Regulatory Challenges Lessons Learned from the OTC Gene Therapy Trial

James M. Wilson, M.D., Ph.D.

Director, Gene Therapy ProgramProfessor, Department of Pathology & Laboratory Medicine

University of Pennsylvania

31 March 20112011 Institutional Review Board Annual Educational Conference

Regulatory Challenges

Lessons Learned from the OTC Gene Therapy Trial

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

Vectors Preclinical Gene Therapy

Sponsor INDCoPI – Grant

Mark L. Batshaw

OTCD Pediatrician

PI IRB – CHOPPI – Grant

Steven E. Raper

General Surgeon Clinical Gene Therapy

PI IRB – HUPCoPI – Grant

Expertise

Roles

VectorAntigen Processing

Cell

Hepatocytes

T Cell Cell killing

Two-Component Model of Vector Toxicity

• Localized

• Delayed

OTC expressionviral gene

expression

Cytokine

Release• Systemic• Immediate

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 byindividuals or institutions

Fines to institutions

No personal fines

Restricted and/or monitored clinical research for 3-5 years

The Scientist2006 | Volume 20 | Issue 2 | Page 36

National Reassessment of Clinical Trial Oversight

Evolution of Clinical Trial Oversight by Penn1999• 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 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.”

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, NEJMNEJM, May 18, 2000

Protecting Research Subjects – What Must Be Done

Donna Shelala, Ph.D.Secretary, HHSNEJM, September 14, 2000

“…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…”

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

•Perception vs reality

•Disprove a negative

•Indirect benefit of promoting success in the field?

Initial response re: COI - NO

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 PropertyPolicies and Procedures

of 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.

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 –

Batshaw –

Raper –

Basic scientistDeveloper of technology

Metabolic specialistCurrent or future clinician

General surgeonExperience 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

RecognitionGrants

PapersTalks

AwardsPromotions

•Wilson & Penn Genovo

•Clinical Trial

ProblemsWith Gene

Therapy Trial

ResearchSubject

Died

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

Does Disclosure of Financial Conflictsof Interest Impact on Subject’s

Willingness to Participate?

COI

Patent

Stock

Consulting

No

21

22

25

Not Sure

3

4

3

Yes

8

6

3

Outcome

Grady et al, J of Law Medicine and Ethics Sept 2006; 34:592-599

The Other Side of the CoinBetter Regulation of (Financial) Conflicts of Interest

Sage WM, Texas Law Review 2007; 85(6): 1413-1463

• Improve protection of research subjects – NO

• Stifle innovative research – YES

• Obscure nonfinancial COI -YES

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.”

Philadelphia Inquirer, December 10 1999

AAMC-AAU Advisory Committee on Financial Conflicts of Interest in Human Subjects Research-

February 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 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

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.”

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 CANCERPublished: 1996-08-02

By Donald C. Drake and Jim Detjen, Inquirer Staff WritersSource: Philadelphia Inquirer, The (PA)

Translational Research CenterPenn Medicine

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