Dec. 8, 1999 (Washington) -- Federal investigators have found preliminary evidence that researchers went beyond pre-agreed scientific boundaries in a gene therapy experiment that tragically misfired, resulting in the death of an 18-year-old patient. Though thousands have died in gene experiments, this case is apparently the first in which the treatment itself proved fatal, and the controversy is 'Topic A' at a three-day meeting of the Recombinant DNA Advisory Committee (RAC) at the National Institutes of Health (NIH) this week.
Kathryn Zoon, PhD, the FDA's director of the Center for Biologics Evaluation and Research, says it appears there were two "protocol deviations" in a study conducted by researchers at the University of Pennsylvania on patients with ornithine transcarbamylase (OTC) deficiency. The rare, potentially fatal disorder allows ammonia levels to rise dangerously in the blood because the patient lacks the OTC, which clears it from the system. The result is liver damage, although in some cases it can be controlled with diet and medication.
At issue is whether the scientists, led by James Wilson, MD, should have allowed Jesse Gelsinger into the study even though the FDA now says his liver wasn't healthy enough, and then whether he should have had the gene therapy on Sept. 13 that led to his death four days later. The FDA is also looking into whether other patients were allowed to stay in the protocol even though they had significant liver damage. Wilson is director of the Institute for Human Gene Therapy at the University of Pennsylvania.
"The agreed-upon arrangement was that if there was a severe toxicity they [the researchers] would call the FDA and stop the trial at that point in time until either the issues were resolved and understood or the trial was [terminated]," says Zoon.
It's suspected that Gelsinger's death was caused by a severe reaction to the weakened cold virus that was used as a vehicle to carry the replacement gene to his diseased liver. Although this technique is commonly used and had been shown to be safe in animal models, researchers acknowledge that these viruses, when active, trigger infections ranging from the common cold to hepatitis.
In a statement read by Wilson to the media, he disputes the FDA's contention that Gelsinger was ineligible to be in the study.
"While his ammonia levels were slightly elevated prior to the administration of the gene therapy, we remain fully comfortable with the clinical decision to ... proceed with the trial," says Wilson. He also denies withholding from the FDA certain toxicity data on other patients. "Our interpretation of the data made available to the FDA ... did not suggest to us that the trial should be modified or halted," he continues.
But the NIH committee is discussing ways to improve the reporting of adverse events like the Gelsinger case. "We're going to have more and better coordination between FDA and NIH. ... Now we'll have, with adverse events in particular, ... a formal coordination standard operating procedure," says Lana Skirboll, PhD, director of the Office of Science Policy at NIH.
The FDA investigation is expected to take several weeks, and Wilson could face a number of administrative or legal sanctions if he's found guilty of violating his agreement with the government. Ironically, Jesse's father, Paul Gelsinger, blames the FDA, not Wilson, for the chain of events leading to his son's death.
Gelsinger believes the FDA, under the influence of the pharmaceutical industry, pushed aside NIH's efforts to release crucial information about gene treatments. "Why are we allowing industry to influence our government? It has no business in government," he says.
Wilson's team has at least one well-known geneticist on his side. W. French Anderson, MD, who is with the University of Southern California and is considered a pioneer in the field, calls Gelsinger's death an "honest mistake."
He testified before the committee that studies like Wilson's could ultimately save millions of lives. "Based on everything I know, if I had been the physician, the night before, I would have gone ahead. I know that Jesse was aware of the fact that his ammonia levels had gone up ... he chose to go ahead," Anderson tells WebMD.
On Thursday, Wilson and his colleagues will defend their actions before the NIH committee, with a response by the FDA. Wilson's statement says he's "disappointed" the agency came forward with its allegations before a thorough scientific discussion had taken place.