Ethical issues in clinical trials

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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 lt12 had lower mortality than Hb gt13
• 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

• Experts find current evidence inconclusive or
  conflicting
• If experts disagree or uncertain, no harm to
  participants
• Clinicians willing to enroll patients

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Clinical equipoise justifies randomization

• 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 11.3
• N715 N717
• 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 11.3
• N715 N717
• 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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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 thats 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

• Disclose
• To institution, IRB, participants
• Doesnt prevent bias

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Responses to conflicts of interest

• Manage
• Review by institutional committees
• But no one looks at scienceethicsconflict of
  interest
• Registry of clinical trials
• But results might not be disseminated

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Responses to conflicts of interest

• 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
  companys 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