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Ethical issues in clinical research

Ethical issues in clinical research. Bernard Lo, M.D. January 25, 2007. 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. S. Korean investigation.

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Ethical issues in clinical research

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  1. Ethical issues in clinical research Bernard Lo, M.D. January 25, 2007

  2. 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

  3. S. Korean investigation • Could not verify genetic identity of donors and lines • 9 lines identical with embryonic stem cell line

  4. 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

  5. Protections for human subjects • IRB review • Assess risks and benefits of research • Independent of researchers

  6. 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

  7. Federal definition of research misconduct • Fabrication • Falsification • Plagiarism • Must be intentional

  8. Why is research misconduct problematic? • Question validity of data • Question conclusions of study • Unmerited rewards • Undermines public trust and support

  9. Research misconduct excludes • Unintentional “honest” error • Sloppiness, incompetence, laziness • Differences of opinion or interpretation

  10. U Pitt investigation of Schatten • Senior author of 2005 paper • Revised paper, negotiated with journal

  11. 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”

  12. Appropriate authorship • Co-authors took credit for work • Did not meet criteria for authorship • Not willing to take responsibility for work

  13. Why have authorship? • Recognition • Job, grants, promotions • Accountability • Prevent fabrication, fraud, plagiarism

  14. Criteria for authorship • Conception and design or data analysis and interpretation, and • Drafting or substantially revising article, and • Approving final manuscript

  15. VIGOR • Published in NEJM 11/200 • Fewer GI side effects on rofecoxib than naproxen (2.1 vs. 4.5)

  16. VIGOR • More Mis on refecoxib (0.4 vs 0.1) • Attributed to protective effect of naproxen

  17. Rofecoxib • Sales over $2.5 billion annually • 80,000 patients

  18. VIGOR • 3 additional MIs on refecoxib reported to FDA before publication but not to academic authors or to NEJM • Known to 2 employee / authors

  19. 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

  20. 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

  21. 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

  22. 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.”

  23. 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

  24. Ethical issues raised • Must publish all results, both negative and positive • Investigators must control study • Sponsor has self-interest, bias

  25. Ethical issues raised • People harmed by unethical research • Evidence base for clinical practice depends on valid research

  26. Take home messages • Informed consent • IRB review • Authorship • Publish unfavorable results • Integrity of researcher

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