IRB review and assessment of risks benefits

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IRB review andassessment of risks / benefits

• Bernard Lo, M.D.
• July 31, 2008

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

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Nazi experiments

• Unacceptable risk
• No consent
• Use of vulnerable subjects

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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

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Tuskegee study

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

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Tuskegee study

• 1974 DHEW issues regulations on funded research
• 1974 Tuskegee Benefit Program

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Fundamental tension in research

• Primary goal is generalizable knowledge, benefit
  to society
• Participants face risks but benefit to others

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Ethical violations in Tuskegee

• Inappropriate risk / benefit ratio
• Lack of informed and voluntary consent
• Targeting of vulnerable population

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Regulations respond to Tuskegee

• Beneficence
• Risks must be acceptable
• Risks must be minimized
• Respect for persons
• Informed and voluntary consent

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Regulations respond to Tuskegee

• Justice
• Equitable selection of subjects
• Protections for vulnerable subjects

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Federal requirements for research

• Review by IRB
• Independent of investigators
• Risks / benefits acceptable
• Risks must be minimized
• Must understand science
• Include psychosocial risks
• Confidentiality

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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

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Study 1 epidemiology of hepatitis C

• Prospective cohort study of incidence of
  hepatitis C and risk factors
• Blood draws
• Questionnaires

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Study 1 epidemiology of hepatitis C

• Target population?
• Injection drug users
• Commercial sex workers
• Vulnerable populations at higher risk need
  special protection

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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)

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Study 1 epidemiology of hepatitis C

• If confidentiality breached
• Legal risk illegal activities
• Social harm stigma, disruption of relationships
• Economic harm loss of employment

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Study 1 epidemiology of hepatitis C

• How to minimize risks?
• Staff training
• Use coded or de-identified data
• Data security

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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

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Study 1 epidemiology of hepatitis C

• Cannot guarantee absolute confidentiality
• Reporting of communicable diseases
• Audits by funders

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(No Transcript)
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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

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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

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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

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Question for audience

• Would repeat angiography be indicated in clinical
  care after starting patient on lipid-lowering
  drug?

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Question for audience

• Conceivable that detect L main stenosis?

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Question for audience

• Do you regard benefit / risk balance as
  acceptable?

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Study 2 What are benefits of study?

• Direct benefits intended by study design
• Drug to lower LDL, monitoring of LDL
• ? Angiography

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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

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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

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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?

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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

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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

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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

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In Study 2

• Are risks minimized?
• Noninvasive means to assess progression of
  vascular occlusion
• CT angiography
• Doppler studies of carotid arteries

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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?

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Question for audience

• Do you regard benefit / risk balance as
  acceptable?

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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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Looking ahead

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

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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

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Practical IRB tips on 8/14

• Bring your questions!