No one who presented a protocol before a meeting of the Recombinant DNA Advisory Committee (RAC) before 1996 ever enjoyed it. It was, indeed, trial by fire as basic scientists, clinicians, bureaucrats, attorneys, ethicists, and patient advocates chewed through the proposed protocols, questioned the validity and extent of the experiments, rewrote the informed consent forms, and debated the population of patients who would be permitted to enter the trial. To add further insult, the investigators involved in gene therapy then had to submit reams of similar paperwork to the US Food and Drug Administration (FDA) for further review. Many in the field complained loud and long about the process, which was eventually streamlined and softened by Harold Varmus, MD, who has just left his post as head of the National Institutes of Health.
However, the power of the RAC—now part of the Office of Biotechnology Assessment—may be resurgent in the wake of the furor over the death of 18-year-old Jesse Gelsinger, who was involved in a phase trial using a modified adenovirus to correct ornithine transcarbamylase deficiency, an inherited disorder that can cause death in affected newborn males because of their inability to properly process nitrogen in food proteins due to a genetic defect in the liver. In a statement on the University of Pennsylvania’s Web page, the researchers involved stated that “The findings suggest that the experimental drug used in the trial—a modified cold virus, or vector, incorporating a potentially corrective gene for Mr Gelsinger’s genetic disease—initiated an unusual and deadly immune-system response that led to multiple organ failure and death.”
In November, it was revealed that 6 people died during gene-therapy experiments on the heart over a 19-month period of time. In those instances, the researchers at the 2 institutions involved said they did not think that the fatalities involved were directly caused by the gene therapy. Instead, they claimed that the patients died of complications from their underlying illnesses. The RAC did not agree. “It may take 5, 6, 7 patients ill, or 20 patients, before we find out, ‘Hey, this is also happening in other people’s trials,’” said Amy Patterson, who oversees the RAC, to the Washington Post.
It was the threat that much of gene therapy would be reviewed behind the closed doors of the FDA that led members of the RAC to oppose Dr Varmus’ plan to streamline the agency 5 years ago; under this plan, the RAC reviewed only new and novel protocols. Many private firms are involved in the development of gene therapy, and companies seek to keep this information private and proprietary. In most instances, the FDA will keep the information confidential; the deliberations of the RAC, however, are mostly held in the public eye.
In January of this year, the FDA halted 8 gene-therapy clinical trials because “the nature and scope of the deficiencies in oversight of the clinical studies raise substantial concerns that similar deficiencies in oversight… may exist and that the subjects enrolled in the proposed clinical investigations would be exposed to a significant and unreasonable risk.” No one in the gene-therapy community seemed surprised by the move and, indeed, most thought that the FDA had to act in this manner because of the reported deficiencies in patient selection for the trials and problems with other portions of the trials. As one researcher who asked not to be named said, the one positive outcome of the disclosure of Mr Gelsinger’s death and the subsequent action against the University of Pennsylvania Institute for Human Gene Therapy may be public disclosure of toxicity in such studies and a closer adherence to FDA guidelines designed to insure patient safety.
Although gene therapy has yet to fulfill the potential expected of it during the past decade, new studies now in press may prove its value in diseases caused by single gene defects. It seems clear that the RAC will once again play a bigger role in the oversight of such studies.
- Copyright © 2000 by American Heart Association