Gene Therapy Institute Faces Uphill Battle

The University of Pennsylvania's Institute for Human Gene Therapy (IHGT) and its director, James M. Wilson, faced increasing pressure from the federal government in late January. The U.S. Food and Drug Administration suspended all eight of the institute's gene therapy clinical trials on Jan. 21. A few days before, the Office for Protection from Research Risks at the National Institutes of Health launched an investigation into whether a clinical trial violated federal regulations governing patient safety. The federal actions stem from the Sept. 17 death of Jesse Gelsinger, an 18-year-old man from Tuscon, Ariz., who died while participating in one of Penn's gene therapy clinical trials. The FDA, after investigating the death, has found "numerous serious deficiencies in the procedures ... for the oversight and monitoring" of clinical trials, the agency wrote IHGT. The letter also stated that such failures would expose subjects to "significant and unreasonable risk." Specific allegations against researchers at the institute include changing research protocols without notifying the FDA; accepting patients who may not have been eligible to participate in the study, such as Gelsinger; and mishandling important documentation. More seriously, the investigators continued the study even after early patients developed grade III toxicity in response to the treatment. FDA protocol requires researchers to suspend the study and notify the regulatory agency when such adverse events occur, even if the adverse effects clear as they did in this trial. The FDA also alleged that the IHGT did not report the deaths of two monkeys in a similar trial until 10 months after the study was completed. In total, the FDA found 18 potential violations. Though Wilson has not responded to recent allegations, he has publicly maintained that there was no way the researchers could have predicted the death of Gelsinger. Before the FDA reinstates the suspended clinical trials, the IHGT must respond to the potential violations and provide a detailed plan for the monitoring and oversight of each clinical study. All aspects of the current clinical trials must be reviewed to determine if the clinical investigators have conducted the studies in accordance with the protocol as submitted in the investigational new drug (IND) application. In the case of deficiencies, the IHGT must report the corrective action that has been taken. The process is likely to take some time. In response to the FDA action, the University of Pennsylvania is assembling an external committee of scientists, all unaffiliated with the university. The committee will make recommendations to University President Judith Rodin on how the IHGT can achieve compliance with the FDA regulations. The scientists will also help the IHGT create detailed monitoring plans for each of the Institute's clinical studies. Gene therapy is still in its earliest stages; the first clinical trial was only 10 years ago. "Thus, advocates and practitioners of gene therapy must adhere to the highest standards of scientific investigation and regulatory/reporting requirements," comments Fintan R. Steele, editor of Molecular Therapy, a new journal published by the American Society of Gene Therapy. Inder Verma, professor of molecular biology at the Salk Institute, also does not believe the FDA's scrutiny has been excessive. "There were violations in the protocol and there was a death of a patient, so the FDA has to investigate to maintain the public's credibility in clinical trials," he comments. Indeed, the IHGT investigators have admitted to some lapses and publicly apologized at the Recombinant DNA Advisory Committee (RAC) meeting last December. There have also been concerns about conflict of interest, because Wilson is founder and part owner of Genovo Corp., Sharon Hill, Pa. Genovo provides substantial research funds for the IHGT. Also, through a 1995 deal with Penn, Genovo and its partners, which include four larger biotech companies, have exclusive rights to commercialize the gene therapy advances developed by the IHGT. In a December 6, 1999 letter to the Washington Post, Wilson responded to these concerns: "The alleged lure of potential financial gain played no role in any clinical decisions." The long-term future of the IHGT--which has been among the highest regarded gene therapy programs in the world--is in serious doubt. If the NIH finds significant violations, it could take away Wilson's federal grants, which account for $5 million of the institute's $22 million budget. Furthermore, Genovo has indicated that it has been considering alternative sites for its research funds. A positive result of the Penn events may be that researchers will revisit their preclinical research, their clinical protocols, and their reporting methods to make sure they are in order. Also, the current investigations have brought to light the deficiencies in the consent process for gene therapy trials. "We have to do a better job educating not only clinical trial volunteers, but the public at large about the science and relevant risks behind current and future trials," maintains Steele. Last year, the National Human Genome Research Institute awarded the University of North Carolina (UNC) at Chapel Hill a $975,000 award to study some of the ethical issues surrounding gene therapy clinical trials and the consent process. Nancy King, professor of social medicine at UNC, Chapel Hill, and an investigator in the study, comments, "The term gene therapy is misleading because it implies efficacy. But nothing that has come out of the research has clearly worked." For instance, the trial in which Gelsinger participated was a safety study, the first step toward developing a treatment for babies suffering from a fatal form of his disorder. It did not offer treatment benefits to any participating subjects. The UNC study aims to build some models to help researchers in general speak more accurately about how, if at all, research is going to benefit subjects. Verma does not believe that the Penn experience will drive investigators away from gene therapy research: "If investigators follow accepted practices, then adverse effects can be explained and researchers can learn from that experience." Based on presentations at recent meetings and manuscript submissions to the journal, Steele believes that many important advances are being made in gene therapy that will undoubtedly translate to the clinic sooner rather than later. Nadia S. Halim can be contacted at nhalim@the-scientist.com.

Gene Therapy Institute Faces Uphill Battle

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