Post on 19-Dec-2015
transcript
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IRB review andassessment of risks / benefits
Bernard Lo, M.D.
bernie@medicine.ucsf.edu
August 9 and 12, 2010
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RCR course
CHR course
Book in bookstore
Epi201 website Updates
Room changes
Starting time? 9 AM?
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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
http://ctsi.ucsf.edu
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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
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Nazi “experiments”
1. Cause intentional and lethal harm
2. No consent
3. Use vulnerable subjects who were
coerced into participating
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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 ethical tension in research
Primary goal is generalizable
knowledge, benefit to society
Participants experience risks but
benefit to others
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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
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Regulations respond to Tuskegee
1. Beneficence Risks must be acceptable in light of
benefits Risks must be minimized IRB must approve study Psychosocial risks?
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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
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Regulations respond to Tuskegee
3. Justice Equitable selection of subjects Protections for vulnerable subjects Access to benefits of research?
Federal regulations
1. Risks / benefits
2. Informed and voluntary consent
3. IRB review and approval
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Topics to cover
What risks must we consider? Biomedical interventions Secondary analysis of existing data Psychosocial risks
How to decrease risks
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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
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Biomedical risks of study
Injection-related adverse effects
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Psychosocial risks of study
Behavioral disinhibition May increase high-risk behaviors
Stigma and discrimination False +HIV test If confidentiality breached
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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 test21
Outcomes of trial
No reduction in HIV incidence Higher incidence in men with Ad5
antibodies, uncircumcised
Research intervention may have
serious unexpected adverse effect
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Birmingham VA research
1.3 million MDs SSN
Not encrypted, not password protected
Employee not authorized to have data
Risk in secondary data analysis
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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
How to protect confidentiality
Train staff
Use coded or de-identified data
whenever possible
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Study 1: How to minimize risks?
Data security Locked paper files Password protection No identified data on laptops, removable
devices Encryption
Certificate of confidentiality
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
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Question for audience
What are risks of study?
How to minimize risks?
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If confidentiality breached
Legal risk: illegal activities, prison
sentence
Economic harm: loss of employment
Certificates of confidentiality
May withhold names and identifiers in
case of subpoena or court order
Issued by NIH Need not be NIH-funded study
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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
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How to decrease risk
Monitor for adverse events
Respond to serious adverse event
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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
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Question for audience
Do you regard benefit / risk balance as
acceptable? Yes No Unsure
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How to reduce risks of study?
Exclude persons at increased risk Exclude Ad5 +, uncircumcised
Monitor adverse effects carefully Continuous monitoring of incident
infections
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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
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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
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Federal regulations
Risks must be reasonable compared to
potential knowledge gained
Risks must be minimized (consistent
with valid research design)
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
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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
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Framework for analyzing study
Importance of informed consent Explicitly discuss that may increase
infection Test comprehension in participants
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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
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