Regulatory Challenges Lessons Learned from the OTC Gene Therapy Trial

1. Regulatory ChallengesLessons Learned from the OTC Gene Therapy Trial James M. Wilson, M.D., Ph.D. Director, Gene Therapy Program Professor, Department of Pathology & Laboratory Medicine University of Pennsylvania 31 March 2011 2011 Institutional Review Board Annual Educational Conference J.M.W. is a consultant to ReGenX Holdings and is a founder of, holds equity in, and receives a grant from affiliates of ReGenX Holdings; in addition, he is an inventor on patents licensed to various biopharmaceutical companies, including affiliates of ReGenX Holdings.

2. OTCD Gene Therapy Leadership Team Expertise Roles James M. Wilson Vectors Preclinical Gene Therapy Sponsor IND CoPI – Grant Mark L. Batshaw OTCD Pediatrician PI IRB – CHOP PI – Grant Steven E. Raper General Surgeon Clinical Gene Therapy PI IRB – HUP CoPI – Grant

3. Two-Component Model of Vector Toxicity Antigen Processing Cell Vector OTC expression viral gene expression Cytokine Release • Systemic • Immediate Hepatocytes T Cell Cell killing • Localized • Delayed

4. Broader Consequences of the OTCD Clinical Trial

5. The Wall Street Journal, January 10, 2000 NIH Not Told of Bad Events in Gene Trial CHRIS ADAMS, Staff Reporter of The Wall Street Journal WASHINGTON—The vast majority of so-called adverse events in many recent gene-therapy trials weren’t promptly reported as required to the National Institutes of Health, according to NIH review. In fact, only 39 of 691 serious adverse events (serious bad reactions or deaths during treatment) in one kind of gene-therapy trial were reported to NIH officials, according to a letter for former NIH Director Harold Varmus to Rep Henry Waxman (D. Calif).

7. Investigations of the OTCD trial • - Internal – Penn and CNMC • OHRP • RAC • NIH • - FDA • GCP • GLP • GMP • - Congress – House and Senate • - United States Attorney in Pennsylvania

8. Allegations • Inadequate documentation • Reports not always timely or accurate • Testing not complete • Consent process flawed • Stopping criteria not always followed • Failure to report animal studies

9. Outcome of Investigations Settled without admission of wrongdoing byindividuals or institutions Fines to institutions No personal fines Restricted and/or monitored clinical research for 3-5 years

10. The Scientist 2006 | Volume 20 | Issue 2 | Page 36

11. National Reassessment of Clinical Trial Oversight

12. Evolution of Clinical Trial Oversight by Penn 1999 • 1 IRB (staff of 5) 2008 • Revitalized IRBs (N=8; staff of 23) • Improved Institutional SOPs • Mandatory Training and Education • Monitoring and Oversight – Office of Human Research • Staff of 14 • Faculty Advisory Committee • Human Research Advisory Committee • Accredited by AAHRPP, a national not-for-profit agency established to accredit human protection programs (Association for the Accreditation of Human Research Protection Programs)

13. Lessons Learned from the OTCD Trial and its Aftermath

14. Lesson # 1: Protocol is a contract with the research subject and the regulatory agencies that must be strictly and literally adhered to.

15. Lesson #2:If you think about reporting - then do so! “unreported monkey deaths”

16. OTC Team Meeting NotesNovember 20, 1998 “Dr. Wilson questioned if this new data changes our intent to proceed with the current human trial. Dr. Raper stated that the data suggest that the 001 vector is safe for our proposed highest dose. Dr. Batshaw stated that he agreed with Dr. Raper. Dr. Wilson questioned if any modifications should be made to protocol prior to proceeding further. Dr. Raper stated that we have already added back in to the protocol several tests to monitor for DIC and that we probably do not need to monitor more any more closely… Dr. Batshaw asked if the data should be submitted with the cohort summary. Mr. Cross stated that we need to alert the FDA of these findings; however, he noted that we have no significant adverse events in the trial. It was decided to add this data to an annual report to the FDA, and that previous data given them had such data included.”

17. Lesson #4:Informed consent requires objective third party participation – the challenge of non-academic conflicts of interest. Lesson #3: It is very difficult to manage real or perceived financial conflicts of interest in clinical trials. Genovo Inc. and the OTCD trial

18. Is Academic Medicine for Sale? Marcia Angell, M.D. Editor, NEJM NEJM, May 18, 2000 Protecting Research Subjects – What Must Be Done “…the public's confidence…has been seriously shaken by the death of 18-year-old Jesse Gelsinger in a gene-transfer trial at the University of Pennsylvania…which presented the appearance of substantial financial conflicts of interest…” Donna Shelala, Ph.D. Secretary, HHS NEJM, September 14, 2000

19. Conflicts of Interest Genovo Inc. - Wilson’s role • No position in company • Not on Scientific Advisory Board • No consultancy fee • No direct role in clinical trials • Stock must be non-voting • Relinquish inventor’s distribution from product sales • Disclosure • Grant with oversight

20. Conflicts of Interest Genovo Inc. - Wilson’s role • No position in company • Not on Scientific Advisory Board • No consultancy fee • No direct role in clinical trials • Stock must be non-voting • Relinquish inventor’s distribution from product sales • Disclosure • Grant with oversight

21. Conflicts of Interest Management Two Oversight Committees Disclosure in Informed Consent Documents “Sponsor Information. Please be aware that the University of Pennsylvania, Dr. James M. Wilson (the Director of the Institute for Human Gene Therapy), and Genovo, Inc. (a gene therapy company in which Dr. Wilson holds an interest) have a financial interest in a successful outcome from the research involved in the study.”

22. Potential of Financial Gain from OTCD Trial? • Not a commercial market • Need to option rights to disease • Financial return tied to IP – no Penn IP Initial response re: COI - NO • Perception vs reality • Disprove a negative • Indirect benefit of promoting success in the field?

23. Bayh-Dole Act 1980 • Discoveries made by faculty/students/staff disclosed to University • Ownership of inventions assigned to University • University must file a patent within 1 year of disclosure • University must commercialize through licensing to companies with preferences to small businesses and manufacturing in the USA • Universities must share with inventors a portion of any revenue received from licensing the invention. The rest invested in education and research.

24. Patent and Tangible Research PropertyPolicies and Proceduresof the University of Pennsylvania05-19-2010 2. I agree to report . . . Any invention in the course of my employment at the University. I hereby irrevocably assign to the Trustees of the University of Pennsylvania all right, tithe, and interest in and to any and all such inventions.

25. What The Doctor Didn’t say: The Hidden Truth About Medical ResearchJerry Menikoff and Edward P. Richards “…the recent attention to financial conflicts may be inappropriately condemning many arrangements that are relatively benign while largely ignoring some more common arrangements that are far more problematic.” page 222 “…it is far from clear that the financial relationships created by giving researchers ownership in possible products dramatically alter the incentives that researchers already have.” page 226 Oxford University Press 2006

26. More common arrangements that are far more problematicNon-Financial Conflicts of Interest: The OTC Trial Wilson – Batshaw – Raper – Basic scientist Developer of technology Metabolic specialist Current or future clinician General surgeon Experience in liver gene therapy

27. Research Success Grants Recognition Papers Talks Awards Promotions What Drives Us as Physician-Scientists?Wilson’s Perspective in the OTCD Trial • To help patients with rare and lethal metabolic diseases • “Academic Treadmill”

28. Wilson & Penn • Genovo • Clinical Trial Problems With Gene Therapy Trial Research Subject Died

29. Financial Conflicts of Interestin Clinical Trials • Disclosure is necessary but not sufficient • Need consensus and national policy • For now – conservative approach • Unintended consequences ? • Stifle progress • Diminish quality

30. Does Disclosure of Financial Conflictsof Interest Impact on Subject’s Willingness to Participate? Outcome COI Patent Stock Consulting Yes 8 6 3 Not Sure 3 4 3 No 21 22 25 Grady et al, J of Law Medicine and Ethics Sept 2006; 34:592-599

31. The Other Side of the CoinBetter Regulation of (Financial) Conflicts of Interest • Improve protection of research subjects – NO • Stifle innovative research – YES • Obscure nonfinancial COI -YES Sage WM, Texas Law Review 2007; 85(6): 1413-1463

32. Gene Therapy Inquiry Urges Better Monitoring, Non Conflict Rule Philadelphia Inquirer, December 10 1999 “. . . The committee said it would consider to make the field safe for patients to participate in clinical trials with conflict of interest rules for scientists who stood to gain financial from the research.”

33. AAMC-AAU Advisory Committee on Financial Conflicts of Interest in Human Subjects Research- February 2008 With respect to pre-clinical research, institutions should considerrequiring covered individuals to indicate if their current non-human subjects research that is linked to any of their reportable financial interests is reasonably anticipated (1) to be a component of an IND submission or (2) to progress to research involving human subjects within the coming 12 months. In such circumstances, the institution’s conflicts of interest committee should have the authority to decide whether any of the policy stipulations that apply to human subjects research should apply to this “pre-clinical” stage of the individual’s research.

34. Proposed Ethics Advisory Boardfor OTCD Trial Membership Chair Dr. Arthur Caplan Pediatric physicians (2) OTCD parent Expert in mental retardation Individuals in ethics, law and theology (2) Charge (meet monthly with team) Ensure safety of research subjects Advise regarding ethics of research design, informed consent etc. Annual Grand Rounds and oral presentation at National Meeting

35. Response of NIH Study Section toThe Ethics Advisory Board - Sept 1994 “The subcontract to the University of Pennsylvania is deleted because Dr. Caplan’s role is inappropriate: expertise in bioethics is available from the Institutional Review Board and Dr. Batshaw himself has more experience with OTC deficiency than all but a handful of individuals in the country and is fully conversant with all of the ethical issues and its management.”

36. Lesson #5: Over selling the potential and timelines of a novel therapeutic platforms has long-term negative consequences.

37. RESEARCH IS YIELDING A REASON TO HOPE CYSTIC FIBROSIS COULD BE THE FIRST DISEASE CONQUERED BY GENE THERAPY. . . Published: 1995-07-23 HOW GENE THERAPY MIGHT CURE HEMOPHILIA TURNING THEORY INTO REALITY . . . Published: 1997-04-07 HIS LAST CHANGE: ‘SUICIDE GENES’ GO AFTER BRAIN CANCER Published: 1996-08-02 By Donald C. Drake and Jim Detjen, Inquirer Staff Writers Source: Philadelphia Inquirer, The (PA)

39. Translational Research CenterPenn Medicine8 Floors