A tumultuous year for gene therapy.

On September 17, 1999, 18-year-old Jesse Gelsinger died at the University of Pennsylvania following administration of recombinant adenoviral vector containing the orinithine transcarbamylase (OTC) gene. In the decade-old history of nearly 400 clinical gene therapy trials involving well over 4000 patients, Gelsinger's was and still remains the only death directly attributable to gene delivery vehicle. Why, then, have gene therapy clinical trials become the focus of the broader debate on protection of research subjects? First, a few facts: (1) Gelsinger suffered from partial deficiency of OTC, which can be managed by drugs and dietary restrictions. (2) The adenoviral vectors used to deliver the OTC gene were unlikely to provide sustained production of the OTC proteins. (3) More than 3.8 × 1013 virus particles were injected into the hepatic artery, the highest total dose given to date. An asymptomatic female participant had received a similar dose (3.6 × 1013 total vector particles). (4) Although the vector was primarily delivered to the liver, postmortem analysis found it in a variety of tissues but less than 1% of the hepatocytes appeared to have been transduced. (5) The precise cause of death remains elusive, but it appears that Jesse's death resulted from a systemic Ad vector-induced shock syndrome, cytokine release, acute respiratory distress, and multiorgan failure. (6) On October 1, 1999, the NIH's Office of Biotechnology Activities (OBA) alerted all principal investigators and sponsors that a clinical trial participant had died following administration of recombinant Ad vector.In addition, OBA requested that investigators and sponsors of all clinical trials provide relevant preclinical and clinical data regarding Ad vector safety, toxicity, any adverse events, and efficacy in all current or inactive human gene transfer/therapy trials (nearly 80 Ad-vector-related protocols). What emerged was the unsettling finding that hundreds of adverse events among volunteers enrolled in gene-transfer experiments were not reported. Faced by a daily barrage of new unreported adverse events, numbering perhaps in the thousands, both the NIH and the FDA came under heavy criticism from both the public and the policy makers. Lost in this lack-of-reporting hysteria was the fact that researchers fully complied with the reporting requirements established by the FDA, the main regulatory body charged with the task of approving clinical trials. In fact, there was a genuine misunderstanding among some scientists as to the extent of reporting required by the OBA, a policy-making body. Furthermore, the definition of “adverse events” was blurry, ranging from reporting local inflammation and mild fever to extensive hospitalization. When the FDA stopped all clinical trials at the Institute of Human Gene Therapy at the University of Pennsylvania after finding several protocol violations, the critics and congress stepped up the pressure for new regulations to protect human subjects in clinical trials.Perhaps Donna Shalala, Secretary of the U.S. Department of Health and Human Services, best summed up the situation:“The majority of government-supported studies adhere to strict protocols and the highest clinical standards. But even one lapse is one too many. The American people expect that clinical researchers will never compromise or neglect the safety of human subjects. The moral and ethical reasons for paying heed to this demand require no explanation. However, there are also practical reasons. To put it simply, if we cannot guarantee sound research in general—and patients’ safety in particular—public support for gene therapy and other potentially lifesaving treatments will evaporate. Volunteers will not show up, and the generous stream of research dollars that Congress and President Bill Clinton have provided in recent years may shrink. So clinical researchers and the institutions that support them must, without exception, maintain the public's confidence in our work, our competence, and, most important, our ethics. ”—New Engl. J. Med., Sept. 14, 2000The gene therapy community, along with all clinical researchers, will need to meet the challenge of new regulations and guidelines proposed by the NIH and the FDA to improve both the quality of clinical trials and protection of volunteers enrolled in the trials. Experimental therapies have inherent risks, but it is our responsibility to assure clinical trial subjects that their welfare is a paramount concern. We also hope that a new set of regulations/guidelines do not simply create more “paper work” and deter well-intentioned and well-trained clinicians from undertaking exciting and groundbreaking new therapeutic approaches. We want to continue to participate and lead the nation in harnessing and providing the benefits of the unprecedented golden age of biomedical research.