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«Minutes of Symposium and Meeting December 8-10, 1999 U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service National Institutes of Health ...»

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Minutes of Symposium and Meeting

December 8-10, 1999



Public Health Service

National Institutes of Health


I. Call to Order and Day One Opening Remarks........................................ 4 II. Keynote: Adenovirus Biology, Pathophysiology, and Adaptation to Gene Therapy............ 5 III. Examples of Adenovirus-Induced Pathophysiology.................................... 6 IV. Safety and Toxicity Data From Clinical Trials Using Adenoviral Vectors................... 10 V. Panel Discussion and Definition of Terms.......................................... 15 VI. Public Comment.............................................................. 18 VII. Day One Closing............................................................. 19 VIII. Day Two Opening Remarks..................................................... 19 IX. Discussion of Severe Adverse Event on Human Gene Transfer Protocol #9512-139: A Phase I Study of Adenoviral Vector-Mediated Gene Transfer to Liver in Adults With Partial Ornithine Transcarbamylase Deficiency................................................... 19 X. Recommendations of the RAC Working Group on Adenovirus Safety and Toxicity........... 30 XI. Data Management............................................................ 32 XII. Minutes of the September 2-3, 1999, RAC Meeting................................... 33 XIII. Day Two Closing............................................................. 33 XIV. Day Three Opening Remarks.................................................... 34 XV. Current Issues in Adverse Event Reporting and Proposed Action........................ 35 XVI. Discussion of Human Gene Transfer Protocol #9906-332: NGF Ex Vivo Gene Therapy for Alzheimer’s Disease........................................................... 44 XVII. Discussion of Human Gene Transfer Protocols #9910-342 and 343: Phase I Trial To Evaluate the Safety of H5.020CMVPDGF-B for the Treatment of a Diabetic Insensate Foot Ulcer and Phase I Trial To Evaluate the Safety of H5.020CMVPDG

–  –  –

The Recombinant DNA Advisory Committee (RAC) was convened for its 76th meeting at 8:00 a.m. on December 8, 1999, at the National Institutes of Health (NIH), Building 10, Masur Auditorium, 9000 Rockville Pike, Bethesda, MD 20892. Dr. Claudia A. Mickelson (Chair) and Dr. Inder Verma (Co-Chair) presided. In accordance with Public Law 92-463, the meeting was open to the public on December 8 from 8:00 a.m. until 2:45 p.m., on December 9 from 8:30 a.m. until 3:00 p.m., and on December 10 from 8:30 a.m. until 3:30 p.m. A committee roster is attached (Attachment I). The following individuals were

present for all or part of the meeting:

Committee Members:

C. Estuardo Aguilar-Cordova, Texas Children's Hospital and Baylor College of Medicine Dale G. Ando, Cell Genesys, Inc.

Xandra O. Breakefield, Massachusetts General Hospital Louise T. Chow, University of Alabama, Birmingham Theodore Friedmann, University of California, San Diego Jon W. Gordon, Mount Sinai School of Medicine Jay J. Greenblatt, National Cancer Institute, National Institutes of Health Eric T. Juengst, Case Western Reserve University Nancy M.P. King, University of North Carolina, Chapel Hill Sue L. Levi-Pearl, Tourette’s Syndrome Association, Inc.

Ruth Macklin, Albert Einstein College of Medicine M. Louise Markert, Duke University Medical Center R. Scott McIvor, University of Minnesota Claudia A. Mickelson, Massachusetts Institute of Technology

Executive Secretary:

Debra W. Knorr, National Institutes of Health

Ad Hoc Consultants and Speakers:

Mark Batshaw, Children’s National Medical Center, University of Pennsylvania Arthur L. Beaudet, Baylor College of Medicine C. Thomas Caskey, Merck & Company, Inc.

Bruce A. Chabner, Harvard Medical School Ronald G. Crystal, Cornell Medical Center Lyndah K. Dreiling, Gencell/Rhône-Poulenc Rorer Pharmaceuticals, Inc.

Wilma Friedman, Columbia University Linda Gooding, Emory University Angus J. Grant, Gencell/Rhône-Poulenc Rorer Pharmaceuticals, Inc.

JoAnn Horowitz, Schering-Plough Research Institute Marshall Horwitz, Albert Einstein College of Medicine David H. Kirn, Onyx Pharmaceuticals, Inc.

David Magnus, Center for Bioethics David J. Margolis, University of Pennsylvania Medical Center David P. Meeker, Genzyme Corporation Richard C. Mulligan, Howard Hughes Medical Institute 1 The Recombinant DNA Advisory Committee is advisory to the National Institutes of Health (NIH), and its recommendations should not be considered as final or accepted. The Office of Biotechnology Activities should be consulted for NIH policy on specific issues.

–  –  –

Glen Nemerow, Scripps Research Institute Amy Patterson, National Institutes of Health Anne M. Pilaro, U.S. Food and Drug Administration Steven Raper, University of Pennsylvania Margaret Rick, Warren Grant Magnuson Clinical Center, National Institutes of Health Jay P. Siegel, U.S. Food and Drug Administration Lana Skirboll, National Institutes of Health Mark Tuszynski, University of California, San Diego Dinko Valerio, IntroGene Inder Verma, Salk Institute Robert Warren, University of California, San Francisco Karen Weiss, U.S. Food and Drug Administration James M. Wilson, University of Pennsylvania Health System Kathryn Zoon, U.S. Food and Drug Administration

Nonvoting Representatives/Liaison Representatives:

Daniel W. Drell, U.S. Department of Energy Melody H. Lin, Office for Protection from Research Risks, National Institutes of Health Andra Miller, U.S. Food and Drug Administration Philip Noguchi, U.S. Food and Drug Administration

National Institutes of Health Staff Members:

Levent Akyurek, NHLBI Suresh Arya, NCI Krysztofs S. Bankiewicz, NINDS Ami Bhatt, NIMH Manfred Boehm, NIH Bryan Brewer, NHLBI John Burklow, OD Connie Caldwell, OD Natasha J. Caplen, NHGRI Henry Chang, NHLBI Donna Chinnasamy, NHGRI Nachimuthu Chinnasamy, NHGRI John Chiorini, NIDCR De-Maw Chuang, NIMH Behor Cohn, NIAID Ross Coppel, NLM Anthony Craig, NIH Lori M. Croskey, Chaplain Intern Claudio D’Ambrosio, NIAID Kleper N.F. De Almeida, NIAID Maria Dinger, NHLBI Neal D. Epstein, NHLBI Julian Escobar, NHLBI Wendy Fibison, NHGRI Ruth L. Fischbach, OD O. Ray Fitzgerald, CC Gregory Frykman, NCI Joseph F. Gallelli, OD Luci Gonzalez, NIAID Stephen Groft, OD Jo Grossheim, Chaplain Intern Brooke H. Haehl, NCI Naoki Hamajima, NHGRI

-2Minutes of the Recombinant DNA Advisory Committee - 12/8-10/1999 Joe Harford, NCI Changting Haudenschild, NHLBI Julie Hedrich, NHLBI Craig A. Higgins, NHGRI Masaru Ichida, NHLBI Christine Ireland, OD John Janik, NCI Jing Jieyu, NCI James Kaiser, NIH Nicholas Keiser, NHGRI Meyoung-Kon Kim, NCI Richard Knazek, NCRR Sachiko Kojigaya, NHLBI Robert Kotin, NIH Helen Kupinsky, NHGRI Robert Lanman, OD Becky Lawson, OD Rebecca Link, NHLBI Jay Lozier, NHGRI Mario Mautino, NHGRI Catherine McKeon, NIDDK Koji Miyazaki, NHLBI Richard Morgan, NHGRI Darrell Morris, NCI John C. Morris, NCI Karen Morrow, NIH Linda M. Muul, NHGRI Gary Nabel, VRC Carolyn Nagler, NCI Shriram Nallamshetty, NHLBI Connie Noguchi, NIDDK Samer Nuwayhid, NCI Ray O’Neill, NCRR Pearl O’Rourke, OSP Makoto Otsu, NHGRI Ryszard M. Pluta, NINDS Robert Pratt, OOPD Rosemary Quitley, COPR Donald Ralbovsky, NIH Nicholas P. Restifo, NCI Bob Roehr, COPR Gene Rosenthal, OD Silvia Santamarina-Fojo, NIH Nava Sarver, NIAID William J. Savage, NIAID Shepherd H. Schurman, NHGRI Justina Schwenberger, NIAID Magda Sgagias, NCI Robert D. Shamburek, NHLBI Alan Shecht, NIDDK Susan E. Sherman, OGC/NIH Thomas Shih, OD Hillary Sigmon, NINR Karen Sikes, OD Sonia I. Skarlatos, NHLBI Anne M. Slavotinek, NHGRI Kumar Srinivasan, NEI

-3Minutes of the Recombinant DNA Advisory Committee - 12/8-10/1999 Victoria S. Statham, NIH Howard Streicher, NCI Masaaki Takatoku, NHLBI Marcia L. Taylor, NIAID Andrea True, NHLBI Harold Varmus, OD Robert E. Walker, NIAID Robert P. Wersto, NIA Judith Whalen, NICHD Brian Wojcik, NCI Ling Xu, NIAID Zhiyong Yang, NIAID Takanobu Yoshi, NIH James A. Zwiebel, NCI


Approximately 450 individuals attended on each of the first 2 days of this 3-day RAC symposium/meeting;

approximately 60 individuals attended the third day. A full list of attendees appears in Attachment II.

I. Call to Order and Day One Opening Remarks/Dr. Mickelson, Dr. Verma, and Dr. Patterson Dr. Mickelson, RAC Chair, called the meeting to order at 8:00 a.m. on Wednesday, December 8, 1999, in the Masur Auditorium at the National Institutes of Health. The notice of this meeting under the NIH Guidelines for Research Involving Recombinant DNA Molecules (NIH Guidelines) was published in the Federal Register on November 18, 1999 (64 FR 63051) and December 7, 1999 (64 FR 68397), and the proposed action on November 22, 1999 (64 FR 63827). Issues to be discussed by the RAC at this symposium and meeting included a 1-day symposium on adenoviral vectors, including adenovirus biology, pathophysiology, adaptation of adenovirus for gene transfer, and safety and toxicity data from clinical trials using adenoviral vectors; discussion of a severe adverse event on Human Gene Transfer Protocol #9512a Phase I study of adenoviral vector-mediated gene transfer to liver in adults with partial ornithine transcarbamylase [OTC] deficiency); current issues in adverse event reporting and proposed action;

discussion of Human Gene Transfer Protocol #9906-322—(1) nerve growth factor ex vivo gene therapy for Alzheimer’s disease; and discussion of Protocols #9910-342 and #9910-343—respectively, a Phase I trial to evaluate the safety of an adenovirus expressing platelet derived growth factor-B (PDGF-B) for the treatment of diabetic insensate foot ulcer and a Phase I trial to evaluate the safety of the same vector, in combination with limb compression bandage, for treating venous leg ulcer.

Dr. Mickelson noted that the family of Mr. Jesse Gelsinger, who died while participating in a gene therapy trial for treatment of OTC, was present at this meeting. This symposium’s purpose was to examine scientific and technical data to come up with guidelines for researchers and the RAC for clinical trials that use adenoviruses.

Dr. Verma reiterated the hallmark of the RAC, which is openness and frankness. The main purpose of this meeting is to learn, gather information, and make recommendations to the RAC to learn more.

Dr. Patterson echoed Dr. Mickelson’s and Dr. Verma’s statements of the major objectives of this symposium: to achieve a more thorough understanding of adenoviral gene transfer and advance the goal of ensuring the safety of patients enrolled in trials. For the first time, a patient was lost in a clinical study of adenoviral gene transfer. The sharing of adverse events data in Phase I trials for the treatment of these severe diseases, which often have a high incidence of naturally occurring adverse events, enhances the possibility that collection and pooling of these data may show patterns that enable improved understanding of the potential toxicities associated with the adenovirus vector. Variables that could influence the safety of this method of gene delivery include the type of adenoviral vector, route of vector administration, dosage, and clinical condition of the patient. The challenge is to apply knowledge and reason to more fully understand the potential toxicities associated with this method as well as to understand the cause of this individual’s death. The RAC will develop a final report on adenoviral vectors, and a proposal may be issued

-4Minutes of the Recombinant DNA Advisory Committee - 12/8-10/1999 for public comment if the RAC’s final report determines that further guidance is needed. After consideration of the public comment, the RAC will transmit its final recommendations to the NIH Director; if approved by the Director, this guidance will be incorporated into the NIH Guidelines.

II. Keynote: Adenovirus Biology, Pathophysiology, and Adaptation to Gene Therapy Adenovirus Molecular Biology and Disease/Dr. Marshall Horwitz, Albert Einstein College of Medicine Dr. Horwitz provided an overview of the adenoviruses, which belong to Adenoviridae, a family of more than 49 serotypes that infect humans. Adenoviruses were discovered at the NIH in 1953 as a cytopathic agent in the tissue culture of tonsils and adenoids; they are associated with a variety of diseases.

Diseases caused by adenoviruses, the risk groups for those diseases, and the serotypes responsible for the syndromes were enumerated by Dr. Horwitz. Adenoviruses cause much disease that has disrupted military recruitment and basic training, due to crowding and stress. Conjunctivitis, diarrhea (particularly in young children), a variety of respiratory diseases, and probably myocarditis are caused by adenoviruses. In immunosuppressed individuals, adenovirus persists in the urinary bladder, can cause a fatal hepatitis, and persists in the gastrointestinal tract. One of the hallmarks of adenoviruses—when they cause in vivo or in vitro infection of tissue—is intranuclear inclusions, which cause characteristic morphologic changes in the nuclei of infected cells.

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