1 Ethical issues in clinical research Bernard Lo, M.D. January 25, 2007.
1 Conflicts of interest Bernard Lo, M.D. September 16, 2010.
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Transcript of 1 Conflicts of interest Bernard Lo, M.D. September 16, 2010.
2
Views of audience
Investment company offers fund whose
selectors have personal stake in fund
going lower. Company also has shorted
fund. Should these interests be disclosed?
1.Yes
2.No
3.Not sure
3
Views of audience
Should such a fund be banned (even if
interests aredisclosed)?
1.Yes
2.No
3.Not sure
My COI disclosure
No relationships with for-profit
companies
Chaired 2009 Institute of Medicine
report on COIs
4
5
What is a conflict of interest?
Special relationships of trust,
dependency
Primary interest in well-being of
clients, patients, integrity of research
Secondary interest in personal gain ($,
professional advancement)
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What is a conflict of interest?
Unacceptable risk that primary interest
unduly influenced by secondary
interest
Points to consider
1. Arrangement may be problematic
even if no proof of bias Hard to tell if bias exists
2. Disclosure necessary but not
sufficient May not know what risks are or how to
reduce them
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Points to consider
4. COI policies should consider• Risk of relationship• Burdens and unintended adverse effects of
policies
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Spiral CT for lung cancer screening
Screened >31,000 high risk persons F/u Stage 1 cancers who had surgical
resection• 10 year estimated survival 92%
“Could prevent 80% of deaths from lung cancer”
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Spiral CT for lung cancer screening
Advocates have pushed states to pay
for screening NY bill would pay only at Cornell
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Spiral CT for lung cancer screening
$200 million NIH trial comparing CT
screening vs. CXR “Allowing hundreds of thousands to die is
unethical”
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Methodologic concerns
No concurrent control group
Lead time bias
Few patients followed for 5 years
Assume at all persons found to have
cancer would die without screening
Ignore false positive scans
13
Financial relationships
$3.6 million from parent company of
cigarette manufacturer
Grant to Foundation for Lung Cancer PI, co-PI as officers Dean, vice-chair of overseers as directors
• Claim didn’t know origin of money
Gift announced publicly
14
Financial relationships
Not disclose 10 patents on CT
screening in some articles and CME
lectures Claim not relevant Cornell receives royalties
15
Financial relationships
Not disclose funding as required To NEJM
• Would not have published
On American Cancer Society grant• Prohibit funding if also tobacco support
16
Points to consider
Voluntary disclosure ineffective Impetus for public disclosure of payments
Institutions have their own COI
Bright people find loopholes
17
Concerns about COIs
Disagreements and errors inevitable Due to reasonable differences of opinion,
slip, or financial profit?
Disclosure not remove risk of bias
19
Academia-industry collaboration to develop new therapies
Antiretrovirals for HIV infection
Pulmonary surfactant
Imatinib, tyrosine kinase inhibitor for
CML
Rituximab, MAB against CD20 on B
cells
21
Concerns about industry-sponsored clinical trials
Most trials now sponsored by industry
Academic investigators may lack Access to data Independent statistical analysis
Drafting of papers by medical writers
23
Association between funding and conclusions
Investigator ties to manufacturer 3.6 times more likely to find drug effective
Sponsored by manufacturer 4.0 times more likely to find drug effective
JAMA 2003; 289: 454
BMJ 2003; 327: 1167
24
Explanations for association
Publication bias against negative trials
Less rigorously designed Evidence not support this
Manufacturers sponsor trials that are
likely to succeed
25
Concerns about industry-sponsored clinical trials
2. Methodologic flaws that favor study
drug
3. Not report negative findings
26
Rosiglitazone allegations
Manufacturer failed to release to FDA
data showing cardiac risk
Audit of RECORD trial showed 12
endpoints on drug not counted
27
Not report negative findings
Celecoxib 6-month data reported, showed benefit. 12-month data known, no benefit
BMJ 2002; 324: 1287
JAMA 2001; 2886: 2398
28
Mission of drug companies
“Drug companies have to continue to
be successful businesses… But their
primary mission is products that save
lives and improve lives.”
“This is an area that’s different from
ice cream, bubble gum, and
automobiles.”
Responses to conflicts of interest
1. Disclosure To university
• Annually
• With grant submission (new NIH requirements)
To IRB To research subjects When submit, present, publish
29
Responses to conflicts of interest
1. Disclosure To public
• Required for some companies by legal settlements
• Voluntary by some companies
• Some state laws
• New federal law (in 2013)
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Arguments for disclosure
“Sunshine the best of disinfectants”
May deter questionable behavior
But may also deter desirable behaviors
32
Concerns about disclosure
Not specific or standardized Categories like “consultant” ambiguous –
scientific or marketing?
May be misinterpreted Discrepancies due to different requirements
Not prevent undue influence or bias Necessary but limited first step
Clinical trial investigators with significant conflicts of interest
Default or presumption is that may not
participate if financial stake in results Patent, royalties Stock options Management position in sponsor
34
Clinical trial investigators with significant conflicts of interest
Exceptions permitted For safety of participants
• Inventor of medical device
For validity of study• Only lab that can conduct assay
35
Clinical trial investigators with significant conflicts of interest
Limit role of conflicted investigator Not tasks that others can carry out
• Recruitment of subjects
• Data analysis
• Drafting of manuscript
May not be PI
Alternatively, may end conflicting role
36
Contracts or grants forIndustry-sponsored clinical trials
Be willing to justify protocol and
conduct of trial
Register with clinicaltrials.gov
37
Contracts or grants forIndustry-sponsored clinical trials
Access to complete raw data
Independent statistical analysis
Control decision to publish May give sponsor draft Short delay for patent finding
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Concerns about current policies
Responses out of proportion to
problems Overreaction to egregious cases Unfair suspicion
Burdensome for physicians Particularly for MDs who act with integrity
Other COI issues
Medical education
Development of practice guidelines
Clinical practice
Institutional COIs
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Take home message
Are policies proportional to problems? How likely and serious is the risk? What are the desirable and detrimental
consequences of policies?