Penn denies major lapses in gene study

Researchers maintain that any minor violations did not lead to a patient's death in September. In its formal response to the U.S. Food and Drug Administration, Penn's Institute for Human Gene Therapy yesterday admitted to breaching some federal research protocols, but maintained that the lapses were minor and did not cause the death of a patient last fall. In the 28-page response sent to the FDA yesterday morning, IHGT officials directly addressed each of the agency's 18 observations, which included that researchers failed to fully inform patients of the study's risks and included patients who were ineligible to participate. The response contradicts testimony given to a U.S. Senate subcommittee last month by the patient's father, who said researchers did not fully inform his son of the study's risks. IHGT officials wrote that all subjects were fully aware of the study's purpose and possible side effects and that each participant signed consent forms before they joined the study. They also wrote that each patient's eligibility to participate in the trial was evaluated and documented before they took part in the experiments. The response came more than three weeks after the FDA placed all eight of the Institute's gene therapy studies on hold on January 21. Speaking on behalf of the IHGT team, Medical School Senior Vice Dean Richard Tannen said yesterday that many of the FDA's observations were well-founded. "There's no question that there were breaches," Tannen said. "There were breakdowns in the protocol." But he added that he doesn't "believe that any of the concerns the FDA expressed? in any way led to this tragic outcome." In a written statement released by the University yesterday, IHGT Director James M. Wilson credited the FDA with identifying "important issues" which arised from the death of 18-year-old Jesse Gelsinger in September. "We have taken its questions and concerns seriously," he added. Wilson and his clinical investigators had been working with scientists, lawyers and senior executives from the University to create the response since the form was issued, Tannen said. Officials at the FDA did not return repeated calls for comment yesterday. According to Tannen, the FDA will now review the IHGT's response and determine if the responses are adequate. Tannen said he anticipates the FDA will accept responses to some observations, but require more investigation for others. While Tannen did not know when the FDA would reply to the IHGT document, he said that if the ban were to be lifted, it probably would not happen before mid-April, when the Institute is scheduled to implement more detailed sets of research guidelines. One major possible violation pointed out by the FDA was that patients were not properly informed of the risks posed by the study. The agency alleged that many patient consent forms were improperly filled out, often signed by witnesses days after patients signed, or lacking in witness signatures completely. In the response, researchers said that while there may have been slight lapses in documentation, patients were well-informed of both the purpose and risk of the study. "We strongly believe that every patient that was admitted to the study had appropriate informed consent," Tannen said. He emphasized that patients spent at least an hour with study investigators, who explained the risks of the trial. Tannen admitted that many consent forms were signed by witnesses late, or not at all because, for instance, patients took the documents home with them. Another possible protocol violation raised by the FDA was the order of patient treatment. The FDA maintained that the study required that the first two patients receiving Gelsinger's dosage be women, who typically have a milder form of the disease. But Gelsinger was the second patient to receive treatment within his cohort. Tannen maintained that there was much ambiguity regarding the required patient order. He said that while an internal IHGT memo indicated that a man should be the third patient receiving treatment, a written FDA document simply stated that a man could not be the first. "There's some confusion about that issue," Tannen said. "It wasn't a willful attempt to breach the protocol." In the response, IHGT researchers also addressed the observation that Gelsinger was ineligible for the trial because his blood ammonia level was too high. Gelsinger suffered from Ornithine Transcarbamylase Deficiency (OTC), a rare inherited liver disorder that inhibits the body's ability to produce enzymes that break down ammonia, a by-product of protein digestion. Tannen explained that although Gelsinger's ammonia level was high when it was taken well before the infusion, other readings taken after the infusion were within protocol limits. He added that the protocol did not specify how long before the infusion ammonia levels should be read. Gelsinger's high ammonia level did not concern the clinical investigators because ammonia levels frequently fluctuate, such as after meals that are high in protein, Tannen said. "There is no reason to believe that that ammonia level contributed to the subsequent tragic event," he said. Gelsinger died in September after IHGT investigators infused genetically altered adenoviruses into his liver in the hopes of providing him with genes to produce the enzymes he lacked. Officials later determined that his death was due to multiple organ failure induced by the infused viruses. Wilson's affiliation with Genovo -- a private research company that Wilson founded, and a major financial backer of IHGT research -- has prompted some critics to suggest that the protocol breaches were spurred by a desire to make profits. "We thought that we had put together a good process to help mitigate the conflict of interest issue," Tannen said. But he added that that process must now be reviewed. He would not comment specifically on Genovo, but he said that he has not seen any evidence that would warrant Wilson's firing. In addition to the IHGT response, University President Judith Rodin has appointed two separate committees to review IHGT and human testing procedures at Penn. One, an external committee of scientists unaffiliated with the University, will conduct a review of oversight and monitoring procedures at the IHGT, focusing on the Institute's compliance with federal regulations. The second committee, chaired by Provost Robert Barchi and made up of University faculty, will review human subject research across the University.

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