Federal regulators yesterday issued a final, 20-page listing of research violations by the director of the University of Pennsylvania's gene therapy program and indefinitely extended a ban on all human gene experimentation there.
The letter rejected point by point a series of defenses proffered by James Wilson, a leading gene scientist and director of Penn's Institute for Human Gene Therapy, who led a controversial experiment that killed a Tucson teenager in September.
"I consider this to be a sponsor with problems adhering to regulations with the FDA," said Kathryn Zoon, director of the Center for Biologics Evaluation and Research, a branch of the Food and Drug Administration.
The action represents the latest setback for one of the nation's highest profile gene therapy research centers. The FDA suspended the fatal experiment last fall, then halted the rest of the institute's human trials in January, after an investigation uncovered evidence of numerous violations of federal patient safety rules.
"We are disappointed that the FDA appears to discount a number of the responses to those charges filed by" the Institute for Human Gene Therapy, the university said in a statement yesterday.
Wilson and his team initially contended that they had committed no serious mistakes or violations in running the experiment and that any lapses were administrative oversights that did not jeopardize patient safety.
In a formal response to FDA charges last month, Penn officials continued to contest some allegations. But they acknowledged the validity of others and promised to tighten compliance at the institute by hiring an independent monitor and making other changes.
FDA officials said they want a more detailed plan from Penn about how and when it intends to address the violations before the agency decides whether to remove or modify the ban on human experiments.
Moreover, yesterday's letter relates only to Wilson's role as administrative overseer of the institute's research program. The letter says future correspondence will assess Wilson's actions while directly conducting clinical experiments.
The violations cited in the letter include the research team's decision to treat Jesse Gelsinger, the teenager who died. The letter said Gelsinger, 18, was too sick to participate in Penn's study of an experimental treatment for a rare liver disorder. The letter also criticized the team's failure to halt the study, as required, when several patients preceding him suffered serious side effects, and to report the problems to the FDA; and the failure to disclose serious side effects, including deaths, suffered by monkeys given the same genetically engineered virus Wilson used in the fatal experiment.
In particular, Penn had argued that those animal side effects, including a clotting disorder known as DIC, were irrelevant to the human experiment. However, the FDA letter stated, "The fact that [Gelsinger] subsequently developed DIC confirms that, despite your assertion to the contrary, the toxicity experienced by the monkeys did have significant implications for the safety of the [human] study."
The letter also cited Penn for failing to properly obtain the informed consent of volunteers, to adequately train staff in conducting human research and to develop basic standard operating procedures for carrying out experiments on people.
Penn's statement said officials had not had sufficient time to "carefully review" the FDA's letter. However, it said, "nothing less than the highest possible standards for the conduct of research are acceptable at the University of Pennsylvania."
Penn has appointed an internal committee and an independent panel of experts to look into the gene therapy institute and the university's human research program overall.
Thomas Murray, president of the Hastings Center, a bioethics think tank in Garrison, N.Y., and a member of a special National Institutes of Health working group looking into federal oversight of gene therapy experiments, said that researchers owe it to volunteers to scrupulously follow rules designed to protect them.
"It's absolutely imperative that people who are being asked to be subjects in gene transfer research and in other kinds of medical research have the full confidence that they are being protected and that all the relevant information has been provided to them and to federal regulators before they agree to participate," he said.