Report of Independent Panel Reviewing the University of Pennsylvania's Institute for Human Gene Therapy

April 27, 2000

Click here for the Appendix to this Report

Click here for Penn's Response to this Report

Background Following the tragic death of Jesse Gelsinger, a participant in a phase I clinical trial of gene therapy for ornithine transcarbamylase (OTC) deficiency, the President of the University of Pennsylvania, Judith Rodin, appointed an independent, external panel to review and evaluate the conduct, oversight, and monitoring of clinical trials at the Institute for Human Gene Therapy (IHGT). This committee met twice in Philadelphia and interviewed twenty people associated with the clinical trials conducted at the IHGT in addition to the President and the Provost of the University. We reviewed scores of documents. We thank the University and many of its people for great cooperation in helping us understand the organization and functioning of the IHGT and the conduct of the OTC studies. Our charge is to report to President Rodin on the challenges facing the University of Pennsylvania and the IHGT in light of recent events. Our work follows an extensive investigation by the Food and Drug Administration (FDA) that involved sixteen days of visits to the University. We have reviewed the two documents sent to the University following these visits, FDA Form 483 and the Warning Letter of March 3, 2000, as well as the University's responses to both of these. We have read carefully "The Report of the Committee to Review the Institute of Human Gene Therapy and the Department of Molecular and Cellular Engineering (MCE)." This internal report, completed in November 1999, is a thorough review with a detailed assessment of IHGT and MCE. We have not conducted an investigation similar to that of the FDA. Since, as far as we know, the FDA has not yet reached a conclusion, we do not believe that it would be helpful for us to comment on the various statements or to try to function as arbiter. Should the University need a point by point analysis of the differences between the observations in FDA Form 483 and the response to Form 483, we suggest that an objective group with knowledge and expertise in regulatory affairs be set up specifically for that purpose. It is our understanding that it is not our role either to assess blame or to exonerate. We have not been asked to comment on the functioning of governmental agencies. Rather we have attempted 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. The committee embarked on its task with certain assumptions about clinical trials and the responsibilities of both investigators and institutions involved in their conduct. Clinical trials are essential if medicine is to progress and the health of each generation is to be better than the last. They can be pursued successfully only if society at large believes in their usefulness and safety. That in turn, will happen only if those in charge of the clinical trials can be counted on to see to it that, on one hand, the study is important scientifically with potential for significant benefit and, on the other hand, that the patients welfare is given the highest priority. Patients take part in clinical trials for a variety of reasons. A number of very ill patients want to enroll believing that a remote chance of benefit even with appreciable risk is preferable to no chance at all. At the other end of the spectrum some may be involved primarily for altruistic reasons. In every case, the patient is dependent on the investigator for both knowledge and care. The patient has a right to rely on the physician and the institution not only to put his or her medical welfare first, but also to provide full information with the certainty that nothing will be done without full informed consent. In sum, the primary responsibility of a physician, whether or not he or she is a clinical investigator, is to the patient. Furthermore, we believe that gene therapy, while unproven, continues to be promising. The potential to relieve suffering and restore health to countless individuals remains. Thus, research in this field should continue. Additionally, we understand that an academically-based enterprise has certain advantages. For example, academic researchers are more likely to develop therapies for rare diseases, which are less likely to be pursued by for-profit entities. Findings 1 . The scientists with whom we spoke are competent individuals with national and international reputations (See Appendix, page 6). We thank them for their cooperation. Creating an Institute for Human Gene Therapy does by that very act put pressure on the people of the Institute to do clinical as well as basic research relating to gene therapy. The scientists clearly stated the scientific rationale for their studies and described the time and effort put into obtaining adequate informed consent forms. They and the University are receptive to the FDA's criticisms. We are certain that both the scientists and the University are committed to correcting any deficiencies and complying with all regulations and have the ability to accomplish that goal. Changes to conform to requirements were underway prior to the FDA's investigation. Some changes recommended by the FDA have already been effected. For example, IHGT has transferred responsibility for monitoring of its clinical trials to an outside Contract Research Organization (Parexel International Corporation) and is developing standard operating procedures for its operations, including guidelines for protocol revisions and the reporting of adverse events. 2. Regulation of clinical trials is both important and necessary. Detailed surveillance is essential, most especially when testing novel biologic therapies. Compared with typical pharmaceuticals, viral vectors (currently the most common form of gene therapy) have vastly different properties, both from traditional drugs and from one another, including difficulty in standardizing the quantification of active viral particles, unique pharmacokinetics, variable immune responses, and risk for direct cellular toxicity. Given these properties, plus heightened public awareness and interest, clinical trials of gene therapy should expect to face increased scrutiny which will likely apply to non-viral forms of gene therapy as well. 3. Universities engaged in clinical trials have three basic routes for complying fully with regulations. Collaborate with pharmaceutical companies, Participate in a multicenter trial, Develop within the university the capability of monitoring and reporting in conformance with all governmental rules and regulations. 4. The visitors were impressed with the magnitude of the effort and the financial commitment required of the University if it wishes to conduct independent clinical trials. Since the University will be judged by the same standards as industry, it will now be necessary to invest considerably more resources for compliance than has historically been necessary for independent university-initiated clinical research. The following are examples of requirements that should now be met by all engaged in clinical trials, whether independent or not (when independent the university, of course, has full responsibility): a. A large group of knowledgeable, skilled scientists and support staff must be in place. Scientists must come from a variety of disciplines. Clinical and basic scientists must understand one another and work closely together. The more clinical trials, the larger the group required. Training for conduct and monitoring must be up-to-date and documented. Personnel turnover must be held to acceptable levels. b. The University must comply in meticulous detail to rules and guidelines of the FDA, the National Institutes of Health (NIH), and the Recombinant DNA Advisory Committee (RAC). Compliance requires both specialists in gene therapy and up-to-date training for scientists and staff. All actions must be carried out precisely and carefully recorded in detail. Hundreds of standard operating procedures must be developed, recorded and put into exact operation. Decisions must be made in close communication and collaboration with federal agencies and IRBs that must be kept aware in a timely fashion of adverse events and changes that require approval. c. A culture that is both collegial and critical is essential. Open communication and freedom to express dissenting views is vital. A critical atmosphere must keep the focus on both the safety of patients and the careful accumulation of relevant scientific data. Many meetings of multidisciplinary groups are necessary to review all happenings. d. Patients must be recruited and fully educated as to all risks. e. Appropriate external advisory and oversight groups need to be recruited and involved. f. Adequate clinical and technical expertise should be involved in each clinical trial. 5. The University of Pennsylvania has been making large investments in building a significant staff and infrastructure for this IHGT. Prior to the tragic event, the scientists involved report that they believed that they were doing what they should in an adequate fashion. However, given the actions of the FDA, which has oversight authority, it is evident that substantial changes must be made. Clearly, if this type of research is to continue, the University and the IHGT must comply completely with all regulations and reporting requirements of the FDA, RAC and other agencies involved. 6. Participation in a clinical trial carries inherent risks. Even if all of the guidelines and regulations of the FDA and NIH/RAC are followed, there is no guarantee that a tragic event will not occur. Recommendations The University should make certain that it has ways of assuring itself that groups conducting independent clinical trials have the required financial resources, knowledge, staff, external advice and understanding of the requirements of federal agencies. In other words, the University should monitor its own capability for monitoring and compliance. The University of Pennsylvania should evaluate the function of its IRBs. Specifically, the workload of each IRB may need to be decreased, in order to allow ample opportunity to carefully evaluate and monitor each clinical trial. There are approximately three to four thousand protocols per year with about 80 adverse events reported per one hundred protocols. Secondly, an IRB should have expertise, or, at a minimum, access to expertise, in evaluating the use of novel therapies such as gene therapy. It might help if individual IRBs were to deal with specialized areas of research, or be enlarged, so that they might be staffed with people knowledgeable about the issues before them. Furthermore, the IRBs should facilitate the sharing of information, especially the occurrence of adverse events, between different trials using similar therapies, such as the same viral vector. The University of Pennsylvania should carefully evaluate the process of ethical decision making. Ethical decisions about clinical trials are complex, especially when using novel agents as in gene therapy. Specifically, we recommend that all ethical discussions regarding the testing of gene therapy in human subjects be overseen by an IRB with expertise in evaluating gene therapy, as discussed above. It is unwise to have bioethicists, involved in decision making, report directly to one of the investigators or the Director of IHGT. The role of academic units of bioethics should be to assist investigators and physicians in clarifying their own ethical dilemmas. We recommend that the University review its policies on conflict of interest, especially with regards to clinical trials. Perceived as well as actual conflicts of interest make clinical trials more open to suspicion and criticism, even in the absence of legal issues. Equity positions by an investigator and/or the University may be ill advised, even if, in reality, there is no practical effect whatsoever. Given that the overriding responsibility of the University and its investigators is to the welfare of patients, the avoidance of conflict of interest that even remotely might detract from putting the needs of patients first becomes paramount. In that regard, investments in new therapies differ from those in other ventures, such as computer technology, which involve no responsibilities for patient care. The University of Pennsylvania should to do everything possible to ensure that informed consent is properly obtained. The letter as well as the spirit of FDA regulations is important. Specific guidelines for obtaining informed consent exist, including: who is to be present at the time of consent, clear documentation of who is providing informed consent, consistent review and signing of consent forms, and clear absence of conflict of interest by those obtaining informed consent. Training may be required to ensure that these are followed. We recommend strongly that full consideration be given to the findings and recommendations of the excellent internal report entitled, "The Report of the Committee to Review the Institute of Human Gene Therapy and the Department of Molecular and Cellular Engineering." We recommend that the University give serious attention to the following questions. We believe that the following issues of major policy must be decided by those responsible for allocating the institution's human and financial resources and for overseeing the direction and functioning of the various units that make up the whole. a. Is there a mechanism, internal or external, whereby the IHGT or any similar intramural operation is evaluated on a regular basis with open discussion and free criticism by knowledgeable people, and the results made available to the University and other interested parties? We add that in such a rapidly evolving field, examinations must be ongoing. b. Does it make sense to have an entire Institute devoted to gene therapy? We recognize the great potential of gene therapy, but its efficacy in humans is still in the process of being established with "proof-of principle" evidence. Would it, for example, make more sense to reconfigure the Institute as support groups for scientists? c. The IHGT has come to play an important role in the research of young faculty with whom we spoke. The Institute provides research- and clinical-grade vectors, mentoring in their use, and great assistance in complying with regulations. We understand that investigators in any clinical trial must be trained in the use of investigational drugs, however, we emphasize that the use of a viral vector necessitates additional training in its unique properties and potential toxicities. Without additional training and guidance, the end result is that young investigators who have relatively little understanding of virology or the basic science of gene therapy can administer this novel therapy, almost as if it were a new conventional drug. Is this role premature? Is there sufficient experience with gene therapy that it is ready for use in this manner? Are the risks well enough understood, to promote widespread testing in inexperienced hands? d. Is it prudent to have, entirely within the University, all of the strengths provided by the IHGT, particularly the production of vectors for clinical testing and the monitoring of clinical trials? Or, might some or all these services better be performed extramurally? William H. Danforth, M.D. Chair, Institute for Human Gene Therapy Independent Panel Chancellor Emeritus and Vice Chair of the Board of Trustees Washington University   Edward J. Benz, Jr., M.D. Sir William Osler Professor and Director of the Department of Medicine Johns Hopkins University School of Medicine   Daniel Callahan, Ph.D. Director of International Programs The Hastings Center   Rochelle Hirschhorn, M.D. Professor of Medicine and Cell Biology and Chief of the Division of Medical Genetics New York University School of Medicine   Joseph B. Martin, M.D., Ph.D. Dean of the Faculty of Medicine Harvard Medical School   Inder Verma, Ph.D. American Cancer Society Professor of Molecular Biology The Salk Institute   Dena Minning Staff to the Independent Panel Medical Scientist Training Program Washington University School of Medicine

Appendix University of Pennsylvania Faculty and Staff Interviewed by Independent Panel Judith Rodin, Ph.D. President, University of Pennsylvania   Stephen Schutt Vice-President and Chief of Staff, University of Pennsylvania   Robert Barchi, M.D., Ph.D. Provost, University of Pennsylvania   James Wilson, M.D., Ph.D. Director, IHGT Chairman, Molecular and Cellular Engineering   Nelson Wivel, M.D. Deputy Director, IHGT Adjunct Professor, Molecular and Cellular Engineering   Arthur Caplan, Ph.D. Director, Center for Bioethics Member, IHGT Executive Committee   Lisa Speicher, Ph.D. Associate Director, Clinical Trials Unit, IHGT Steve Raper, M.D. Principal Investigator of OTCD Clinical Trial Associate Professor of Surgery   Mark Batshaw, M.D. Co-investigator of OTCD Trial (no longer at University of Pennsylvania)   Stephen Eck, M.D., Ph.D. Assistant Professor, Hematology/Oncology   Daniel Sterman, M.D. Assistant Professor, Pulmonary and Critical Care Director, Interventional Pulmonology   Ronald Rubenstein, M.D., Ph.D. Assistant Professor of Pediatrics   Katherine High, M.D. Professor of Pediatrics Medical Director, Hematology Laboratory Member, IHGT Executive Committee   Jean Bennett, M.D., Ph.D. Assistant Professor, Ophthalmology James Hoxie, M.D. Professor, Hematology/Oncology   Nicholas Kefalies, M.D., Ph.D. Professor Emeritus of Medicine, Infectious Diseases Professor, Biochemistry and Biophysics Chair, Institutional Review Board   Peter Binnion, M.D. Chair, IRB 2 (reviewed OTC)   Joe Sherwin Director, Office of Regulatory Affairs   Peter Erichsen Vice President and General Counsel   Lee Dobkin Deputy General Counsel for Compliance   Stephen J. Immelt Partner, Hogan & Hartson, LLP, Baltimore, MD office   Robert P. Brady Partner, Hogan & Hartson, LLP, Washington, DC office

Ed Note: Please see the University's Response to this Report.

Almanac, Vol. 46, No. 34, May 30, 2000

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