PHILADELPHIA --- The Institute for Human Gene Therapy at the University of Pennsylvania today (Feb. 14) filed its response to Inspectional Observations made by the Food and Drug Administration on Jan. 18, 2000, as the result of its investigation into the death of Jesse Gelsinger, an 18-year-old with a rare metabolic disease who was participating in an experimental gene therapy trial for the disease known as ornithine transcarbamylase (OTC) deficiency, an inherited disorder that in its most common form causes death in affected newborn males due to a genetic defect in the liver.

The IHGT immediately placed the OTCD clinical trial on hold following Jesse Gelsinger's death on Sept. 17, 1999. The IHGT had informed the FDA of Jesse Gelsinger's deteriorating condition prior to his death and, following his death, promptly notified the FDA, the Recombinant DNA Advisory Committee of the NIH and the Institutional Review Board.

The IHGT response to the FDA continues an extensive review of research at the University of Pennsylvania, ordered by President Judith Rodin, including a comprehensive review of all aspects of research using human subjects, considering everything from the mechanics of the approval process to oversight to accountability and research outcomes; and an independent review of oversight and monitoring of clinical trials at the Institute for Human Gene Therapy, which will be conducted by research scientists who are unaffiliated with the University of Pennsylvania.

"We understand that nothing less than the highest possible standards for the conduct of research are acceptable at the University of Pennsylvania," said Richard Tannen, M.D., professor of medicine and senior vice dean at the School of Medicine. "The thoughtful process that has led to our [FDA] response is an important step which, together with the other important initiatives underway, will ensure that the conduct of research at Penn does, in fact, meet those standards."

The FDA identified "...important issues arising out the OTCD trial," said James M. Wilson, John Herr Musser Professor of Research Medicine and director of the IHGT, and, he said "...we have taken its questions and concerns very seriously."

Dr. Wilson said, that the IHGT will continue to cooperate, fully and completely, with the FDA, the National Institutes of Health and all other interested agencies in their respective reviews.

He also said that IHGT "...will continue to work closely with the FDA to implement revised clinical procedures relating to monitoring and related practices and to provide additional patient safeguards to the fullest extent possible in clinical research settings."

The 28-page IHGT response to the FDA makes the following points:

• The record demonstrates that each and every patient who participated in the OTCD trial gave informed consent to participate.
• The IHGT contemporaneously documented each patient's eligibility to participate in the OTCD trial.
• The IHGT did submit data in January 1999 on the toxicity levels of two participants in the OTCD trial, data that should have been submitted in October 1998 and in November 1998, and data that should have been discussed with the FDA before proceeding with the trial, but the FDA had these comprehensive reports on these patients in its possession for more than six months prior to August 1999, when it approved the continuation of the trial into the sixth cohort of patients, which included Jesse Gelsinger.
• While the IHGT had numerous documented procedures governing clinical trials, Standard Operating Procedures relating to clinical trials at the IHGT would have helped to ensure that all necessary communications and notifications to the FDA were made on a timely basis and that clear and unambiguous acknowledgement of such communications was obtained before proceeding to new stages of the trial.
• An animal study involving two primates was performed in connection with a different, and unrelated, clinical trial involving the use of a different genetic material for the treatment of a different disease, colorectal cancer. A third primate in the study did receive the same generation vector used in the OTCD trial, but at a higher dose, and it exhibited mild illness, but not death. All three animals in the study received a dosage approximately 17 times higher than the highest dose in the OTCD trial. In sum, the study did not have significant implications for the safety of the OTCD trial.
• The available scientific evidence does not establish any causal link between Jesse Gelsinger's plasma ammonia level prior to the infusion of genes and his death. Note: Neither the FDA's observations nor its public comments have asserted any such causal link.
• There is absolutely nothing in his medical chart to suggest a causal link between Jesse Gelsinger's gender and his death.

The University of Pennsylvania has made a commitment to cooperate, fully and completely, with the appropriate regulatory agencies and public officials in the examination of Jesse Gelsinger's death.