Where Did They Go Wrong Autopsies in Human Subjects Research Misbehavior

1. Where Did They Go Wrong?Autopsies in Human Subjects Research Misbehavior Tracy J. Wilson-Holden Office of Research Compliance October 12, 2006

2. 6/30/2012 2 Why Look at Other’s Mistakes? Bramstedt and Kassimatis, 2004Clinical Investigative MedicineA Study of Warning Letters Issued to IRBs by the US FDA Conclusion: Consistent weaknesses found across IRBs

3. 6/30/2012 3 Why Look at Other’s Mistakes? Brewer, Sherry, 2006Protecting Human SubjectsWhen Things Go Wrong… “Staying informed about the legal environment for research could makethe difference in planning ahead or looking back to see what went wrong.”

4. 6/30/2012 4 http://www.fda.gov/foi/warning.htm

5. 6/30/2012 5 http://www.hhs.gov/ohrp/compliance/letters/index.html

6. 6/30/2012 6 http://ori.dhhs.gov/misconduct/cases/

7. 6/30/2012 7 Potential Sanctions Warning letter issued(and published on website) Requires response from investigator outlining a plan for corrective actions Period of restricted activity Hold on all studies Permanent debarment/disqualification Criminal Prosecution

8. 6/30/2012 8 Recent History University of Pennsylvania, 1999 Gene therapy experiment 18 year old Jesse Gelsinger died Raised issue of Conflict of Interest PI was the founder of biotechnology company involved in the study Biotech company was heavily invested in the University’s Institute of Human Gene Therapy

9. 6/30/2012 9 Outcomes - James M. Wilson, M.D., Ph.D. Settlement reached with US Attorney’s Office 02/09/05 (restrictions are from that date forward) 5-year restriction from leading FDA trials designated monitor for three years once permitted to do human studies Monitoring for animal research that could influence the safety of human research One human study at a time Remains a full professor at Penn Bench and animal research

10. 6/30/2012 10 Outcomes - University of Pennsylvania $517,496 settlement with the government Penn’s Institute of Human Gene Therapy has shut down (Wilson stepped down as director in 2002) Increased internal oversight

11. 6/30/2012 11 Outcomes – other parties Mark Bratshaw and Steven Raper (co-investigators) Restricted and supervised clinical activities for three years Complete education and training for human research participant protectionsand clinical research Children’s National Medical Center $514,622 settlement with the government Increased internal oversight

12. 6/30/2012 12 Case Study #1 – from FDA website Daniel Amsterdam, Ph.D.Erie County Medical Center Corporation2004 Study name was redacted Included finger stick and venipuncture

13. 6/30/2012 13 Charge “You failed to protect the rights, safety, and welfare of the subjects under your care...” Enrolled 225 subjects but did not document that subjects met the enrollment criteria One subject, whose age was available, was too old to participate.

14. 6/30/2012 14 Charge Enrolled and tested subjects beginning October 17, 2002 Training of testing personnel did not happen until the period of October 21 through October 30, 2002 subject testing results forms did not include operator’s initials

15. 6/30/2012 15 Charge The initial informed consent form signedby one of the subjects was not available for review during the inspection.

16. 6/30/2012 16 Sanctions Written response within 15 days Failure to implement effective corrective actions, or if more problems discovered, possibility of initiation of disqualification proceedings.

17. 6/30/2012 17 Case Study #2 – from ORI website Xiaowu LiUniversity of California at San Francisco(UCSF) Grants: Adhesion and proliferation in oral cancer progression Oral melanoma alpha v beta 3 expression and metastasis Regulatory function of fyn in oral SCC invasion

18. 6/30/2012 18 Charge – Falsification of Images Paper published online: “Laminin-5 promotes cell motility by regulating the function of the integrin [alpha]6 [beta]1 in pancreatic cancer”

19. 6/30/2012 19 ORI Statement Pancreatic cancer has a poor prognosis Knowledge of factors that facilitate metastasis crucial to development of better treatments Could have misled other researchers

20. 6/30/2012 20 Sanctions For a period of three (3) years: Excluded from contracting or subcontracting with ANY agency of the US Government Excluded from any PHS (Public Health Service) advisory role Advisory committees Boards Peer review committees Consultant

21. 6/30/2012 21 Case Study #3 – from ORI website Eric T. Poehlman, Ph.D.University of Vermont College of Medicine 17 Federal grant applications 10 published articles From 1992-2002

22. 6/30/2012 22 Charges Reported data on fictitious subjects Changed values for test results Created trends that were not reflectedin the actual research data Destroyed electronic evidence Presented false testimony and falsified documents Influenced witnesses

23. 6/30/2012 23 Sanctions Barred for life from seeking or receiving funding from ANY federal agency Permanently excluded from participation in all Federal health care programs 366-day prison term

24. 6/30/2012 24 Effects of the Poehlman Case Relatively little impact on the core assumptions or research directions Did not affect the underlying assump-tions about how the body changes during aging May reduce evidence, but does not invalidate concepts

25. 6/30/2012 25 Quotes from Poehlman Case “The defendant, as tenured faculty, enjoyed full academic independence to pursue his own research areas, …and could not be dismissed, except in extraordinary circumstances…Clearly the defendant abused this position of trust in committing his fraud.”  US Attorney’s Office

26. 6/30/2012 26 Quotes from Poehlman Case “Preserving the integrity of the grant process…is a priority for the Dept. of Justice. This prosecution demonstrates that academic researchers will be held fully accountable for fraud and scientific misconduct.” David V. Kirby  US Attorney

27. 6/30/2012 27 Case Study #4 – from ORI website Paul H. KornakStratton VA Medical CenterAlbany, New York Research coordinator for several cancer clinical trials Between 1999 and 2003

28. 6/30/2012 28 Charge Criminally negligent homicide He caused the death of a study subject when he altered blood chemistry results so the patient could be enrolled in a study. The patient was truly ineligible due to impaired kidney and liver function

29. 6/30/2012 29 ORI Case Summary From May 1999 to July 2002 “he would and repeatedly did submit false documentation regarding patients and study subjects and enroll and cause to be enrolled persons as study subjects who did not qualify under the particular study protocol.”

30. 6/30/2012 30 Sanctions Permanently debarred from participating in any and all Federal agency transactions $639,000 in restitution paid to two pharmaceutical companies and the VA 71-month prison term

31. 6/30/2012 31 Responsible Investigator James A. Holland, MD September 22, 2004“Notice of Initiation of Disqualification Proceedings and Opportunity to Explain” letter sent from the FDA

32. 6/30/2012 32 Charges Failed to protect the rights, safety and welfare of subjects under your care Repeatedly or deliberately submitted false information to the sponsor Repeatedly or deliberately failed to comply with cited regulations

33. 6/30/2012 33 Sanctions…? The FDA trail ends there. There is no listing of his response or any notification of an agreement he may have struck with the FDA. James A. Holland remains a practicing physician in Georgia

34. 6/30/2012 34 Case Study #5 – from FDA website Elizabeth L. Hohmann, MDMassachusetts General Hospital(July 10, 2006) Safety and Shedding of Attenuated Listeria Vaccine Safety and Immunogenicity of Attenuated Salmonella Typhimurium

35. 6/30/2012 35 Charge “You failed to submit an Investigational New Drug Application to FDA for your clinical investigation.” administered an unapproved attenuated strain of Listeria vaccine to 20 subjects without submitting an IND to the FDA

36. 6/30/2012 36 Charge “You failed to ensure that informed consent was obtained according to the provisions of 21 CFR Part 50…” Subjects signed informed consent form before it was approved by the IRB Subjects signed a revised form before it was approved by the IRB Subjects signed an obsolete version of the informed consent form

37. 6/30/2012 37 Charge “You failed to promptly report to the IRB all changes to the research activity and failed to promptly report all unanticipated problems involving risk to human subjects.” Failed to notify the IRB that Study 2 was placed on clinical hold Failed to promptly report to the IRB unexpected adverse events

38. 6/30/2012 38 Charge Did not promptly report to the IRB that a subject had increased liver enzymes IRB notification was required within 24 hours with a follow-up written report within 10 days IRB notified nearly six weeks after the event

39. 6/30/2012 39 Sanctions Investigator must submit written notification within 15 days of the steps planned to prevent the recurrence of similar violations Must include any documentation to show that correction has been achieved

40. 6/30/2012 40 FDA Warning Letter “Please be advised that failure to implement effective corrective actions…could result in… injunction and initiation of clinical investigator disqualification proceedings…”

41. 6/30/2012 41 Top 10 Lessons… 10. Get IRB approval before initiating the study 9. Be sure study staff is appropriately trained 8. Disclose personal and institutional conflicts of interest 7. Use caution in stating risks and benefits 6. Use only currently-approved informed consent documents

42. 6/30/2012 42 Top 10 Lessons… (continued) 5. Ensure that subjects meet the enrollment criteria 4. Maintain adequate and accurate records 3. Know the adverse event reporting requirements for your IRB and sponsors 2. Personally conduct and supervise your studies 1. Don’t think it can’t happen to you!

43. 6/30/2012 43 Websites FDA http://www.fda.gov/foi/warning.htm OHRP http://www.hhs.gov/ohrp/compliance/letters/index.html ORI http://ori.dhhs.gov/misconduct/cases/ Case Office of Research Compliance http://ora.ra.cwru.edu/research/orc/

44. 6/30/2012 44 Research Seminar Series Friday, October 20, 2006 MSASS 320 (Mandel School of Applied Social Sciences) Check “Yes” or “No”: Creating a Well-Designed Survey Research Process 9:00 AM - 10:30 AM   The CREC Program: Getting Started 10:30 AM - 11:00 AM   Register at: http://ora.ra.cwru.edu/research/orc/education/onlinecalendar.cfm

45. 6/30/2012 45 Research Seminar Series CREC Mini-Camp Friday, November 3, 2006 Bowell A, University Hospitals 8:00 am – 1:00 pm Session 1:Best Practices for Responsible Investigators Session 2:Conflict of Interest in Research - Should it Be Eliminated or Managed Session 3:INDs and IDEs: Responsibilities of Investigator Sponsors