1. 1 IRB review and assessment of risks / benefits Bernard Lo, M.D. bernie@medicine.ucsf.edu August 9 and 12, 2010

2. 2 RCR course  CHR course  Book in bookstore  Epi201 website  Updates  Room changes  Starting time? 9 AM?

3. 3 RCR course  Final project 1. If primary data collection, ethics part of your grant 2. If secondary data collection, ethics part of your grant under which data collected 3. Take exam with cases that pose ethical dilemmas

4. http://ctsi.ucsf.edu

5. 5 Overview of today  Why do we have IRBs?  What are the federal regulations for human subjects research?  What risks are acceptable in research?  Case examples

6. 6 Nazi “experiments” 1. Cause intentional and lethal harm 2. No consent 3. Use vulnerable subjects who were coerced into participating

7. 7 Tuskegee study 1932Study started 1936Journal told that local MDs asked not to treat subjects 1940Subjects not treated in military 1947USPHS Rapid Treatment Centers

8. 8 Tuskegee study 1968Whistleblower Peter Buxtun 1969CDC, local chapters of AMA and NMA reaffirm support 1970News coverage

9. 9 Tuskegee study 1974DHEW issues regulations on funded research 1974 Tuskegee Benefit Program

10. 10 Fundamental ethical tension in research  Primary goal is generalizable knowledge, benefit to society  Participants experience risks but benefit to others

11. 11 Ethical violations in Tuskegee 1. Serious harm to participants  Deliberately withhold standard treatment 2. Consent not informed  Deception during consent process 3. Unfair selection of participants  Take advantage of vulnerable population

12. 12 Regulations respond to Tuskegee 1. Beneficence  Risks must be acceptable in light of benefits  Risks must be minimized  IRB must approve study  Psychosocial risks?

13. 13 Regulations respond to Tuskegee 2. Respect for persons  Informed and voluntary consent  Not capable of consent (children, adults who lack decision-making capacity)  Impracticable to obtain consent

14. 14 Regulations respond to Tuskegee 3. Justice  Equitable selection of subjects  Protections for vulnerable subjects  Access to benefits of research?

15. Federal regulations 1. Risks / benefits 2. Informed and voluntary consent 3. IRB review and approval 15

16. Topics to cover  What risks must we consider?  Biomedical interventions  Secondary analysis of existing data  Psychosocial risks  How to decrease risks 16

18. HIV vaccine trial  Vaccine to induce cellular immunity to HIV  Subjects at high risk for HIV  Injection drug users  Multiple sexual partners Commercial sex workers 18

19. Biomedical risks of study  Injection-related adverse effects 19

20. Psychosocial risks of study  Behavioral disinhibition  May increase high-risk behaviors  Stigma and discrimination  False +HIV test  If confidentiality breached 20

21. Measures to reduce risk  At every visit, risk reduction counseling, condoms  Reduces power  Monitoring of high-risk behaviors  No difference in placebo and vaccine groups  Cards, letters to explain false + HIV test 21

22. Outcomes of trial  No reduction in HIV incidence  Higher incidence in men with Ad5 antibodies, uncircumcised  Research intervention may have serious unexpected adverse effect 22

23. Birmingham VA research  1.3 million MDs  SSN  Not encrypted, not password protected  Employee not authorized to have data  Risk in secondary data analysis 23

24. Letter from VA  “We at the VA take information security and privacy very seriously. We apologize for any inconvenience or concern this situation may cause, but we believe it is important for you to be fully informed of any potential risk to you” 24

25. How to protect confidentiality  Train staff  Use coded or de-identified data whenever possible 25

26. 26 Study 1: How to minimize risks?  Data security  Locked paper files  Password protection  No identified data on laptops, removable devices  Encryption  Certificate of confidentiality

27. Study on use of marijuana in cancer patients  Determine prevalence of use  Compare pain relief and chemotherapy- related nausea in users and non-users  One study site MD Anderson in Texas 27

28. Question for audience  What are risks of study?  How to minimize risks? 28

29. 29 If confidentiality breached  Legal risk: illegal activities, prison sentence  Economic harm: loss of employment

30. Certificates of confidentiality  May withhold names and identifiers in case of subpoena or court order  Issued by NIH  Need not be NIH-funded study 30

31. Certificates of confidentiality  May withhold names and identifiers in case of subpoena or court order  Not well tested in courts  Issued by NIH  Need not be NIH-funded study 31

32. How to decrease risk  Monitor for adverse events  Respond to serious adverse event 32

33. 33 New HIV vaccine trial  DNA plasmids express gag, pol, nef  Adenovirus vector booster that encodes for gag, pol, env  Differ from earlier vaccine  More balanced CD4 and CD8 response  More immunity to HIV rather than Ad

34. 34 Question for audience  Do you regard benefit / risk balance as acceptable?  Yes  No  Unsure

35. 35 How to reduce risks of study?  Exclude persons at increased risk  Exclude Ad5 +, uncircumcised  Monitor adverse effects carefully  Continuous monitoring of incident infections

36. 36 How to reduce risks of study?  Stop trial if significantly increased infections in vaccine group  Data and Safety Monitoring Committee Independent of sponsor and investigators  Statistical stopping rules

37. 37 Questions regarding new trial  How to combine risks and benefits into overall assessment?  Primary efficacy endpoint = viral load in new infections  Primary safety endpoint = new infections

38. 38 Federal regulations  Risks must be reasonable compared to potential knowledge gained  Risks must be minimized (consistent with valid research design)

39. Framework for analyzing study  Underlying condition/prognosis is serious  Foregoing trial has costs  Potential benefit of study is high  Likelihood and magnitude of benefit requires in-depth scientific review 39

40. Framework for analyzing study  Risk of study intervention is high  DSMB decided that any statistically significant increase in HIV incidence would terminate the study 8-2 split in first 10 incident infections 40

41. Framework for analyzing study  Importance of informed consent  Explicitly discuss that may increase infection  Test comprehension in participants 41

42. Take home message  Risks can be serious, even in secondary analysis and questionnaire research  Assessment of benefits and risks made by IRB independent of investigators 42