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Ethical issues in clinical research

Bernard Lo, M.D.

January 25, 2007

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Timeline of Hwang case

2/04 SCNT yielded 30 blastocysts and

one stem cell line

5/05 11 SCNT cell lines from 185

oocytes, 31 blastocysts

8/05 Cloning of dog, Snuppy

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S. Korean investigation

Could not verify genetic identity of

donors and lines

9 lines identical with embryonic stem

cell line

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S. Korean investigation

2261 oocytes from 119 donors Papers reported only 427 oocytes 66 compensated, contrary to publication Technicians, grad student donated, contrary

to previous statements Failed to fully explain risks 15/79 treated for ovarian hyperstimulation

syndrome

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Protections for human subjects

IRB review Assess risks and benefits of research Independent of researchers

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Protections for human subjects

Informed and voluntary consent Respect people’s right to decline to

participate in research Hard to say no if dependent Exceptions for research with existing

records and materials

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Federal definition of research misconduct

Fabrication

Falsification

Plagiarism

Must be intentional

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Why is research misconduct problematic?

Question validity of data

Question conclusions of study

Unmerited rewards

Undermines public trust and support

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Research misconduct excludes

Unintentional “honest” error

Sloppiness, incompetence, laziness

Differences of opinion or interpretation

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U Pitt investigation of Schatten

Senior author of 2005 paper Revised paper, negotiated with journal

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U Pitt investigation of Schatten

“Concerted and deliberate effort to

distance self from Dr. Hwang and joint

publication” “In sharp contrast to full participation…in

media spotlight following publication”

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Appropriate authorship

Co-authors took credit for work

Did not meet criteria for authorship

Not willing to take responsibility for

work

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Why have authorship?

Recognition Job, grants, promotions

Accountability Prevent fabrication, fraud, plagiarism

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Criteria for authorship

Conception and design or data

analysis and interpretation, and

Drafting or substantially revising

article, and

Approving final manuscript

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VIGOR

Published in NEJM 11/200

Fewer GI side effects on rofecoxib than

naproxen (2.1 vs. 4.5)

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VIGOR

More Mis on refecoxib (0.4 vs 0.1) Attributed to protective effect of naproxen

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Rofecoxib

Sales over $2.5 billion annually

80,000 patients

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VIGOR

3 additional MIs on refecoxib reported

to FDA before publication but not to

academic authors or to NEJM Known to 2 employee / authors

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APPROVe study (2/05)

Thrombotic events 1.50 on rofecoxib

vs. 0.78 on placebo Led to voluntary withdrawal of drug Increased risk after 18 months

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Public events

Vioxx withdrawn from market 9/04 Attributable MI, CVA 160,000

Lawsuits by patients

Defense strategy At high risk for MI Weren’t taking drug long enough

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APPROVe problems

Count only events while on Rx or up to

14 days after stopping Academic authors claimed they were just

following the protocol

Presented all events to FDA 5/06 Curves diverge at 4 months, not 18

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APPROVe problems in peer review

“Going out on limb by emphasizing 18

month issue”

“Hand of sponsor is too evident ..

Written consistently in manner

designed to support the company’s

public positions.”

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APPROVe problems in peer review

“Aggressively promotes safety of up to

18 months of use … beyond the data of

the study”

Journal originally asked authors to

drop references to 18 months

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Ethical issues raised

Must publish all results, both negative

and positive

Investigators must control study Sponsor has self-interest, bias

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Ethical issues raised

People harmed by unethical research Evidence base for clinical practice depends

on valid research

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Take home messages

Informed consent

IRB review

Authorship

Publish unfavorable results

Integrity of researcher

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