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

2 Timeline of Hwang case 2/04SCNT yielded 30 blastocysts and one stem cell line 5/0511 SCNT cell lines from 185 oocytes, 31 blastocysts 8/05Cloning 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

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

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

18 Rofecoxib  Sales over $2.5 billion annually  80,000 patients

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

20 APPROVe study (2/05)  Thrombotic events 1.50 on rofecoxib vs on placebo  Led to voluntary withdrawal of drug  Increased risk after 18 months

21 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

22 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

23 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.”

24 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

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

26 Ethical issues raised  People harmed by unethical research  Evidence base for clinical practice depends on valid research

27 Take home messages  Informed consent  IRB review  Authorship  Publish unfavorable results  Integrity of researcher