It's Time to End RAC Review of Gene Therapy Protocols

The recent recommendation of the Board of Directors of the American Society of Gene and Cell Therapy that the National Institutes of Health (NIH) Recombinant DNA Advisory Committee (RAC) end its review of clinical protocols in human gene therapy and human gene marking is a welcome and necessary step in the continuing evolution of the oversight of clinical gene therapy.¹ In the late 1980s and early 1990s, the RAC and the Division of Cell and Gene Therapy of the Center for Biologics Evaluation and Research at the US Food and Drug Administration (FDA) met often in informal sessions following RAC meetings to discuss and review various aspects of clinical trials in gene marking and therapy. Indeed, RAC review was a productive part of the process when these early gene transfer protocols were being considered. This pooling of expertise was a completely new approach to therapeutics that greatly aided both groups. However, owing in large part to the emergence of a strong and capable full-time group devoted to cell and gene therapy within the FDA, RAC review is no longer necessary.

The RAC was established by then–NIH Director Donald Frederickson in 1974 in response to scientific, public, and political concern over the positive and negative ramifications of recombinant DNA technology. In his formulation of the RAC, Frederickson instructed that one-third of RAC members be nonscientists—the so-called public members. These nonscientists, including ethicists, theologians, and university presidents, offered a broad public perspective on the technology. The NIH established its initial guidelines for research involving recombinant DNA molecules in 1976 (ref. 2). The guidelines were to be followed by all institutions receiving NIH funding. Several controversial issues were publicly debated at RAC meetings in the 1980s, including growth of recombinant organisms in large volume, construction of recombinant molecules encoding potent toxins, and environmental release of recombinant molecules. The RAC has thus made significant contributions to the continually evolving field of recombinant DNA technology. A critical question in 2012 is how the RAC can continue to play a beneficial and useful role in the oversight of the field of recombinant DNA technology, including clinical gene therapy.

How did the RAC get into review of clinical protocols in gene therapy? First, it was natural that the application of recombinant technology to humans qualified under the definition of recombinant DNA. Second, the initial clinical protocols in gene marking and gene therapy came from three NIH scientists: French Anderson, Michael Blaese, and Steven Rosenberg. It was important to these scientists to have public discussions of their proposals to (i) mark tumor-infiltrating lymphocytes of melanoma patients with genetic markers and (ii) administer the gene encoding adenosine deaminase to patients genetically lacking it.

The continued role of the RAC has been questioned before. In 1995, then–NIH Director Harold Varmus noted that the NIH was not a regulatory agency and suggested that it would be more useful for the RAC to serve in an advisory role relevant to gene transfer research, including human clinical trials.³ Philip Noguchi, then head of the FDA's cell and gene therapy group, noted that US federal laws and statutes clearly state that FDA is the final arbiter of the design and performance of all clinical trials, including those in gene therapy. Despite these comments, however, he said that it was not yet the time to cease RAC review.⁴ Noguchi realized that his FDA team could still benefit from the public review and discussion that the RAC offered, and others agreed.^5,6

The number of gene therapy clinical trials continues to increase. According to one estimate, there are 1,166 past and present gene therapy clinical protocols from US laboratories and companies (http://www.wiley.com/legacy/wileychi/genmed/clinical). The RAC, meeting just a few times a year, cannot perform adequate review of these clinical protocols. It is now appropriate to re-examine the role of the RAC in gene therapy clinical protocols.

The FDA maintains an entire group working full-time in the review of cell and gene therapy protocols, and the RAC no longer contributes added value to this review. Having been on both sides of the issue—having served two terms on the RAC, including one as chair in the late 1980s and early 1990s when the first gene marking and therapy protocols were submitted and reviewed and now serving in the biotechnology industry—I fully comprehend that it requires an enormous effort to prepare and submit clinical protocols to the FDA. A significant amount of staff time is required from the research, development, manufacturing, clinical affairs, regulatory, quality control, quality assurance, project management, and other groups, which often must spend months preparing documents for submission. It is not a simple cut-and-paste exercise to prepare a similar yet distinct document for the RAC.

There is no shortage of issues in recombinant DNA technology for the RAC to consider. These include newer vector systems, lab and patient safety, and ethical issues. The return of the RAC to its early role as a public forum and advisory group for the discussion and debate of relevant issues would be a far more productive use of its members' skills and would be consistent with one of the committee's important missions: to address issues of interest to the broader public and government in this continually emerging field.

The RAC has always been composed of dedicated and knowledgeable members. Over its lifetime, it has made significant contributions to the clinical review of gene therapy protocols and other areas of recombinant technology. Clearly, there is more work for the committee to do. I respectfully request that the NIH Director end the duplicative and unnecessary review of clinical review of gene therapy protocols so that the RAC can focus on issues more central to its primary intended objective.