The Recombinant DNA Advisory Committee (RAC) of the National Institutes of Health has been urged to recommend that gene-therapy researchers be required to report all ‘adverse events’ occuring during their trials, whether or not they are related to the treatment the patients are receiving.
The proposal came during a three-day meeting that discussed the death earlier this year of Jesse Gelsinger (see above). Committee officials struggled to define how much information gene-therapy researchers must submit, both publicly and privately, and admitted that those involved in the Gelsinger trial failed on both fronts.
On the public front, the researchers did not report to the RAC a change in the clinical trial's protocol. The committee had approved the protocol to treat ornithine transcarbamylase deficiency with an adenoviral vector administered intravenously.
But when the RAC was temporarily disbanded in 1996, the US Food and Drug Administration (FDA), with the researchers' cooperation, changed the route of administration. The vector was now to be administered in an artery leading directly to the liver in an effort to minimize the problem of the vector's wide distribution throughout the body.
“We recognize that we probably should have come to the RAC” after the protocol change, says Mark Batshaw, chief academic officer at Children's National Medical Center in Washington. By the time the trial was under way in 1997, a revived but weakened RAC had lost its authority to approve most gene-therapy clinical trials.
Kathryn Zoon, director of the FDA's Center for Biologics Evaluation and Research, presented “preliminary evidence of approximately two protocol violations” by the researchers. Both involved failure to disclose information to the FDA.
First, the researchers decided to treat Gelsinger despite levels of ammonia in his liver that were higher than the limits allowed for enrolment.
James Wilson, director of the Institute for Human Gene Therapy at the University of Pennsylvania in Philadelphia, where the trial was conducted, defended the decision, saying that Gelsinger's ammonia level at the time of enrolment was fine, technically meeting the requirement of the written protocol. The researchers also treated Gelsinger to reduce the level before he received the vector.
Wilson also initially denied the second charge — that the researchers should have notified the FDA within two weeks when two patients, each of whom received a smaller dose than Gelsinger, had shown higher than normal levels of liver enzymes.
Wilson pointed out that the group had immediately notified the FDA about two previous patients with similar problems, and agency representatives had allowed the trial to continue. He also said he had filed a written report detailing the liver enzymes eight months before treating Gelsinger.
But Steven Raper, associate professor of surgery at the University of Pennsylvania, accepted the next day that they “should have called the FDA” about each of the patients.
To prevent further such confusion over the reporting rules, the RAC considered a proposal that gene-therapy researchers should publicly disclose all adverse effects that accompany gene therapy.
The proposal goes beyond FDA requirements, as it would require disclosure on both expected and unexpected adverse events in the clinical protocol, regardless of whether they are directly related to the treatment.