Alex Philippidis Senior News Editor Genetic Engineering & Biotechnology News

Goal is to restrict involvement in clinical trials and focus the RAC on questions of public concern.

The principal U.S. professional society representing gene therapists is awaiting word from NIH about whether or not there will be re-examination of the role of its Recombinant DNA Advisory Committee (RAC). They aim to limit its longstanding role in clinical trials while continuing its service as a forum for discussing and educating professionals on policy issues.

The American Society of Gene & Cell Therapy (ASGCT) touched off the debate earlier this year, when its president and her predecessor conveyed the society’s view that RAC should focus on broader issues rather than review the clinical protocols of individual researchers. They sent a letter to Amy Patterson, M.D., director of NIH’s Office of Biotechnology Activities (OBA), and issued a statement seven days later at a RAC meeting.

ASGCT president Xandra O. Breakefield, Ph.D., told GEN that since then, predecessor R. Jude Samulski, Ph.D., has had several conversations with Dr. Patterson and exchanged several e-mails with NIH director Francis S. Collins, M.D., Ph.D. “There appears to be general agreement among them that it would be a good time to review the purview of the RAC through an external review by experts, possibly by the Institute of Medicine,” said Dr. Breakefield, who is also a professor of neurology at Harvard Medical School and a geneticist in the molecular neurogenetics unit at Massachusetts General Hospital. “We are all waiting for a decision to be made on this by Dr. Collins.”

NIH is not prepared to say much. Soon after the letter and statement emerged, Dr. Patterson told ScienceInsider that NIH had no plans to abolish RAC but was “happy to think about ways to streamline the RAC process.”

RAC’s History

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.

Future Role

In her March 8 statement, Dr. Breakefield articulated ASGCT’s view that since the 1995 panel, “investigators in the field of gene therapy and administrators in these regulatory agencies have become highly knowledgeable and experienced in review of these protocols, with thousands of trials having been conducted and many showing promising benefit. We feel, therefore, that it is time to reevaluate the mission and modus operandi of the RAC to better serve the need of the research community and public as a whole.”

NIH funding for gene therapy has stayed flat in recent years: $248 million in research grants was awarded in FY 2011, the same as projected for FY 2013; $249 million was won by researchers in FY 2008, the same as projected for this fiscal year. Gene therapy clinical trial funding was similarly level: It dipped from $16 million in FY 2008 to $14 million in FY 2011, and is expected to stay at that number for FY 2012 and the following fiscal year.

Those figures reflect years of equally flat or slightly declining NIH budgets and gene therapy’s recovery from years of setbacks, from a patient death in 1999 to FDA’s suspension of trials four years later. As the field moves beyond basic research toward trials with better results, those numbers should start increasing, heightening the need to rethink RAC’s role.

The RAC could better serve researchers by building on its historic strength of serving as a forum for issues of importance by organizing workshops and symposia for discussion of focused issues with experts, Dr. Breakefield told GEN. “In the future, these could include review of novel vectors—their uses and potential biosafety risks; discussion of the benefits and risks of prenatal therapy using vectors that currently have shown low-to-no toxicity in children and adults; analysis of any serious adverse event incidents from all perspectives; and issues on how to facilitate moving forward gene therapies that have shown benefit in clinical trials,” Dr. Breakefield said. “In general, they should focus on questions of public concern and areas in which the NIH director feels more information is needed.”

The revival of gene therapy over the past decade offers an opportunity for revisiting how the field’s clinical trials should be regulated. Since both NIH and FDA are involved, this would be suitable for review by the FDA-NIH Joint Leadership Council or an offshoot such as a working group.

In considering RAC’s fate, the council or its offshoot should resolve to minimize future overlap by dividing its functions: The educational and policy purposes enable the support and conduct of gene therapy research, thus they should remain under NIH, either through RAC or preferably a new gene therapy advancement office.

Additionally, RAC’s review of novel clinical protocols should not disappear but instead be shifted to the safety- and effectiveness-focused FDA, where it can function as that agency’s 12th advisory committee, either under the current RAC name or another name. The standards for requiring additional scrutiny of protocols should be narrowed to those that significantly depart from familiar practices, which are most likely to spark legitimate safety and effectiveness questions.

Alex Philippidis is senior news editor at Genetic Engineering & Biotechnology News.

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