![Page 1: 1 IRB review and assessment of risks / benefits Bernard Lo, M.D. bernie@medicine.ucsf.edu August 9 and 12, 2010](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649d395503460f94a13358/html5/thumbnails/1.jpg)
1
IRB review andassessment of risks / benefits
Bernard Lo, M.D.
August 9 and 12, 2010
![Page 2: 1 IRB review and assessment of risks / benefits Bernard Lo, M.D. bernie@medicine.ucsf.edu August 9 and 12, 2010](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649d395503460f94a13358/html5/thumbnails/2.jpg)
2
RCR course
CHR course
Book in bookstore
Epi201 website Updates
Room changes
Starting time? 9 AM?
![Page 3: 1 IRB review and assessment of risks / benefits Bernard Lo, M.D. bernie@medicine.ucsf.edu August 9 and 12, 2010](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649d395503460f94a13358/html5/thumbnails/3.jpg)
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
![Page 4: 1 IRB review and assessment of risks / benefits Bernard Lo, M.D. bernie@medicine.ucsf.edu August 9 and 12, 2010](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649d395503460f94a13358/html5/thumbnails/4.jpg)
http://ctsi.ucsf.edu
![Page 5: 1 IRB review and assessment of risks / benefits Bernard Lo, M.D. bernie@medicine.ucsf.edu August 9 and 12, 2010](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649d395503460f94a13358/html5/thumbnails/5.jpg)
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
![Page 6: 1 IRB review and assessment of risks / benefits Bernard Lo, M.D. bernie@medicine.ucsf.edu August 9 and 12, 2010](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649d395503460f94a13358/html5/thumbnails/6.jpg)
6
Nazi “experiments”
1. Cause intentional and lethal harm
2. No consent
3. Use vulnerable subjects who were
coerced into participating
![Page 7: 1 IRB review and assessment of risks / benefits Bernard Lo, M.D. bernie@medicine.ucsf.edu August 9 and 12, 2010](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649d395503460f94a13358/html5/thumbnails/7.jpg)
7
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
![Page 8: 1 IRB review and assessment of risks / benefits Bernard Lo, M.D. bernie@medicine.ucsf.edu August 9 and 12, 2010](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649d395503460f94a13358/html5/thumbnails/8.jpg)
8
Tuskegee study
1968 Whistleblower Peter Buxtun
1969 CDC, local chapters of AMA and
NMA reaffirm support
1970 News coverage
![Page 9: 1 IRB review and assessment of risks / benefits Bernard Lo, M.D. bernie@medicine.ucsf.edu August 9 and 12, 2010](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649d395503460f94a13358/html5/thumbnails/9.jpg)
9
Tuskegee study
1974 DHEW issues regulations on
funded research
1974 Tuskegee Benefit Program
![Page 10: 1 IRB review and assessment of risks / benefits Bernard Lo, M.D. bernie@medicine.ucsf.edu August 9 and 12, 2010](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649d395503460f94a13358/html5/thumbnails/10.jpg)
10
Fundamental ethical tension in research
Primary goal is generalizable
knowledge, benefit to society
Participants experience risks but
benefit to others
![Page 11: 1 IRB review and assessment of risks / benefits Bernard Lo, M.D. bernie@medicine.ucsf.edu August 9 and 12, 2010](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649d395503460f94a13358/html5/thumbnails/11.jpg)
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
![Page 12: 1 IRB review and assessment of risks / benefits Bernard Lo, M.D. bernie@medicine.ucsf.edu August 9 and 12, 2010](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649d395503460f94a13358/html5/thumbnails/12.jpg)
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?
![Page 13: 1 IRB review and assessment of risks / benefits Bernard Lo, M.D. bernie@medicine.ucsf.edu August 9 and 12, 2010](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649d395503460f94a13358/html5/thumbnails/13.jpg)
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
![Page 14: 1 IRB review and assessment of risks / benefits Bernard Lo, M.D. bernie@medicine.ucsf.edu August 9 and 12, 2010](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649d395503460f94a13358/html5/thumbnails/14.jpg)
14
Regulations respond to Tuskegee
3. Justice Equitable selection of subjects Protections for vulnerable subjects Access to benefits of research?
![Page 15: 1 IRB review and assessment of risks / benefits Bernard Lo, M.D. bernie@medicine.ucsf.edu August 9 and 12, 2010](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649d395503460f94a13358/html5/thumbnails/15.jpg)
Federal regulations
1. Risks / benefits
2. Informed and voluntary consent
3. IRB review and approval
15
![Page 16: 1 IRB review and assessment of risks / benefits Bernard Lo, M.D. bernie@medicine.ucsf.edu August 9 and 12, 2010](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649d395503460f94a13358/html5/thumbnails/16.jpg)
Topics to cover
What risks must we consider? Biomedical interventions Secondary analysis of existing data Psychosocial risks
How to decrease risks
16
![Page 17: 1 IRB review and assessment of risks / benefits Bernard Lo, M.D. bernie@medicine.ucsf.edu August 9 and 12, 2010](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649d395503460f94a13358/html5/thumbnails/17.jpg)
![Page 18: 1 IRB review and assessment of risks / benefits Bernard Lo, M.D. bernie@medicine.ucsf.edu August 9 and 12, 2010](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649d395503460f94a13358/html5/thumbnails/18.jpg)
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
![Page 19: 1 IRB review and assessment of risks / benefits Bernard Lo, M.D. bernie@medicine.ucsf.edu August 9 and 12, 2010](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649d395503460f94a13358/html5/thumbnails/19.jpg)
Biomedical risks of study
Injection-related adverse effects
19
![Page 20: 1 IRB review and assessment of risks / benefits Bernard Lo, M.D. bernie@medicine.ucsf.edu August 9 and 12, 2010](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649d395503460f94a13358/html5/thumbnails/20.jpg)
Psychosocial risks of study
Behavioral disinhibition May increase high-risk behaviors
Stigma and discrimination False +HIV test If confidentiality breached
20
![Page 21: 1 IRB review and assessment of risks / benefits Bernard Lo, M.D. bernie@medicine.ucsf.edu August 9 and 12, 2010](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649d395503460f94a13358/html5/thumbnails/21.jpg)
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
![Page 22: 1 IRB review and assessment of risks / benefits Bernard Lo, M.D. bernie@medicine.ucsf.edu August 9 and 12, 2010](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649d395503460f94a13358/html5/thumbnails/22.jpg)
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
![Page 23: 1 IRB review and assessment of risks / benefits Bernard Lo, M.D. bernie@medicine.ucsf.edu August 9 and 12, 2010](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649d395503460f94a13358/html5/thumbnails/23.jpg)
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
![Page 24: 1 IRB review and assessment of risks / benefits Bernard Lo, M.D. bernie@medicine.ucsf.edu August 9 and 12, 2010](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649d395503460f94a13358/html5/thumbnails/24.jpg)
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
![Page 25: 1 IRB review and assessment of risks / benefits Bernard Lo, M.D. bernie@medicine.ucsf.edu August 9 and 12, 2010](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649d395503460f94a13358/html5/thumbnails/25.jpg)
How to protect confidentiality
Train staff
Use coded or de-identified data
whenever possible
25
![Page 26: 1 IRB review and assessment of risks / benefits Bernard Lo, M.D. bernie@medicine.ucsf.edu August 9 and 12, 2010](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649d395503460f94a13358/html5/thumbnails/26.jpg)
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
![Page 27: 1 IRB review and assessment of risks / benefits Bernard Lo, M.D. bernie@medicine.ucsf.edu August 9 and 12, 2010](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649d395503460f94a13358/html5/thumbnails/27.jpg)
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
![Page 28: 1 IRB review and assessment of risks / benefits Bernard Lo, M.D. bernie@medicine.ucsf.edu August 9 and 12, 2010](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649d395503460f94a13358/html5/thumbnails/28.jpg)
Question for audience
What are risks of study?
How to minimize risks?
28
![Page 29: 1 IRB review and assessment of risks / benefits Bernard Lo, M.D. bernie@medicine.ucsf.edu August 9 and 12, 2010](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649d395503460f94a13358/html5/thumbnails/29.jpg)
29
If confidentiality breached
Legal risk: illegal activities, prison
sentence
Economic harm: loss of employment
![Page 30: 1 IRB review and assessment of risks / benefits Bernard Lo, M.D. bernie@medicine.ucsf.edu August 9 and 12, 2010](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649d395503460f94a13358/html5/thumbnails/30.jpg)
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
![Page 31: 1 IRB review and assessment of risks / benefits Bernard Lo, M.D. bernie@medicine.ucsf.edu August 9 and 12, 2010](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649d395503460f94a13358/html5/thumbnails/31.jpg)
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
![Page 32: 1 IRB review and assessment of risks / benefits Bernard Lo, M.D. bernie@medicine.ucsf.edu August 9 and 12, 2010](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649d395503460f94a13358/html5/thumbnails/32.jpg)
How to decrease risk
Monitor for adverse events
Respond to serious adverse event
32
![Page 33: 1 IRB review and assessment of risks / benefits Bernard Lo, M.D. bernie@medicine.ucsf.edu August 9 and 12, 2010](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649d395503460f94a13358/html5/thumbnails/33.jpg)
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
![Page 34: 1 IRB review and assessment of risks / benefits Bernard Lo, M.D. bernie@medicine.ucsf.edu August 9 and 12, 2010](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649d395503460f94a13358/html5/thumbnails/34.jpg)
34
Question for audience
Do you regard benefit / risk balance as
acceptable? Yes No Unsure
![Page 35: 1 IRB review and assessment of risks / benefits Bernard Lo, M.D. bernie@medicine.ucsf.edu August 9 and 12, 2010](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649d395503460f94a13358/html5/thumbnails/35.jpg)
35
How to reduce risks of study?
Exclude persons at increased risk Exclude Ad5 +, uncircumcised
Monitor adverse effects carefully Continuous monitoring of incident
infections
![Page 36: 1 IRB review and assessment of risks / benefits Bernard Lo, M.D. bernie@medicine.ucsf.edu August 9 and 12, 2010](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649d395503460f94a13358/html5/thumbnails/36.jpg)
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
![Page 37: 1 IRB review and assessment of risks / benefits Bernard Lo, M.D. bernie@medicine.ucsf.edu August 9 and 12, 2010](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649d395503460f94a13358/html5/thumbnails/37.jpg)
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
![Page 38: 1 IRB review and assessment of risks / benefits Bernard Lo, M.D. bernie@medicine.ucsf.edu August 9 and 12, 2010](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649d395503460f94a13358/html5/thumbnails/38.jpg)
38
Federal regulations
Risks must be reasonable compared to
potential knowledge gained
Risks must be minimized (consistent
with valid research design)
![Page 39: 1 IRB review and assessment of risks / benefits Bernard Lo, M.D. bernie@medicine.ucsf.edu August 9 and 12, 2010](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649d395503460f94a13358/html5/thumbnails/39.jpg)
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
![Page 40: 1 IRB review and assessment of risks / benefits Bernard Lo, M.D. bernie@medicine.ucsf.edu August 9 and 12, 2010](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649d395503460f94a13358/html5/thumbnails/40.jpg)
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
![Page 41: 1 IRB review and assessment of risks / benefits Bernard Lo, M.D. bernie@medicine.ucsf.edu August 9 and 12, 2010](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649d395503460f94a13358/html5/thumbnails/41.jpg)
Framework for analyzing study
Importance of informed consent Explicitly discuss that may increase
infection Test comprehension in participants
41
![Page 42: 1 IRB review and assessment of risks / benefits Bernard Lo, M.D. bernie@medicine.ucsf.edu August 9 and 12, 2010](https://reader035.vdocuments.net/reader035/viewer/2022062421/56649d395503460f94a13358/html5/thumbnails/42.jpg)
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