inducement if payment • Exceptions to consent • Not capable of consent (children, adults who lack decision-making capacity) • Impracticable to obtain consent

13. Study 1: epidemiology of hepatitis C • Prospective cohort study of incidence of hepatitis C and risk factors • Blood draws • Questionnaires

14. Study 1: epidemiology of hepatitis C • Target population? • Injection drug users • Commercial sex workers • Vulnerable populations at higher risk need special protection

15. Study 1: epidemiology of hepatitis C • Medical risks minimal • Physical risks of questionnaires tiny • Psychosocial risks considerable • Highly sensitive data • Alcohol and substance abuse • Sexual behaviors, STDs, HIV • Illegal activities: sex for $, IDU • (Psychiatric illness)

16. Study 1: epidemiology of hepatitis C • If confidentiality breached • Legal risk: illegal activities • Social harm: stigma, disruption of relationships • Economic harm: loss of employment

17. Study 1: epidemiology of hepatitis C • How to minimize risks? • Staff training • Use coded or de-identified data • Data security

18. Study 1: epidemiology of hepatitis C • How to minimize risks? • Data security • Do not store identified data on laptops, removable devices • Encryption • Certificate of confidentiality • Inform participants of risk during consent process

19. Study 1: epidemiology of hepatitis C • Cannot guarantee absolute confidentiality • Reporting of communicable diseases • Audits by funders

21. Study 2: cholesterol-lowering drug • Phase II RCT to study whether new drug to lower LDL prevents progression of coronary disease • Compare to standard statin • Known to lower LDL more than statins

22. Study 2: cholesterol-lowering drug • Primary endpoint is progression of CAD on follow-up angiography compared to baseline angiography • Secondary endpoints • Combined cardiac death + MI • Ischemia on exercise nuclear imaging

23. Study 2: context • Drug already approved by FDA on basis of LDL reduction • Is advantage in vascular progression a surrogate endpoint? • More power to detect surrogate endpoint than clinical endpoint

24. Question for audience • Would repeat angiography be indicated in clinical care after starting patient on lipid-lowering drug?

25. Question for audience • Conceivable that detect L main stenosis?

26. Question for audience • Do you regard benefit / risk balance as acceptable?

27. Study 2: What are benefits of study? • Direct benefits intended by study design • Drug to lower LDL, monitoring of LDL • ? Angiography

28. Study 2: What are benefits of study? • Collateral benefits of being in study, independent of research intervention • Education about CAD risk • Attention of staff • Payment for participation • May not be considered by IRB as benefit

29. Study 2: What are risks of study? • Procedures that offer prospect direct benefit • Adverse effects of study drug • Procedures to answer research question • Risks of angiography

30. Questions regarding Study 2 • May invasive procedures not indicated in clinical care be allowed in research? • How can risks and benefits of complex study be combined into overall assessment?

31. For interventions that offer prospect of direct benefit • Greater level of risk acceptable than for interventions solely for research • Balance of benefits / burdens should be comparable to standard care

32. For interventions that offer no prospect of direct benefit • May not justify by benefits of study drug • Study drug might reduce cardiac events • May not justify by collateral benefits

33. For interventions that offer no prospect of direct benefit • Risks must be reasonable compared to potential knowledge gained • Risks must be minimized consistent with valid research design

34. In Study 2 • Are risks minimized? • Noninvasive means to assess progression of vascular occlusion • CT angiography • Doppler studies of carotid arteries

35. In Study 2 • What is potential knowledge gained? • Is greater reduction in LDL clinically meaningful? • What will this study add to what is already known?

36. Question for audience • Do you regard benefit / risk balance as acceptable?

37. Outcome of Study 2 • Endpoint was progression of carotid disease evaluated by Doppler • Study was negative study • Was short-term benefit realistic?

39. Looking ahead • When is IRB review not necessary? • Not research • Certain survey, interview research • Certain research with existing data and biological specimens

40. Looking ahead • When may IRB review be expedited? • Minimal risk in technical sense • On list approved by DHHS • Venipuncture • Noninvasive • Not XRs • Minor changes • Continuing review

41. Practical IRB tips on 8/14 • Bring your questions!