Presidential Address

3^rd Annual Meeting of the
American Society of Gene Therapy
Savio L.C. Woo, PhD, President of ASGT 1999-2000, and
Professor and Director of the Institute for Gene Therapy and Molecular Medicine
at Mount Sinai School of Medicine, NY
9:20 AM, Thursday, June 01, 2000
Denver, CO

Dr. Verma, Members and Guests,

Thank you for coming to the Third Annual Meeting of the American Society of Gene Therapy. At last count, we have 1,800 registrants in this meeting which features 975 scientific abstracts, the most ever in our Society's history. As you can see from the Scientific Program of the meeting, we have 15 scientific symposia covering the most exciting areas in the science of gene transfer with lectures given by leaders of the respective fields of study, 180 oral presentations selected from the submitted abstracts by the Abstract Review Committee Chaired by Dr. David Bodine at the National Human Genome Research Institute and over 700 poster presentations, as well as several corporate-sponsored symposia in which the most recent advances in gene therapy product development will be discussed. In the Educational Program organized by the Education Committee chaired by Dr. Xandra Breakefield at Harvard this year, there are dozens of sessions on gene transfer vectors and system biology relevant to gene therapy applications, as well as several sessions on how to prepare protocols for clinical gene transfer studies and how to successfully apply for federal funding in gene transfer research by knowledgeable officials from the FDA and the NIH, respectively. In addition, there will be a High School and College Teacher Education Outreach Program scheduled on Saturday morning, which is organized by Dr. Paula Gregory, at Ohio State University, and it is intended to share with the teachers the basic principles and potential applications of gene therapy to treat disease, and hope that they will be able to transfer the knowledge to their respective students in the future. It is important that we tirelessly continue our efforts in public education as a better informed public will certainly be better able to appreciate the benefits and risks in gene therapy.

I am also delighted to report to you that out Society has "really" grown in the past few years. We started with about 1,000 members in 1996, and we now have over 2,400 members, representing an unbelievable compound annual growth rate of about 25%. The Membership Committee, under the leadership of its Chairman, Dr. Donald Kohn at the University of Southern California, has initiated an aggressive membership recruitment campaign and over 400 new members have been added to our society's roster in this calendar year alone. Starting January of this year, management of our society has been provided by Executive Director, Inc. in Milwaukee, Wisconsin and Ms. Elizabeth Dooley has been identified as the Executive Director of ASGT. She is also responsible for putting together this annual meeting and providing all logistical supports, and please let her know if you need any help or additional services.

Acting upon the recommendations of the Advisory Board Chaired by Dr. George Stamatoyannopoulos at the University of Washington, the founding president of our society, The Board of Directors has enthusiastically implemented an awards program for the 3 most outstanding abstracts submitted by graduate students and 3 by post-doctoral fellows to our society's annual meetings. Thanks to the generosity of the Chiron Corp. this year, these "outstanding trainee research awards" will be accompanied by a $500 check each, in addition to $500 of travel subsidy to attend this meeting. The awardees were also selected by the Abstract Review Committee and the awards will be presented to the recipients at the conclusion of this Plenary Session.

A most notable initiative of our Society this year has obviously been the launching in this January of Molecular Therapy, the Society's official scientific journal. Although printed by the Academic Press, the Society owns the title to this journal. After an exhaustive search by the Publications Committee chaired by Dr. Elizabeth Nabel currently at the National Heart, Lung and Blood institute, Dr. Inder Verma of the Salk Institute was identified as the Editor-In-Chief of this journal, and the recommendation was jubilantly accepted by the ASGT Board of Directors. With Dr. Verma's long-standing dedication to the Society and his exquisite taste for quality of science in gene transfer as well as other fields, we all look forward to the day when Molecular Therapy will become THE preeminent scientific journal in the discipline of gene therapy. Dr. Verma ought to be complimented for his successful recruitment of an outstanding Editorial Board, as well as Dr. Finton Steele as Editor of the journal. Dr. Steele has an outstanding track record in scientific publishing, and I will ask him to give you an update in a moment on the current status of the journal, as well as his vision on how to help the Society achieve its goal of having THE leading scientific journal in our discipline.

Another new initiative launched this year has been the formation of an Industrial Liaison Committee as a standing committee of the ASGT, which is chaired by Dr. Alan Smith of Genzyme and comprised of members from 16 biotechnology and pharmaceutical companies involved in gene therapy research and product development. Under Dr. Smith's leadership, a new Biotechnology Symposium has been added to the scientific program in this year's meeting. In addition, a series of 5 different Workshops on Vector Production has been organized and scheduled in the afternoons from Thursday through Saturday this week. The objectives of these workshops are to have free exchanges on how various gene transfer vectors can be produced for pre-clinical experimentation as well as clinical application, so that methods and experiences learned by professional experts in companies can be shared with the scientific community. A most exciting aspect of these workshops are pledges by all invited speakers and panelists that the topic areas will be discussed without proprietary restrictions, and we wish to compliment members of the Industrial Liaison Committee and the workshop contributors on this extraordinary gesture.

1999 also marks an extraordinary year for the discipline of gene therapy. While scientific and clinical evidence reported in the most recent scientific journals suggested that the world has just witnessed the first successful application of gene transfer to treat life threatening diseases, clinical translation research in our discipline has also suffered its first patient loss as a direct consequence of the gene treatment. Jesse Gelsinger was an 18-year-old patient suffering from a moderate form of rare urea cycle disorder secondary to a partial deficiency of the hepatic enzyme ornithine transcarbamylase, who died last September at the University of Pennsylvania after receiving, through intrahepatic artery infusion of a relatively high dose of a E1 and E4-deleted recombinant adenovirus expressing the correct human enzyme. To pay our respect to the young man who has given his life in pursuit of an ideal treatment that will one day be able to provide a cure for others affected by the same disorder and beyond, and to assure him in spirit that the scientific community is galvanized to do our very best to help fulfill his dream one day by learning everything possible from his tragic loss, I ask that we all stand in a moment of silence in remembrance of Jesse, as well as the cause he represented.

The investigators of the clinical study at U. Penn. immediately reported the patient's death to the FDA and the RAC as required by the federal regulations and guidelines. In contrast to the widely presumed cause of death being severe hepatotoxicity or disseminated intravascular coagulation at the time, subsequent pathological analyses indicated that the official cause of death was multi-organ failure secondary to adult respiratory distress syndrome induced by a systemic inflammatory response to the recombinant adenovirus vector itself. This is a finding that needs to be further explored to determine whether the outcome is specific to this particular patient or to recombinant adenovirus administered systemically. The RAC has wisely recommended that subsequent clinical trials involving the administration of recombinant adenoviruses to patients through various routes to monitor the recipients's systemic pro-inflammatory cytokine profiles until a definitive lesson on the response to this type of vector in humans can be learned.

At the subsequent December RAC Meeting last year, it was revealed by the FDA that there were apparently multiple protocol violations during the conduct of this clinical trial, and existing protocols sponsored by the Human Gene Therapy Institute at U. Penn., including the OTC trial, were put on Clinical Hold until the cited deficiencies can be satisfactorily corrected. Although the investigators have since responded to the FDA citations, the clinical holds are still in effect to date. The ASGT expects its members to rigorously follow federal and institutional guidelines in clinical gene transfer studies, and through Dr. Verma's testimony in Senator Frist's subcommittee hearing on gene therapy on February 2, 2000, the society advocated that the investigators be held accountable for violation of federal regulations in the conduct of clinical research involving patients, and decisive actions be undertaken swiftly by the responsible federal regulatory agencies.

Triggered by the U. Penn incident, Dr. Harold Varmus, then director at the NIH, instructed the RAC to gather data on all patient adverse events since clinical trials involving gene transfer started a decade ago. To the horror of everyone, it was discovered that of the 652 patient adverse events involving adenovirus administration to patients that were reported to the FDA only 6% were reported to the RAC in a timely fashion as required by the NIH guidelines. Although greater than 90% of these unreported adverse events were subsequently determined by the NIH to be unrelated to gene treatment, under-reporting of patient adverse events to the RAC in such a massive scale has become a major concern to the federal regulatory agencies, The Congress and the public. The reasons were at least two-fold. First, investigators incorrectly assumed that reporting to the RAC became unnecessary after a role change of the RAC several years ago, when it no longer has the authority to approve clinical protocols in gene transfer. Second, investigators wrongfully assumed that only those adverse events related to the gene treatment itself need to be reported to the RAC which stands for Recombinant DNA Advisory Committee. Both are explanations rather than excuses to the under-reporting of adverse events, as it is primarily the investigator's responsibility to follow all relevant federal regulations and guidelines in clinical gene transfer studies. As a consequence to this revelation, the American Society of Gene Therapy has adopted a Policy that was published in the first issue of Molecular Therapy in January, which states in part:

"Members must adhere to the tenets of all the regulatory schema that are in place, as well as those that are adopted in the future. Adherence to oversight principles is important in maintaining public credibility about a newer form of biotechnology that still seeks hard evidence of success, but that tremendous potential in shaping future therapies for a wide variety of diseases. In that context, that ASGT fully supports the NIH in its efforts to establish clear directives about adverse events reporting so that tragic incidences can be reduced to the lowest possible level and so that the field can move forward in the most efficient and responsible manner".

Dr. Varmus also appointed an Advisory Committee to the Director (ACD) in gene therapy last December to re-evaluate the responsibilities of the RAC in order to better protect patient safety and enhance compliance in adverse events reporting. The ASGT has submitted its recommendations to the ACT, which asked that the federal regulatory process on clinical gene transfer be strengthened and streamlined. At present there are multiple overlapping federal agencies with regulatory responsibilities on clinical gene transfer, and each has its own set of reporting requirements. Ideally the system should be such that the investigators will need to report to a single federal agency, which will then distribute the reports to all other sister agencies where appropriate. An alternative will be for all responsible federal agencies to completely unify their reporting requirements, including the use of identical reporting forms. The investigators can then submit identical copies to all relevant federal agencies at the same time without undue burdens.

While enhancing the reporting of adverse events, the ASGT also asked that a federal process be developed that will permit the reports be critically analyzed and efficiently managed before being made public. The inherent value in any information gathering system lies in its relevance. Patients engaged in various gene transfer studies are often very ill with terminal diseases, and many will succumb to their underlying disease over time. In order to properly inform the public regarding the real benefits or risks in clinical gene transfer studies, natural outcome must be distinguished from those adverse events that are related to gene transfer itself, and they will need to be segregated into clearly defined categories in the records maintained and updated regularly by the agency responsible for the reporting of these events to the public.

Another area of major concern to the scientific community and the public is the real and/or perceived financial conflict of interest among investigators conducting clinical trials. An extreme case would be that of an investigator conducting a clinical trial sponsored by a for-profit company that is partly or wholly owned by the same investigator. In order to ensure the safety and the interests of the patients who voluntarily participate in clinical trials involving gene transfer and to assure the public that these clinical studies are conducted without financial conflicts, ASGT adopted in April a Policy recommended by its Ethics Committee chaired by Dr. Lucio Luzzatto at the Memorial Sloan Kettering Cancer Center. The Policy is published in the May issue of Molecular Therapy, which states:

"In gene therapy trials, as in all other clinical trials, the best interest of the patients must be always primary. International, national and institutional guidelines on standards of care must be rigorously followed, approved protocols strictly adhered to, serious adverse events promptly reported to all appropriate regulatory and review bodies. Relevant federally and institutionally established regulations in financial conflicts must also be abided by. In addition, all investigators and team members directly responsible for patient selection, the informed consent process and/or clinical management in a trial must not have equity, stock options or comparable arrangements in companies sponsoring the trial. The American Society of Gene Therapy requests its members to abstain from or to discontinue any arrangement that is not consonant with this policy."

It is gratifying indeed that after the general membership was notified through e-mail of this policy a couple of months ago, the society has only received supporting calls, and not a single complaint from the membership. I wish to take this opportunity to compliment our members for your support of this policy.

On March 7, 2000, the FDA and the NIH jointly announced two new initiatives to protect participants in gene therapy trials: The Gene Therapy Trial Monitoring Plan and The Gene Transfer Safety Symposia, and I was asked to comment on them in Senator Frist's second subcommittee hearing on gene therapy on May 25, 2000. Testifying on your behalf, I stated that the ASGT strongly supports the establishment of a federal regulatory system that will maximally ensure patient safety AND provide investigative opportunities to produce useful outcomes in human gene transfer studies that will lead to development of novel therapeutics for disease treatments in the future. Specifically, the gene therapy clinical trial-monitoring plan calls for sponsors of all clinical gene transfer trials to establish monitoring procedures that will need to be reviewed and approved by the FDA. To ensure the quality of monitoring, a key element in the plan is that it needs to be performed by a third party that is not directly involved with the studies, such as independent clinical research organizations, which are selected by and report to the sponsors. This procedure will be effective in trials where the sponsors and the investigators are separate entities, which constitute most of the industry-sponsored trials. However in trials where the sponsors and the investigators are the same individuals, which constitutes most of the physician-sponsored trials in academia, the document recognized that the above procedure will result in the monitors reporting to the sponsors who are also the investigators, and stated that the NIH will need to develop an appropriate procedure to assure independent monitoring.

The challenge here will be to identify means in a scientifically and clinically sound way to ensure patient safely, but without incurring excessive costs that will stifle academic clinical research which are often more innovative, experimental in nature and pilot in scale. Furthermore, academic research also targets diseases that do not constitute large or lucrative markets to attract industrial investments. If these studies are not encouraged, many potentially treatable disorders will continue to exact a heavy toll in society. The ASGT will enthusiastically cooperate with the NIH and the FDA in developing such an effective and equitable monitoring procedure.

The initiative also calls for more rigorous quality assurance and quality control testing of gene therapy products, which is appropriate for advanced clinical trials where a single product is administered to many patients. However, in small-scale studies conducted by academic institutions involving patients with life threatening conditions, special consideration will need to be given as many different products will need to be tried and each will be given to a limited number of patients. The FDA recognized this need in the manufacturing of monoclonal antibodies and implemented a distinct set of regulations for experimental studies of life threatening conditions. This foresight stimulated the successful application of monoclonal antibodies in an ever-broadening range of diseases to date, including breast cancer and lymphoma. A similar arrangement for gene therapeutics will stimulate clinical translational research and expedite development of novel treatments for life threatening diseases.

The gene transfer safety symposia calls for the NIH and FDA to offer 4 symposia annually to better educate clinical investigators and their team members on all aspects of clinical gene transfer studies, including and not limited to, good clinical practice in research, adverse events reporting and gene transfer product quality control and assurance. These symposia will be given by experts in the relevant fields and offered to all interested individuals and organizations in the country through teleconferencing. The ASGT unequivocally supports this initiative, as a more educated clinical investigator will be better able to design and conduct clinical studies, as well as generate quality results while improving patient safety at the same time.

The initiative also calls for the FDA and the NIH to provide support for professional organizations and academic centers interested in holding safety conferences focused on gene therapy. The ASGT enthusiastically embraces this concept and we have included an additional session in the Educational Program of this annual meeting, on NIH/FDA Guidelines for Clinical Trials and Compliance, co-moderated by Dr. Amy Patterson, Director of the Office of Biotechnology Activities at the NIH and Dr. Philip Noguchi, Director of the Division of Cellular and Gene Therapies at the FDA, which is scheduled at 7:00 - 10:00 p.m. tonight in Room C207/C209. I would certainly encourage all members and guests involved or interested in clinical gene transfer studies to attend this session. In addition, the Education Committee and Dr. Verma, our incoming president, are in the process of organizing an intensive clinical gene transfer training course, together with the FDA and NIH, that will be offered over a 2-3 day period in conjunction with our Society's Annual Meetings in the future. Appropriate CME credits will be given, and certificates will be issued, to members who have successfully completed the training course.

On May 23, 2000, Secretary Donna Shalala of the Department of Health and Human Services (HHS) announced five initiatives to further strengthen protections of human research subjects, including those involving gene transfer. The ASGT applauds the HSS initiatives to significantly enhance 1. Education and training; 2. informed consent; 3. improved monitoring and 4. conflict of interest, which have already been described in the Society's testimonies in Senator Frist's two subcommittee hearings. Regarding the fifth HSS initiative to seek legislation for the FDA to levy civil monetary penalties, the ASGT believes that the investigators and their institutions should be held accountable for willful non-compliance of federal regulations and guidelines in the conduct of clinical research involving patients. The Society also stated in its response to the HSS announcement: "When it comes to protecting patient safety in clinical trials, the ASGT firmly believes that the same set of high standards should be applied in all fields of medicine."

I also testified in Senator Frist's subcommittee hearing that gene therapy is a novel technology that promises to provide effective treatments for a variety of diseases in the future, and glimpses of hope that these promises will be fulfilled are coming to light. In a Phase I gene transfer trial for the treatment of Hemophilia B by Dr. Kathryn High at the Children's Hospital of Philadelphia and Dr. Mark Kay at the Stanford University, significant reduction in whole blood clotting times was observed in patients for several months after receiving intramuscular administration of the lowest dose of a recombinant AAV vector expressing the human coagulation factor IX gene. In another Phase I trial of Severe Combined Immune Deficiency Syndrome secondary to a genetic deficiency of the gamma chain of cytokine receptors, better known as X-linked SCID or the bubble boy disease, several affected children treated by Dr. Alain Fischer in France with autologously transplanted bone marrow cells reconstituted with the normal human gene in vitro, have in turn reconstituted their immune systems for up to one year, and the children are now living normally with their families! While most encouraging, these results were obtained from only a few patients and further clinical studies must be conducted in order to ascertain that gene therapy is effective in curing these deleterious disorders. The results of these exciting studies, as well as two other clinical studies in gene therapy for cancer, will be presented in the Scientific Symposium entitled "Recent Advances in Clinical Gene Therapy" scheduled at 10:30 this morning in Ballroom 2/3.

What about other inherited disorders, or more complicated diseases like cancer, diabetes, heart disease, dementia, etc.? What are their prospects of being treated effectively by gene therapy as well? After all we are at the dawn of the past-genome era, and each and every fifty to one hundred thousand human genes can potentially be used as medicine to treat some form of disease. The reality is that gene therapy is a new biomedical discipline that is still in its infancy. In order to realize its full potential to treat a variety of diseases in the future, much basic science research and pre-clinical studies will need to be pursued to rigorously establish efficacy and safety in relevant animal models of disease. As biologic responses in cultured cells and in animals may or may not reflect completely what will actually happen in humans however, there can be no substitute to clinical testing of the new treatment modalities in patients. To assure the public that clinical gene transfer studies will be conducted by investigators in a responsible manner, the American Society of Gene Therapy strongly supports the refinement of federal regulatory processes that will simultaneously encourage research and ensure patient safety.

In summary, during the past year there has been enormous progress made in science and technology development of gene transfer in animal studies that has begun to be successfully applied in the clinic. While there were also serious set-backs, we need to reach equitable resolutions in a scientifically and clinically sound manner and then move forward, so that we can reach our goal one day when treating diseases by gene therapy is not only effective and safe, but also as common as vaccinations and prescription drugs today. With that note, I wish to thank you for giving me the privilege and the honor of serving as your president this year. While it has been a most challenging year to be president of our Society and at times I wonder whether there is an end to all the misfortunes happening in our field, how the various Standing Committees and Board of Directors have responded to these challenges in the most constructive way that is enthusiastically supported by the general membership constitutes a great sense of responsibility and pride on our community, and it has truly been an extraordinary experience that I shall forever cherish in my heart. Thank you and have a great meeting!