Scientists have acknowledged some lapses in protocol during their recent gene-therapy experiment at Penn in which an 18-year-old man died, but they don’t believe those deviations were responsible for his death.
During a three-day meeting called by the Recombinant DNA Advisory Committee (RAC) of the National Institutes of Health last month (as the Gazette was going to press), researchers from Penn and the Food and Drug Administration presented divergent preliminary findings from their separate investigations into the death of Jesse Gelsinger. Gelsinger died on Sept. 17, four days after he was injected with a genetically modified cold virus designed to deliver a potentially corrective gene to his liver [“Gazetteer,” Nov/Dec].
The meeting was held to review the safety of the Penn trial and to discuss an NIH proposal that would require scientists to disclose within 15 days any deaths or “serious adverse events” that occur in gene-therapy trials. While the team at Penn was commended by a member of the RAC for its prompt disclosure of Gelsinger’s death, FDA officials argued that Gelsinger, who suffered from a genetic liver disorder, was too sick at the time of his treatment to have participated in the study. In addition, the agency said it was not informed of a change in the study’s patient-consent form that prevented participants from learning about the deaths of four monkeys that had received similar treatment, albeit at higher dosage levels. It also charged that the research team—led by Dr. James M. Wilson, the John Herr Musser Professor and Chair of Molecular and Cellular Engineering who serves as director of the Institute for Human Gene Therapy—failed to halt the trial and promptly notify the agency by phone or fax when two previous patients had serious reactions to the treatment. Wilson, however, stated in a press conference that “months” before Gelsinger’s therapy, his team provided the FDA with “comprehensive data,” in writing, about the liver-toxicity levels of all patients. And in a letter to the Washington Post, he argued that the “informed-consent document signed by Jesse Gelsinger and all participants in the OTC trial accurately reflected risks, including death.”
Wilson and the other two researchers—Dr. Steven Raper, associate professor of surgery, and Dr. Mark Batshaw of the Children’s National Medical Center in Washington—noted that the ammonia level in Gelsinger’s blood (an indication of liver function) fell within the parameters of the trial protocol at the time of his enrollment. Although the level was slightly elevated just before he was treated, they believed it could be managed through intravenous medicines.
The scientists apologized to the FDA and the advisory committee for diverging from some of the regulations established for the experiment, which began in April 1997, but in the words of Wilson: “At no time during or prior to this trial did we in any way expect to see what we saw in Jesse Gelsinger.” According to a statement released by Penn’s Health System, “A review of extensive animal studies performed prior to the launch of the clinical trial and the experiences of the previous 17 participants in the trial revealed no information that would have predicted the events that led to Mr. Gelsinger’s death.”
Like the other study participants, Gelsinger, of Tucson, Ariz., was born with ornithine transcarbamylase (OTC) deficiency, a condition that prevents the liver from properly processing the nitrogen in food proteins. The research team was trying to develop a way to deliver genes directly into the liver cells to manufacture the missing chemical.
Gelsinger’s death was triggered by “an unusual and deadly immune-system response” to the experimental drug used in the trial, according to the preliminary findings of the Penn investigators. First Gelsinger developed a fever, “followed by an injury to the liver,” according to a statement released by the Health System; his blood also clotted abnormally. Those conditions subsided within 48 hours, and Health System officials stated that he “appeared to be improving.” But on the third day, Adult Respiratory Distress Syndrome set in as his lungs and other organs failed; he died of oxygen deprivation and other factors the following day after being taken off life-support.
The Health System noted that the researchers “remain committed to fully evaluating all potential leads” and sharing what they learn “in order to prevent another such occurrence.” Among the possible leads discovered during his autopsy was an abnormality in his bone marrow, which may have predated his treatment.
In his letter to the Post, Wilson said: “We have been pained and truly humbled” by Gelsinger’s “unexpected and tragic death,” and vowed that as they continue their investigation, “we are sustained by the knowledge that our motives and actions have been consistent with the ideal of advancing our understanding of this devastating disease so that an effective treatment may be developed.”
Paul Gelsinger, Jesse’s father, blamed the FDA for not overseeing the trial more carefully, but remained supportive of the research team at Penn. “They have told me everything” about the experiment, he said. “I want them to continue their work. That’s what Jesse would want.”
Dr. Arthur Caplan, director of Penn’s Center for Bioethics and Trustee Professor of Bioethics in Molecular and Cellular Engineering, argued that what’s needed is “not just better federal oversight but more [university-level] review of subjects in this research and in high–risk research across the board,” because most problems can be better detected at the local level.
The recent media scrutiny of human gene therapy is ironic, Caplan added. “A year or so ago, The New York Times magazine ran a story about this mom who couldn’t get her kid into a gene-therapy trial at Yale because of the bureaucracy. The same magazine ran a story a year later [about Gelsinger’s death], asking, ‘Why are we going so fast with this gene therapy?’ We can’t make public policy by headline with respect to gene therapy. We’ve got to be in there for the long haul.”
