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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”

1. Unacceptable risk

2. No consent

3. 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

1. Inappropriate risk / benefit ratio

2. Lack of informed and voluntary

consent

3. Targeting of vulnerable population

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Regulations respond to Tuskegee

1. Beneficence Risks must be acceptable Risks must be minimized

2. Respect for persons Informed and voluntary consent

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Regulations respond to Tuskegee

3. 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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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!