1 IRB review and assessment 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” 1. Unacceptable risk 2. No consent 3. Use of vulnerable subjects

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

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

6 Tuskegee study 1974DHEW 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 1. Inappropriate risk / benefit ratio 2. Lack of informed and voluntary consent 3. Targeting of vulnerable population

9 Regulations respond to Tuskegee 1. Beneficence  Risks must be acceptable  Risks must be minimized 2. Respect for persons  Informed and voluntary consent

10 Regulations respond to Tuskegee 3. 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

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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?

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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!