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Executive Summary

FDA's Center for Biologics Evaluation & Research is preparing for an expected increase in applications for gene therapy human trials by attempting to anticipate special issues or variations in application review which may be required for the new technology. The foremost question for CBER will be definitional: how to decide which products to regulate and which to leave unregulated as the practice of medicine. At a Jan. 15 session of the BioEast conference in Washington, D.C., CBER's Suzanne Epstein, PhD, noted that one of the important policy issues facing the agency is "where is the boundary between somatic cell therapy [which FDA regulates] and transplantation [which it does not]." FDA is currently thinking about the regulatory distinctions, Epstein observed. The agency is understood to be working on a written statement on gene therapy for public comment. CBER would like to have that statement out by the end of this year. The agency recognizes that it has about a year before it may face an upswing in applications for gene therapy INDs. There are currently about a dozen protocols for gene therapy in place with projections of a doubling or trebling of that number within the next year (see related story, preceding page). The first in vivo gene therapy application is likely to be filed during 1992 for an inhaled treatment of cystic fibrosis by Ronald Crystal, MD, at the National, Heart, Lung & Blood Institute, using an adenovector supplied by Genetic Therapy, Inc. Because it is inhaled and not injected into the body, the cystic fibrosis therapy may be less problematic than others as an initial in vivo gene therapy. Urging "input" from manufacturers and gene therapy sponsors, Epstein listed some of the policy questions which interest the agency: "whether the product is extensively manipulated, or is it really just some cells taken out, maintained and put back in; whether the cells are altered in their properties, or if they are really just maintained; and also whether the cell's preparation has potential as a marketable pharmaceutical (if you have thousands of vials of a cell-line which you send to pharmacies and sell as opposed to something which really has minimal manipulation and is much more like 'practice of medicine'." She noted that "this is all an open area." FDA could opt to regulate gene products in some cases by focusing on the vectors or purging agents used in the preparation of genes for bone marrow transplantation. Epstein reported that the CBER policy committee looking into these questions "has entertained the possibility that the vector will be the handle that we hang the regulation" on. She added, however, that "it is very unlikely that it would be given carte blanche so that if the vector is more or less licensed as a biological product anyone can use it on any kind of cell therapy." She noted that bone marrow transplantation might be regulated by an indirect approach. "If the decision is made that bone marrow is not regulated as a biological product but the purging agents or positive selecting agents are regulated, then perhaps the vector would be regulated and the marrow cells just go in as a transplant," Epstein said. The careful characterization of cell lines and genetic packaging will be stressed by FDA, Epstein said. "The novel aspect related to gene therapy [is that] any genetic constructs for packaging cell lines have to be characterized in detail." FDA will treat "each vector that is distinct [as] a different biological product," Epstein said. "Until we get persuaded otherwise, a new vector does have to be safety tested," she pointed out, stating that there will not be "a generic acceptance of vectors that are 'similar' to each other." FDA may change that policy "with time as this becomes more routine. But, for now, a different vector or different packaging cell should be characterized. These constructs could include all the variations: DNA attached to proteins or polyethylene glycol, with lipids, anything, different types of viruses." Epstein pointed out that FDA and NIH regulatory efforts in the early IND stages dovetail. Responding to the question of whether a sponsor needs RAC (NIH's Recombinant DNA Advisory Committee) approval before coming to FDA, Epstein said "before the formal IND comes in and is approved, it is actually preferable for you to have RAC approval." Epstein said that she had "learned recently... that [it] is considered an incomplete IND if it hasn't received its RAC approval if one is required." If a firm is not working with a government-funded institution which obligates it to get RAC approval, "you do not have to go through the RAC. But if you are in the process of going through the RAC, you can come in to see us as a pre-IND phase, but the formal application is incomplete" without RAC okay, Epstein said. Epstein noted that FDA's role in regulating gene therapy is being considered in the context of larger treatment issues. "There is currently agitation in the country for some form of regulation of transplantation because of transmission of HIV. There may be a registration system; it seems likely that FDA may be involved in some way."

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