Adverse event reporting: Essential for science and public trust
Authors: Inder M. Verma
Journal: Molecular Therapy (2001)

The most sensational revelation following the death of Jesse Gelsinger in September, 1999, was a lack of adverse event reporting. Screaming newspaper headlines accused scientists of not reporting hundreds of alleged adverse events following clinical gene therapy trials. During a United States Senate hearing on the safety of gene therapyrelated clinical trials, several senators derided the lack of good mechanisms for adverse event reporting. Ethicists went so far as to recommend the formation of a separate agency to monitor adverse events that would report directly to the Department of Health and Human Services. However, few noted the fact that, by law, all adverse events had to be reported to the US Food and Drug Administration (FDA), which gives final approval to all gene therapy related clinical trials. The media outrage was largely directed against the Office of Recombinant DNA Activities (now OBA, Office of Biotechnology Activities), which had reporting mechanisms in place but no effective enforcement. Since then, an effort to harmonize adverse event reporting between the FDA and OBA has resulted in proposed final guidelines and regulations, which are still undergoing scrutiny and refinements. Serious reservations remain among some academics and most commercial companies as to how this information will be managed and disseminated. A direct outcome of this bad press is the resolve of many gene therapy practitioners to become more vigilant and proactive. A good example: Mark Sands, of the Washington University School of Medicine in St. Louis, MO, has been studying the long-term consequences of adeno-associated virus (AAV)-mediated gene therapy in a mouse model of mucopolysaccharidosis type VII (MPSVII), which has a defect in the β-glucuronidase (GUSB) gene. On November 17th, 2000 Sands and colleagues sacrificed three 1.5-year-old MPSVII mice that had received at birth a single intravenous injection of AAV-GUSB vector. Although the AAV-GUSB treated mice showed biochemical and general clinical improvement, upon gross examination the researchers found that two of the three mice had relatively large liver nodules. A few days later they discovered that another long-term treated mouse had a similar lesion. Alarmingly, none of the seven age- and strain-matched control mice had similar lesions. The researchers then established (with the help of pathologists) that the lesions were hepatocellular carcinomas or angiosarcomas. On December 7, 2000, Sands alerted both Phil Noguchi (Director of the Division of Cellular and Gene Therapies at the FDA) and Cathy McKeon of the National Institute of Diabetes and Digestive and Kidney Diseases. As ASGT president, I was also informed of these data. After review, the FDA informed the sponsors of AAV-based clinical trials of Sand's results and convened a meeting on March 7, 2001, in conjunction with OBA to discuss the results in public. During this three-month period many laboratories working on AAV-mediated gene therapy in pre-clinical models collected relevant data. At this time, it seems that the observations of Sands and his colleagues are an isolated and perhaps unique situation. Clearly, more experiments are warranted but the FDA decided against putting a hold on AAV-mediated gene therapy clinical trials based on currently available data. Primum non nocere (“first” or “above all do no harm”), attributed to Hippocrates — although not well-documented — is the bedrock of medicine. New medical modalities have inherent risks and all adverse events cannot be anticipated, even in the best-planned clinical trials. The best we can do is be vigilant and watchful, and communicate. The public is more forgiving if the process is open and transparent. Hats off to Mark Sands and his colleagues for displaying this spirit.