HUMAN GENE THERAPY FOR ADENOSINE DEAMINASE DEFICIENCY TO BE SUBMITTED FOR FDA REVIEW; NIH's RAC SUBCOMMITTEE GETS FIRST DRAFT PROPOSAL FOR CLINICAL TRIALS
FDA's first official look at potential gene replacement therapy will be a preliminary proposal by an NIH researcher for the treatment of adenosine deaminase deficiency (ADA). W. French Anderson, Chief of Molecular Hematology at the National Heart, Lung and Blood Institute, told an NIH Recombinant DNA Advisory Committee (RAC) working group that he plans to submit to FDA preclinical data and a draft protocol, in the form of a drug master file, for ADA gene transplantation. Anderson presented a 100-page draft proposal for human gene therapy clinical tests to the RAC subcommittee at its April 24 meeting. Human gene therapy involves the in vitro insertion of a gene into cells that are then transplanted into a patient suffering a genetic disorder. Anderson predicted at last year's Institute of Medicine annual meeting that ADA would be the first candidate disorder for such therapy. ADA deficiency is characterized by a virtual absence of T- and B-cell immune function; most victims of the disease die of infection by two years of age. The treatment proposed by Anderson involves inserting the ADA gene into the patient's bone marrow cells and then transplanting the marrow back into the patient. The RAC subcommittee will circulate Anderson's proposal to RAC members and make a presentation to the full committee at its fall meeting. RAC will be requested to scrutinize the draft as if it were a formally submitted proposal; however, RAC will not be asked to approve or disapprove the protocol. In addition to familiarizing RAC with preclinical data, the draft protocol likely will accelerate the review process if and when an actual proposal is submitted. Anderson estimated that the final proposal is at least one year away. According to Anderson, "it's unfair and inappropriate" to submit a human gene therapy proposal "until the consensus is already there that it's time for a clinical protocol and the issues have already been resolved. . . Now it can be discussed at the RAC" without approval pressure, he said. In addition to RAC, the working group plans to circulate the data and draft protocol to a group of about 12 ad hoc consultants. The subcommittee intends to reconvene this summer to compile its own comments and those of the consultants. Working group Chairman LeRoy Walters, Georgetown University Center of Bioethics, instructed the subcommittee to indicate "what types of additional information or what types of additional data we would want to see" before a human gene therapy proposal is formally submitted. Anderson told the subcommittee that several issues need to be addressed before clinical trials can begin. For example, he noted that the safety of the viral system used to transport the ADA gene into the bone marrow cells needs to be determined. However, working group member Arno Motulsky, University of Washington, cautioned Anderson not to raise problems with the draft protocol that "probably don't exist." To indicate that "very hypothetical" dangers are cause for concern would unnecessarily inflame public opinion and could be "doing a disservice" to patients with ADA deficiency, Motulsky said. RAC Executive Secretary William Gartland commented that it might be "desirable" to have future human gene therapy draft proposals presented to RAC in this manner. He noted, however, that many researchers lack the time and resources needed to present massive preclinical data to the subcommittee.
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