University of Pennsylvania Announces Series of Actions to Strengthen Oversight and Monitoring of its Clinical Trials

Actions Follow Independent Review Panel Report

IHGT to Discontinue Clinical Trials

 The University of Pennsylvania is taking a series of actions designed to strengthen oversight and monitoring of its clinical trials, enhance the organization and focus of its Institute for Human Gene Therapy, reinforce its Institutional Review Board's role in oversight and patient protection, address issues of ethical decision making in research using humans and comprehensively review its policies on conflict-of-interest.

The actions were announced May 24 following the receipt of a report by an independent review panel, appointed by President Judith Rodin to conduct a comprehensive review of oversight and monitoring of clinical trials at the Institute for Human Gene Therapy ("IHGT").

The independent review by distinguished research scientists unaffiliated with Penn was chaired by William H. Danforth, M.D., chancellor emeritus and vice chair of the board of trustees at Washington University in St. Louis, and was designed "to understand the operations of the IHGT and its handling of clinical trials and to point out areas that [we] believe require thought, attention, further investigation or correction."

"Our clinical research programs at the University of Pennsylvania must meet the highest possible standards for academic excellence and patient safety and care," Dr. Rodin said. "Nothing less is acceptable."

Actions Penn is taking include:

  • Assessing all clinical trials to determine the level of monitoring necessary for strict compliance with all applicable regulations.
  • Focusing the IHGT mission on molecular and cellular work and animal model experimentation. Consistent with this focus, IHGT will no longer conduct clinical trials.
  • Initiating a comprehensive review of ethical decision-making specific to all research using humans, and creating an Institutional Review Board ("IRB") with special expertise in evaluating gene therapy.
  • Conducting a formal, comprehensive review of the IRB system to strengthen its abilities to protect the vital interests of patients, building on significant changes in IRB policies and procedures already in place.
  • Reviewing policies and procedures on conflict-of-interest specific to both perceived and actual conflicts, including those inherent in investment and funding of provocative medical therapies.

"We are extremely grateful to Dr. Danforth and to the members of the committee, who brought their collective insight and considerable experience to the task," Dr. Rodin said, "and we are very encouraged by the Danforth Committee's explicit findings that the University and IHGT are committed to compliance with all applicable regulations and to correct any past deficiencies, that we were changing processes and practices to conform to the FDA's requirements before that agency began its investigation and that we have already instituted a number of important changes.

Focusing the IHGT Mission

"IHGT is a site of important research on a therapy that may provide great benefits to human beings in the future," she said, "and we will continue to support it." The University "has greatly benefited from the Danforth Committee's questions about the scope of the IHGT," and its role in the conduct of research using human subjects at the University.

"Penn and IHGT have jointly determined that IHGT can best serve the important future of gene therapy by resolutely focusing on molecular and cellular work and animal model experimentation." It will not, she said, serve as a sponsor of clinical trials in the future.

The decision to discontinue sponsorship of clinical research by IHGT will not impede the conduct of gene therapy clinical trials that may take place elsewhere within the University.

Strengthening Oversight of Clinical Trials Involving Humans

Dr. Rodin said that the University believes that the Danforth Committee is correct in suggesting that clinical trials involving human subjects at universities across the country will require increasingly stringent oversight and regulatory compliance. Consistent with the suggestions of the committee, the University is taking the following the actions:

  • Every clinical trial at Penn will be professionally assessed by the University's Office of Regulatory Affairs ("ORA") to determine the level of monitoring the trial will require for strict compliance with all applicable regulations;
  • Each of the limited number of current clinical trials at Penn that have no external sponsorship and monitoring will be reviewed by a professional contract research firm to determine any additional monitoring the trial may require. The University is presently recruiting firms for this purpose.
  • The University is developing a set of clear standards that will guide the review and monitoring of all clinical trials; and
  • The University is developing a compendium of Standard Operating Procedures for research involving human subjects at Penn and a process for ensuring that all investigators have access to, are cognizant of and are in full compliance with these procedures.

Initiating a Comprehensive Review of Ethical Decision-making

The University is undertaking a comprehensive review of ethical decision-making specific to research using human subjects at the University, and future ethical discussion regarding the testing of gene therapy in human subjects will be overseen by an Institutional Review Board with special expertise in evaluating gene therapy. In addition, the School of Medicine will establish a new, free-standing Department of Bioethics that will include the current Center for Bioethics.

Conducting a Formal, Comprehensive Review of the IRB System

The University already has begun a formal, comprehensive review of its Institutional Review Board system to strengthen the IRB's ability to protect the vital interests of patients as well as other relevant issues. This review will include examining the proposals being developed by Congress and others. It also will build on the significant changes already in place at Penn following an external review completed last summer and the appointment of ORA Director Joseph R. Sherwin, Ph.D. IRB policies and procedures have been strengthened to ensure, among other things, and include:

  • Strict adherence to all IRB regulatory requirements.
  • Implementation and use of a new database tracking system that identifies primary and secondary reviewers and monitors IRB discussion of substantive issues and its recommendations for changes in protocols and consent forms. (This new database tracking system was available on Oct. 1, 1999.)
  • A new 24-hour adverse event hotline that is monitored on nights and weekends by the IRB Director and Associate Director. (This new 24-hour adverse event hotline was available on Feb. 1, 2000.)
  • Substantial, regular training and education for IRB members and staff.
  • Training for Medical School faculty, which ultimately will be integrated into a requirement for certification of both principal investigators and research coordinators before permitting submission of protocols for IRB review.
  • A new ORA web site and a new brochure that has been distributed to the University's research community. (The new ORA web site was available on Dec. 15, 1999; the brochure is in its second printing.)
  • Several new professional staff in the ORA; additional positions are being recruited as of this writing.
  • The ORA is in the process of developing new Standard Operating Procedures for IRB members that clearly delineate the requirement for continuing review and the responsibilities of the convened IRB, the chair and the staff.

Reviewing Policies and Procedures on Conflict-of-interest

The University believes that perceived as well as actual conflicts make clinical trials open to criticism and suspicion, and that investments in new medical therapies are uniquely controversial.

The proposed new guidelines of the American Society for Gene Therapy, issued in April 2000, would prohibit all investigators and team members directly responsible for patient selection, the informed consent process and/or clinical management in a trial from having equity, stock options or comparable arrangements in companies sponsoring the trial. These guidelines are consistent with restrictions that Penn established five years ago.

"Nevertheless," Dr. Rodin said, " the University agrees with the Danforth Committee that a full review of our policies on conflict-of-interest should be undertaken at this time. She said that a 10-person panel of distinguished members of the Penn faculty, chaired by Provost Robert L. Barchi, has begun a review of all aspects of Penn's research using human subjects.

"While we have moved aggressively in a variety of areas," Dr. Rodin said, "we recognize that we have considerable work to do to ensure that we structure the best possible climate for clinical trials, one that always ensures the interests of our patients are of paramount importance.

"We will continue to work with our colleagues throughout the academic community and with regulators and with lawmakers to accomplish that task."

Joining Dr. Danforth on the independent review panel were: Joseph B. Martin, M.D., Ph.D., dean of the faculty of medicine, Harvard Medical School; Edward J. Benz, Jr., M.D., Sir William Osler Professor and chair of the department of medicine, Johns Hopkins University School of Medicine; Inder Verma, Ph.D., American Cancer Society Professor of Molecular Biology, The Salk Institute, La Jolla, California; Rochelle Hirschhorn, M.D., professor of medicine and cell biology and chief of the division of medical genetics, department of medicine, New York University School of Medicine; and Daniel Callahan, Ph.D., director of international programs, The Hastings Center, Garrison, New York.

Posted 5/24/2000