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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