Legislation to tighten up the supervision of federally funded human gene-therapy trials was introduced into the US House of Representatives last week. The move occurred on the day a Senate subcommittee hearing examined the problems of monitoring such trials.
The hearing was triggered by the case of Jesse Gelsinger, the Arizona man who died four days after receiving experimental gene therapy at the University of Pennsylvania (see Nature 401, 517; 1999). But the subcommittee explored other issues concerning clinical research in humans.
According to a spokeswoman, the proposed legislation, introduced by Dennis Kucinich (Democrat, Ohio), had been drafted before Gelsinger's death. Under the legislation, authority for monitoring federally funded human clinical trials would be transferred from the Office for Protection from Research Risk, under the US Department of Health and Human Services, to an independent agency.
Arthur Caplan, director of the University of Pennsylvania's Center for Bioethics, argued that the rise in clinical-trial holds issued by the US Food and Drug Administration (FDA) indicates a general problem. The FDA issued few clinical holds in the eight years before 1999, but last year stopped at least five trials not involving gene therapy.
At last week's hearing, William Frist (Republican, Tennessee) said that systems to protect human subjects enrolled in clinical trials “are not working”, and he was not certain that new regulatory bodies would solve the problem.
The Gelsinger case revealed a failure to report adverse events in gene-therapy trials. After his death, the National Institutes of Health (NIH) asked researchers using adenoviral vectors — the delivery vehicle used in Gelsinger's trial — to report all adverse events.
Eventually, 652 became public (see Nature 403, 237; 2000), including several deaths not directly attributed to gene therapy. Last week's hearing revealed 40 more adverse events, related to vectors other than adenovirus.
Researchers are required to report “serious and unexpected” adverse events only to the FDA, although they must disclose all adverse effects to the NIH's Recombinant DNA Advisory Committee (RAC).
Former RAC chair LeRoy Walters, director of the Kennedy Institute of Ethics at Georgetown University, testified that NIH's 1996 reduction of the RAC's powers had sent a “mixed message” to researchers, possibly indicating that they were no longer required to report to the RAC.
Walters also said that problems in securing a patient's informed consent revealed “a system-wide problem not unique to gene therapy”. Paul Gelsinger, the patient's father, testified that researchers had not told his son that two monkeys had died on the experimental treatment.
The researchers had also incorrectly told Gelsinger that a previous subject had benefited from the gene therapy. The two problems were among 18 used by the FDA to to justify shutting down five other gene-therapy trials at the University of Pennsylvania (see Nature 403, 354; 2000).
More inspections may prevent future problems, said Michael Blaese, chief scientific officer of Kimeragen, a Pennsylvania-based biotechnology company. Blaese, previously a gene-therapy researcher at the NIH, noted that trials on the NIH campus were audited frequently.
Jay Siegel, director of the FDA's Office of Therapeutics Research and Review, testified that the agency typically conducts on-site investigations as a drug or treatment nears approval. He said that the agency has begun to do spot checks at a “very limited” number of clinical sites. “We would like to do more.”
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Research Policy (2020)