Gene Therapy in the United States: A Five-Year Status Report

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Abstract
At the time of the report, 94 of the 106 protocols receiving favorable RAC review had been approved by the NIH Director, with 12 awaiting NIH approval, pending submission of further information requested by the RAC. One protocol favorably reviewed by the RAC was disapproved by the NIH Director, and one single patient protocol, not recommended for approval, was ultimately permitted to proceed by the Director. Seventy-eight of the protocols were also approved by the FDA. Nineteen studies were closed because they had completed recruitment of patients; three studies were approved by the NIH but were never initiated; 55 were ongoing; and 14 were approved by the NIH and FDA but had not yet enrolled patients. As of June, 1995, 597 subjects in the United States had received experimental genetic material. This represents over 85% of the total patients worldwide who have received gene therapy (Marcel et al., 1995). Figure 1 illustrates the rate of increase in the cumulative number of protocols approved over the past 5 years. Although gene transfer studies were initiated in 1989, it was not until 1991 that there were multiple new projects approved in a single year. The total number of patients who underwent gene transfer is not evenly distributed among protocols. Two protocols (both involving HIV vaccination and both sponsored by Viagene, Inc.) account for 168 of the patients entered whereas all other protocols had entered 45 or fewer patients each. About 35, or 6%, of the patients have been children under 18 years of age. One hundred three (97%) of the studies are classified as Phase I (evaluation of safety), two, as Phase I/II, and only one (gene therapy for HIV) approved in March, 1995, is considered a Phase II (preliminary evaluation of efficacy) study. There are no Phase III (evaluation of efficacy) studies of human gene transfer to date. Therefore, the explicit emphasis of the research so far has been on determining the safety of gene transfer procedures, sometimes with efficacy as a secondary goal. One hundred thirty-four of the 597 enrolled patients have died since the inception of gene transfer studies. In the interest of maximizing the accrual of information on the anatomic distribution and persistence of transferred genes in treated patients, as well as potential unexpected toxicities, the RAC encourages all investigators to obtain autopsies specifically targeting these questions. The autopsy rate for those protocols for which complete information regarding post mortem examination was available is 21%, a number that compares favorably with figures reported from academic centers in general, but is below what one would hope for protocols in which the effort, expense, and interest is as great as in these studies. Thirty-seven separate institutions in the United States are currently involved in human gene transfer trials. Most are academic institutions and the majority rely on outside sources for the vectors or gene delivery agents that are used in their protocols. A total of 34 vector suppliers have been identified, with 32% of protocols using vectors supplied by academic institutions and the rest (68%) using vectors supplied by industry. Most suppliers provide the vector for only a single protocol. However, the largest vector supplier, Genetic Therapy Incorporated, is responsible for the genetic material used in 39 (37%) of the protocols. Apart from the cost of the vector itself, which is usually absorbed by the supplier, funding for gene transfer protocols comes primarily from the NIH. Approximately 55% of investigators reported at least partial NIH funding for their gene transfer studies, with the remainder receiving funds from both academic institutions and private foundations. Only 3–5% of protocols were funded solely by private industry, although the majority received partial industrial support including the cost of the vector. One ongoing concern of academia, industry, and consumer advocacy groups has been the balance between adequate regulatory control of new technologies versus the speed at which potentially life-saving experimental therapies can be brought to the clinic. The Data Management Subcommittee of the RAC attempted to analyze some of the variables involved in the experimental phase of gene therapy with regard to that issue. Federal guidelines for Recombinant DNA Research Activities dictated that all protocols must first receive local Institutional Review Board (IRB) and Institutional Biosafety Committee (IBC) approval before being considered. Submissions to the FDA and RAC can be made simultaneously, but final FDA approval is contingent both on RAC and NIH Director approval. Although the data provided by the investigators are incomplete, sufficient information is available from 55–80 protocols to estimate the time from initial approval by the investigator's own IRB and IBC to RAC approval, from RAC approval to NIH Director approval, from RAC approval to FDA approval and from final approval of all agencies to entry of the first patient (Table 1). The median time between each stage of approval ranged from 3 months to 7 months. Thus, it often takes 1–2 years for a protocol to be completely approved from the time it passes the local IRB and IBC. It should be noted that the time to protocol approval has accelerated considerably in the past year due to a combination of increased experience on the part of investigators and regulators and development of accelerated and combined approval procedures by NIH and FDA.