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Ethical issues in clinical trials
Bernard Lo, M.D.
February 7, 2008
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Outline of talk
Do we need clinical trials?
When is randomization justified?
May negative findings be withheld?
What are responsibilities of
investigators in trials?
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Treating patients with hESC
Testimonials on Internet
Charge $50,000
Scant publication in journals Independent follow up: no “functional
benefit”
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Treating patients with hESC
India Board for Medical Research
rejected grant application Not explain how obtain or purify cells
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Regulatory issue
May innovative treatments be
introduced in clinical practice without
evidence of safety and efficacy?
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Ethical issue
Do physician-investigators have ethical
duty to determine whether new
interventions are effective and safe?
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Experimental interventions ineffective or unsafe
Autologous bone marrow
transplantation in breast cancer
Torcetrapib raises HDL, lowers
LDL but increases mortality
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CHOIR
Target Hgb 13.5 vs. target Hgb 11.3
1432 patients with CKD, no dialysis
Time to composite endpoint death, MI,
CVA, hospitalization for CHF
NEJM 206; 355: 2085
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Literature review
RCT target Hct 42 vs Hct 30 in patients
with heart disease on dialysis More MIs in high Hct group, but not
significant. Trial halted (1998)
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Literature review
Meta-analysis of dialysis patients
(2004) Hb <12 had lower mortality than Hb >13 RR = .04 (0.71 to 1.0)
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Randomization
Most rigorous design
In clinical care, MD recommends what
is best for individual patient
Requires ethical justification
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Clinical equipoise justifies randomization
1. Experts find current evidence
inconclusive or conflicting• If experts disagree or uncertain, no harm to
participants
2. Clinicians willing to enroll patients
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Clinical equipoise justifies randomization
3. Participant agrees to be randomized• Should be told results of pertinent other
trials
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Outcomes at 16 months
Hgb 13.5 Hgb 11.3N=715 N=717
Endpoint 125 97
17.5% 13.5%
Hazard ratio 1.34, 95% CI = 1.03-1.74
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Outcomes at 16 months
Hgb 13.5 Hgb 11.3N=715 N=717
Death 52 (7.3%) 35 (5.0%)
CHF 64 (9.0%) 47 (6.6%)
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Vitorin
Combination ezetimibe + simvastatin
Prescribed to 800,000 patients, cost $4
billion
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ENHANCE trial
Compare progression of carotid
plaques in ezetimibe + simvistatin vs.
simvistatin alone
Finished 3/ 2006
Press reports 12/07 that results not
released
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ENHANCE trial
Press release Jan 2008
No benefit on plaque progression
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Ethical concerns raised by Vitorin trial
Withholding of negative findings? Harm future patients Protect trade secrets?
Role of academic PI of study?
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American Heart Association
“Study was not large enough or long
enough to determine whether the
combination drug is more or less
effective than the single drug in
reducing heart attacks or deaths”
Check with doctor
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American Heart Association
Not mention that AHA receives $2
million annually from manufacturer of
Vitorin
AHA site has direct link to
manufacturer webpage
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QuickTime™ and aTIFF (Uncompressed) decompressor
are needed to see this picture.
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Conflicts of interest
“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.”
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Conflicts of interest
Primary mission of clinical trial
investigator is to generate valid
knowledge
Different than drug marketing or sales
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Responses to conflicts of interest in clinical trials
1. Disclose To institution, IRB, participants Doesn’t prevent bias
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Responses to conflicts of interest
2. Manage Review by institutional committees
• But no one looks at science+ethics+conflict of interest
Registry of clinical trials• But results might not be disseminated
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Responses to conflicts of interest
3. Forbid certain actions or situations Authors must have
• Access to data• Control over data analysis• Freedom to publish
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VIGOR (11/04)
Fewer GI side effects on rofecoxib than
naproxen (2.1 vs. 4.5)
Rofecoxib sales over $2.5 billion
annually
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VIGOR adverse effects
More MIs on refecoxib (0.4 vs 0.1) Attributed to protective effect of naproxen
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VIGOR adverse effects
3 additional MIs on refecoxib before
publication Reported to FDA before publication Known to 2 employee / authors
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What should authors do about inaccurate findings?
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What should authors do?
Report to academic authors
Report to NEJM
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APPROVe study (2/05)
Thrombotic events 1.50 on rofecoxib
vs. 0.78 on placebo Increased risk after 18 months Led to voluntary withdrawal of drug
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Selection of endpoint in APPROVe
Count only events while on Rx or up to
14 days after stopping Count AEs over entire follow-up Methodology concerns? What kind of bias might be introduced?
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Selection of endpoint in APPROVe
Academic authors said they were just
following the protocol from sponsor
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APPROVe problems
Presented all events to FDA 5/06 Curves diverge at 4 months, not 18
Was choice of endpoint based on
sound science or litigation concerns? Defend lawsuits against patients on drug for
short time
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Peer review with APPROVe
“Aggressively promotes safety of up to
18 months of use … beyond the data of
the study”
“Hand of sponsor is too evident ..
Written consistently in manner
designed to support the company’s
public positions.”
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Concerns raised by rofecoxib trials
Invalid and biased presentation of
results
Defenses against bias ineffective Academic investigators
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Take home message
Give trial a catchy NAME
Ethical issues are inherent in clinical
trials
Investigators, referring clinicians,
reviewers, readers need to be aware of
ethical issues and how to resolve them