The unexpected gene therapy death of 18-year-old Jesse Gelsinger has unleashed a public outcry over who is to blame.
And while there is no simple answer, there is also no shortage of possible candidates: the investigators at the University of Pennsylvania who carried out the experimental therapy; the local institutional review board that purportedly omitted animal data in the informed consent form; the government agencies that oversee gene therapy; and a biotechnology industry eager to cash in on a promising medical field.
"Everybody has to share in the guilt of what's happened here," said Abbey S. Meyers, president of the National Organization of Rare Disorders in New Fairfield, Conn., and a former member of the Recombinant DNA Advisory Committee, the federal group that initially recommended approval of the gene study to treat Gelsinger's rare liver disorder.
|
Meyers said that Gelsinger entered the study "believing he had been given the truth" a supposition cast in doubt during the often emotional, exhaustive hearing.
On at least two occasions, the Penn investigators indicated that they had not followed adverse reporting procedures, a lapse for which they publicly apologized. In one instance, the researchers failed to notify the U.S. Food and Drug Administration about serious, although transient, side effects seen in several patients treated before Gelsinger; in the other, the study protocol was changed, altering the route of the gene's administration, which was not reported to the RAC.
Jesse's Legacy
In testifying before the RAC, James W. Wilson, M.D., Ph.D., director of the Institute for Human Gene Therapy at the University of Pennsylvania, Philadelphia, and the trial's sponsor, said his research team has been "permanently changed" by the turn of events that led to Gelsinger's death from adult respiratory distress syndrome 4 days after undergoing the experimental procedure. "But I have to believe positively," he said of that change. "Indeed, this is Jesse's legacy."
|
"My sense was that this was a safer procedure if it went into the hepatic artery," Wilson said. "But I regret that we did not inform the RAC a group that I respect."
Wilson indicated that the researchers were very surprised when they found on autopsy that the hepatic infusion led to "significant vector [distribution] outside the liver" including high amounts in both the spleen and the bone marrow. The bone marrow had other signs of abnormality as well, he said, suggesting a possible preexisting condition that might explain, in part, the massive immune response seen in Gelsinger. In particular, Wilson noted, Gelsinger's levels of IL-6 an immune stimulant spiked in a manner similar to other patients but, unlike theirs, never came back down.
"I am not here to suggest that IL-6 is the specific problem," Wilson said. "But we feel it is a good measure that we have activated innate immunity."
Adenoviral vectors are used to ferry genes into target cells in approximately one-third of the 357 gene therapy protocols approved to date. Wilson said the vector used in Gelsinger's therapy had been retested extensively in primates at the exact same dose he received with only minor increases in the animals' liver enzymes. "We have concluded at this point that there is nothing different in the production line [of vector] that could explain Jesse's death," Wilson told the RAC.
Nor, Wilson said, did Gelsinger's elevated ammonia level a sign of liver dysfunction unduly alarm investigators. One of them, Mark L. Batshaw, M.D., chief academic officer at Children's National Medical Center in Washington, D.C., and previously at the University of Pennsylvania, said the doctors measured Gelsinger's ammonia level 2 hours after his gene infusion and it was at 60 (30 is normal). But Batshaw said the teenager had a high fever and "we assumed it was related to that rather than a challenge to the liver."
Batshaw described for RAC members the plight of OTC patients, only 50% of whom survive 5 years, most with profound disabilities. He also defended the investigators' choice to initiate dose-escalating studies in adult patients who, like Gelsinger, had a partial OTC deficiency that was not imminently life-threatening.
And like Wilson, Batshaw publicly apologized to the RAC for failing to inform the committee about the post-RAC-approval protocol change. "At the time," he said, "the RAC was undergoing tremendous turmoil."
The study in which Gelsinger proved to be the 18th and final patient was one of the last approved by the RAC in 1995 before its membership was pared by National Institutes of Health Director Harold Varmus, M.D., from 25 to 15 and the group lost its authority to recommend protocol approvals.
Behind Closed Doors
That loss of voting power, some at the hearing contended, reduced the RAC to little more than a "debating society" and relegated important safety information to proprietary status behind closed doors at FDA.
Although Wilson and his team received praise for immediately reporting Gelsinger's death to FDA and NIH's Office of Recombinant DNA Activities which, in turn, informed members of the RAC there was palpable concern about industry claims at a RAC meeting last fall that adverse events should be under a proprietary umbrella.
"Gene therapy is one of those fields where it is not business as usual,' " contended former RAC chairman LeRoy Walters, Ph.D., who is the director of the Center for Bioethics at Georgetown University. "This is still a novel field that needs special, time-limited, enhanced oversight . . . and real time reporting of adverse events."
Walters, along with 15 other former RAC members, wrote a letter in November 1999 to Varmus and Department of Health and Human Services Secretary Donna Shalala expressing concern over the changes to the OTC protocol as well as the industry stance on the reporting of adverse events. They urged a public meeting and a review of NIH's role in the oversight of clinical gene transfer research.
At the hearing, an announcement was made that such a review is under way, although details were sketchy. However, said Lana Skirboll, Ph.D., NIH associate director for science and policy, Varmus has asked an ad hoc group, which will include patient advocates and other lay persons, to determine whether the current NIH framework for oversight and public discussion of clinical gene transfer research is appropriate; whether existing mechanisms are adequate for coordinating with FDA and other review groups such as local IRBs; and what NIH's role should be in the future with regard to reporting, analyzing, and public discussion of serious adverse events.
To the FDA, expedited reporting of a serious adverse event is not necessary if it is an expected event, which is usually described in an investigator's brochure and often related to underlying disease, according to Karen Weiss, M.D., director of the Division of Clinical Trials Design and Analysis at FDA's Center for Biologics Evaluation and Research. But if an event is both serious and unexpected, as in Gelsinger's case, then the study sponsor must report it to the FDA by phone or fax within 7 calendar days, she said. Written reports are also mandated within 15 days of a sponsor learning about an adverse event.
Theodore Friedman, M.D., a leading gene therapist and a pediatrics professor at the University of California, San Diego, took issue with the "expected" definition. "I am troubled by the notion that something is unexpected until you see it in the first human patient," Friedman said.
|
"The difference here," noted Ruth Macklin, Ph.D., a professor of bioethics at Albert Einstein College of Medicine, Bronx, N.Y., is that the investigator not the sponsor has to report to the RAC" within 15 days.
But one RAC member, C. Estuardo Aguilar-Cordova, Ph.D., director of Gene Therapy Laboratories at Texas Children's Hospital, Baylor College of Medicine, Houston, said two definitions of serious adverse events that of FDA and that of the RAC would be burdensome to investigators and harmful to the future of gene therapy.
To some, however, that harm has already been done. Gene therapy has never cured anyone, but until Gelsinger's death, its safety, or at least a perception of safety, was presumed. "The public trust has been violated," noted one physician in the audience. "There has been a clear failure in the system."
Still, RAC chairman Claudia Mickelson, Ph.D., a biosafety officer at the Massachusetts Institute of Technology, Boston, made it clear the committee has no intention of backing away from this potentially therapeutic approach. And FDA officials, whose agency has the authority to take sanctions in the Gelsinger case, said the OTC study at Penn is on clinical hold, pending results of its investigation, and that one other trial, sponsored by the Schering-Plough Corporation, Madison, N.J,. has also been suspended. But there is no "blanket hold" on gene therapy at this time, an FDA spokesperson said.
This article has been cited by other articles in HighWire Press-hosted journals:
![]() |
||||
|
Oxford University Press Privacy Policy and Legal Statement |