Regulatory Challenges
Lessons 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.
OTCD Gene Therapy Leadership Team
James M. Wilson
Mark L. Batshaw
Steven E. Raper
Preclinical Gene Therapy
OTCD
Pediatrician
General Surgeon
Clinical Gene Therapy
Sponsor IND
CoPI – Grant
PI IRB – CHOP
PI – Grant
PI IRB – HUP
CoPI – Grant
Expertise Vectors
Roles
Two-Component Model of Vector Toxicity
Antigen Processing
Cell
Vector
viral
gene
expression
OTC expression
Cytokine
Release
• Systemic
• Immediate
T Cell
• Localized
• Delayed
Hepatocytes
Cell killing
Broader Consequences of the OTCD
Clinical Trial
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).
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
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
Outcome of Investigations
Settled without admission of wrongdoing by
individuals or institutions
Fines to institutions
No personal fines
Restricted and/or monitored clinical research for 3-5 years
National Reassessment of Clinical
Trial Oversight
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)
Lessons Learned from the OTCD Trial
and its Aftermath
Lesson # 1:
Protocol is a contract with the research
subject and the regulatory agencies that
must be strictly and literally adhered to.
Lesson #2:
If you think about reporting - then do so!
“unreported monkey deaths”
OTC Team Meeting Notes
November 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.”
Lesson #3:
It is very difficult to manage real or
perceived financial conflicts of interest
in clinical trials.
Genovo Inc. and the OTCD trial
Lesson #4:
Informed consent requires objective
third party participation – the challenge
of non-academic conflicts of interest.
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 18year-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
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
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
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.”
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?
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.
Patent and Tangible Research Property
Policies and Procedures
of the University of Pennsylvania
05-19-2010
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.
What The Doctor Didn’t say:
The Hidden Truth About Medical Research
Jerry 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
More common arrangements that are far more problematic
Non-Financial Conflicts of Interest: The OTC Trial
Wilson –
Basic scientist
Developer of technology
Batshaw – Metabolic specialist
Current or future clinician
Raper –
General surgeon
Experience in liver gene therapy
What Drives Us as Physician-Scientists?
Wilson’s Perspective in the OTCD Trial
• To help patients with rare and lethal
metabolic diseases
• “Academic Treadmill”
Research Success
Grants
Recognition
Papers
Talks
Awards
Promotions
•Wilson & Penn
Genovo
•Clinical Trial
Problems
With Gene
Therapy Trial
Research
Subject
Died
Financial Conflicts of Interest
in Clinical Trials
• Disclosure is necessary but not sufficient
• Need consensus and national policy
• For now – conservative approach
• Unintended consequences ?
– Stifle progress
– Diminish quality
Does Disclosure of Financial Conflicts
of Interest Impact on Subject’s
Willingness to Participate?
Outcome
COI
Patent
Stock
Consulting
Yes
8
6
3
Not Sure
3
4
3
Grady et al, J of Law Medicine and Ethics Sept 2006; 34:592-599
No
21
22
25
The Other Side of the Coin
Better 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
Philadelphia Inquirer, December 10 1999
Gene Therapy Inquiry Urges Better
Monitoring, Non Conflict Rule
“. . . 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.”
AAMC-AAU Advisory Committee on Financial
Conflicts of Interest in Human Subjects ResearchFebruary 2008
With respect to pre-clinical research, institutions should
consider requiring 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.
Proposed Ethics Advisory Board
for 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
Response of NIH Study Section to
The 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.”
Lesson #5:
Over selling the potential and timelines
of a novel therapeutic platforms has
long-term negative consequences.
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)
Translational Research Center
Penn Medicine
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