Despite its public silence, NIH’s attention to the issue, reflected in the dialogue with ASGCT, suggests that the agency is at least thinking about revisiting RAC’s role in gene therapy. It wouldn’t be the first such re-examination.
In 1974, public and researcher fear about gene splicing prompted NIH to create RAC, with a dual mission that included advising the NIH director on the conduct and oversight of research involving recombinant DNA as well as serving as a public forum for discussing the resulting issues. NIH’s initial charge to RAC was developing the NIH Guidelines for Research Involving Recombinant DNA Molecules, published in 1976. RAC continues to advise NIH on changes to the Guidelines.
In the two decades that followed, as Dr. Breakefield noted, RAC’s role expanded to include final say over all clinical protocols in gene therapy, with authority to approve or disapprove trials. In 1995, NIH’s then-director Harold Varmus requested that an ad hoc expert review committee assess “the changing role of the RAC, the ways it may need to modify its operations, and how it should function to coordinate and facilitate productive gene therapy research.”
The ad hoc team noted: “To avoid duplication of effort and unnecessary delay, RAC should no longer carry out case by case review of every clinical gene transfer protocol,” leaving that task to FDA as well as institutional review boards and biosafety committees. That led to a change in RAC’s stated mission, from serving as a prerequisite for approval to offering advice on the protocols governing trials.
Yet there remains some overlap between RAC and FDA. For one thing FDA’s numerous gene therapy guidances include some details related to clinical trial protocols. Gene therapy products are regulated by FDA’s Center for Biologics Evaluation and Research.
The 1995 ad hoc panel also kept RAC’s prominent role in gene therapy by recommending that: “Review of protocols by the RAC in an open public forum should continue in several areas of concern in which a particular protocol or new technology represents a significant degree of departure from familiar practices.”
Those areas of departure—which back then encompassed much of the current gene therapy field—“include, but are not limited to, the use of novel vectors, particularly in cases in which modified human pathogens (such as herpes viruses or lentiviruses) are being evaluated; gene transfer in utero, potential germ line modification, and other similar manipulations; and gene transfer in normal volunteers.
“Review of protocols by the RAC is warranted in other situations that could lead to the formulation of significant new policy,” the ad hoc committee added, in a catchall recommendation that effectively upheld RAC scrutiny for most gene therapy clinical trials.
RAC reviews human gene transfer trials conducted at, or sponsored by, NIH-funded institutions; those trials must be registered with OBA.