Assessment of adenoviral vector safety and toxicity: report of the National Institutes of Health Recombinant DNA Advisory Committee.

Given the nature of clinical research, it is not uncommon for gravely ill participants to succumb to their underlying disease in the course of a trial. However, in September, 1999, the gene transfer research community was alerted to the report of the death of a young man enrolled in a gene transfer trial at the University of Pennsylvania.1 In this case, the research participant was not in extremis at the time of enrollment, nor did it seem likely that his death was due to his underlying condition, a partial deficiency of ornithine transcarbamylase (OTC). This raised critical questions as to whether the death might have been, in whole or in part, due to a toxic reaction to the adenovirus (Ad) vector employed to deliver a functional copy of the OTC gene to the participant, to conditions unique to the patient, and/or to the conduct of the trial. If the death was deemed directly attributable to administration of an experimental gene transfer vector, it would be the first such case in the history of gene transfer clinical research. Federal agencies involved in the oversight of gene transfer clinical research took immediate actions as dictated by their respective missions and authority. In the case of the National Institutes of Health (NIH), oversight of human gene transfer research is embodied in the NIH Guidelines for Research Involving Recombinant DNA Molecules (NIH Guidelines) and the activities of the Recombinant DNA Advisory Committee (RAC; see Appendix A for roster). Both the NIH Guidelines and the RAC are administered by the NIH Office of Biotechnology Activities (OBA), which develops and implements NIH policies and procedures for the safe conduct of recombinant DNA activities, including human gene transfer clinical research. The NIH Guidelines set forth policies and procedures designed to maximize the safety of basic recombinant DNA research and to provide guidance for optimal design of preclinical and clinical gene transfer research and standards for informed consent. Investigators conducting gene transfer research, either funded by the NIH or carried out at an institution that receives NIH support for recombinant DNA research of any type, are required to comply with the NIH Guidelines. As advances in the science and safety of gene transfer research warrant, the RAC recommends changes in the NIH Guidelines to the NIH Director. The RAC’s most visible role, however, is the public review of gene transfer clinical protocols. This public review involves an in-depth discussion of the preclinical safety data, the design of the protocol, the informed consent document, and any overarching scientific, safety, or ethical issues relevant to the specific protocol.