The federal government yesterday halted all human gene therapy experiments involving a prominent researcher at the University of Pennsylvania, saying an investigation into the September death of a teenager there found the school's prestigious program in serious disarray.
Investigators at the Food and Drug Administration said they found numerous violations of federal research regulations and shortcomings in the protection of human subjects at Penn's Institute for Human Gene Therapy, which is led by researcher James M. Wilson.
Penn could not provide investigators with proof that any of the volunteers in the fatal study had been eligible to participate or had been adequately warned of the risks of the research, FDA officials said. They also said Penn had not properly monitored the health of volunteers after the experiment began, and lost track of several lots of the experimental genes that had been infused into patients' livers.
The findings go beyond FDA revelations in December that the Penn researchers had not stopped the experiment as required after four successive volunteers suffered serious side effects, then allowed 18-year-old Jesse Gelsinger into the study even though he was not healthy enough to qualify. Gelsinger died from the treatment Sept. 17, in what is believed to be the first death caused directly by gene therapy.
"Putting everything together, there appears to be a real problem with how they conduct their day-to-day operations," said Philip D. Noguchi, director of FDA's division of cellular and gene therapies.
The FDA's decision to suspend all seven active or pending gene therapy studies at Penn's institute sent shock waves through the genetic research community. Gene therapy, which seeks to cure diseases by giving people new DNA, was already at the center of a national controversy because of recent revelations that some researchers had not been reporting side effects as required, even as some companies were seeking to reduce the level of federal oversight of the field.
Preliminary evidence of lapses at Penn, which emerged soon after Gelsinger's death last fall, had deepened the field's woes. Yet many researchers had suspected that regulators would settle for a mild punishment, given Penn's status as one of the preeminent gene therapy research centers in the country and the high ranking of Wilson, past president of the American Society for Gene Therapy (ASGT).
Yesterday's action proved otherwise.
"I certainly hope this will be a message to all investigators that we really need to conform to regulations," said Savio L.C. Woo, president of the ASGT and director of the Institute for Gene Therapy and Molecular Medicine at Mount Sinai School of Medicine in New York.
Gene therapy has grown enormously from its beginnings in 1990, when a 4-year-old girl became the first patient to be treated with genes. Yet despite the initiation of hundreds of studies involving thousands of patients suffering from a variety of diseases, and a growing financial investment by private companies hoping to profit from the novel approach, the field has yet to document its first cure. In recent years, the field has come under criticism from some scientists, ethicists and others for moving ahead too quickly, jeopardizing patients.
That such a high-profile institution would have so many serious lapses "does give us pause," Noguchi said. The FDA plans to step up its educational programs and inspections of other research centers, he said, to make sure any similar conditions elsewhere do not go undetected.
Responding to the FDA report, University of Pennsylvania president Judith Rodin yesterday announced that university provost Robert L. Barchi would appoint an independent committee of scientists with no affiliation to the university to review the gene institute's oversight and monitoring of clinical trials and to recommend any needed remedial action.
The university is also expected to respond in detail to the FDA's findings. Noguchi said the agency will take that response into account before it decides what, if any, sanctions to impose beyond the suspension of clinical trials.
The FDA's action comes three days after the National Institutes of Health quietly opened a separate investigation into gene therapy experiments at Penn. Gary Ellis, director of the NIH's Office for Protection of Research Risks, said his office sent a letter to the university on Tuesday initiating that investigation, which he predicted might go on for as long as a year.
Penn's institute is one of the largest academic gene therapy centers in the world, with an annual budget of about $25 million and links with private biotechnology companies. Wilson, who is a key investigator in all seven gene therapy studies suspended by the FDA, has come under increased scrutiny in the months since Gelsinger's death, in part because of revelations that he had a potentially large financial stake in the outcome of the Gelsinger study.
The study suspensions, called clinical holds, also have repercussions for outside corporations that directly or indirectly sponsor the institute's clinical trials, including Genovo Inc., of suburban Philadelphia, a company founded by Wilson, and Biogen, a Massachusetts company that has poured $37 million into the institute and Genovo.
A spokesman for Genovo declined to comment, referring all questions to Wilson, who could not be reached late yesterday. Genovo has an interest in the successful outcome of some gene therapy experiments at the institute, including the Gelsinger study, which has been on hold since his death.
The FDA's findings, which are called "observations" at this stage pending Penn's formal response, are the result of a two-month investigation involving multiple visits to Philadelphia to examine laboratory and hospital records. Investigators found that the researchers had admitted all 18 patients into the Gelsinger study without ever documenting that any fit the eligibility requirements of the study, which was to test the safety of an experimental treatment for a rare inherited liver disorder called ornithine transcarbamylase deficiency.
Only after Gelsinger died and the study was suspended did the researchers create eligibility forms for participants, none of which had been signed when investigators came on the scene in late November.
Moreover, for half of the 18 patients enrolled, investigators could find no documentation that the volunteers had been properly told of the experiment's risks or of the kinds of procedures that would be conducted on them, including invasive liver biopsy studies.
The consent form had also been altered without FDA notification to eliminate the mention that monkeys had died of a similar procedure, and it did not disclose that earlier volunteers had suffered serious side effects.
"If Gelsinger was never told that four people before him had Grade 3 [serious] toxicities and that monkeys had been killed by this kind of treatment, then you have to ask, did he really give informed consent or did he just give consent?" asked Leon Rosenberg, a geneticist at Princeton University who pioneered research on Gelsinger's disease.Staff researcher Alice Crites contributed to this report