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Government suspends Penn. gene research

PHILADELPHIA-The federal government on Friday suspended all gene therapy studies at the University of Pennsylvania's Institute for Human Gene Therapy after a two-month investigation into the death of an 18-year-old patient found repeated violations of federal research protocol.

In a startling two-page letter to the IHGT, the U.S. Food and Drug Administration cited "numerous serious deficiencies" in the Institute's oversight and monitoring of the clinical trial in which Jesse Gelsinger, who died last September, was enrolled. The agency also wrote that similar deficiencies in other studies could expose patients to a "significant and unreasonable risk."

Among the most serious of the of the allegations are that researchers - led by IHGT Director James Wilson -l ied to patients about the risks involved, changed research protocols without notifying the FDA, included in the study patients like Gelsinger who should not have been eligible to participate and mishandled important documentation.

The moratorium affects only the IHGT. All other University research projects will continue as usual, university spokesman Ken Wildes said.

University President Judith Rodin directed the IHGT to respond "promptly and completely" to the possible violations and the letter, according to a statement released Friday.

"Dr. Rodin has pledged that we will continue to cooperate with the FDA," Wildes said, adding that the suspension came as a shock to University administrators.

Also on Friday, Rodin directed Provost Robert Barchi to assemble an external committee of scientists - all unaffiliated with the university - to perform an institutional review of the IHGT, Wildes said.

The committee will make recommendations to Rodin on how the IHGT can achieve compliance with FDA regulations. The scientists will also help the IHGT create detailed monitoring plans for each of the Institute's clinical studies.

Wildes was not certain about the size of the committee or what the selection criteria would be. He speculated on Saturday that the committee would be formed within the next few weeks.

The decision drew national media attention to Penn and its gene therapy program, which until now had been considered among the best in the world. It also increases the scrutiny on Wilson, a renowned researcher who has served as president of the American Society for Gene Therapy. He came to Penn to found the Institute in 1993.

According to media reports, prominent researchers in the field appeared to back away in their support of Wilson once the extent of the violations became clear. Though he was unavailable for comment over the weekend, Wilson has consistently defended his work and maintained that there was nothing he or his colleagues could have done to prevent Gelsinger's death.

Listed among the study's 18 possible violations are that at least one patient enrolled in the study was ineligible, and that investigators continued the study even after early patients developed grade III toxicity in response to their treatment.

According to FDA protocol, if any patients develop such toxicity levels, researchers must immediately suspend the study and notify the regulatory agency.

The FDA also alleged that the IHGT did not report the deaths of two monkeys in a trial similar to the study until 10 months after the study was completed. The primate trial was conducted at the same time as the human trial.

The IHGT is expected to issue a response to the FDA report this week.

Alan Milstein, the attorney representing Paul Gelsinger, the father of the patient who died, explained that his client thinks the FDA's action is appropriate.

"The FDA report speaks volumes as to mistakes that were made," Milstein noted. "Many of the observations made by the FDA suggest that Jesse should not have taken part in the experiment at that time."

Until now, Paul Gelsinger has been a staunch supporter of Wilson and his team. But Milstein said his client is now in the process of evaluating all the information that is being released.

"Given what the FDA said about Penn's mistakes, he still has concerns about the FDA's oversight," Milstein explained. "It's too easy just to blame Penn."

Paul Gelsinger is scheduled to testify on Wednesday in front of a U.S. Senate committee examining the FDA's regulatory role in the world of gene therapy, which seeks to cure diseases by essentially changing a patient's DNA. After 10 years of research, the field has yet to see much success. Jesse Gelsinger is believed to be the first person to die as a direct result of gene therapy.

Philip Noguchi, director of gene therapy research at the FDA, said the list of possible violations is a summary of observations made by field investigators.

He explained that his agency began investigating the IHGT study on November 30, after noticing "inconsistencies" between the researchers' permit and the study itself.

"[Dr. Wilson] now has an opportunity to respond to those questions," Noguchi said. "And based on that, we will decide if any actions need to be taken."

Noguchi would not speculate as to whether Gelsinger's death could have been caused by negligence on the part of the IHGT scientists.

"Many of the inconsistencies were about toxic events that weren't reported in a timely fashion," Noguchi said. He added that it is very likely that had the inconsistencies been reported earlier, there would have been a dialogue between the IHGT and the FDA.

Mark Batshaw, now the chief academic officer at Children's National Medical Center in Washington, D.C., was an IHGT investigator who worked on the study.

"I believe... there will be a fair understanding of what went on [in the study]," he said. He added that he believes the 18 observations will be found to not have contributed to Gelsinger's death.