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SANDOZ CLOZARIL IS RECOMMENDED FOR APPROVAL IN TREATING SCHIZOPHRENIC PATIENTS REFRACTORY TO STANDARD THERAPIES; BENEFITS OUTWEIGH RISK OF AGRANULOCYTOSIS

Executive Summary

Sandoz' Clozaril (clozapine) should be approved for the treatment of schizophrenics refractory to other neuroleptic agents, FDA's Psychopharmacologic Drugs Advisory Committee recommended at its April 26 meeting. The committee voted unanimously in favor of approval. Committee member David Dunner, MD, Harborview Medical Center, Seattle, Washington, summarized the panel's consensus on clozapine's risk/benefit balance: "I feel that if the drug is used in [schizophrenics refractory to other treatments] than "the benefits outweigh the risks of this particular compound." The initial NDA for Clozaril was submitted to FDA in April 1983. However, because of the drug's potential to cause agranulocytosis, clozapine was given an early stage review by the Psychopharmacologic Drugs Advisory Committee in February 1984. At that meeting, the committee recommended that the drug not be dropped because of its agranulocytosis potential but that additional data needed to be compiled to support use in treating resistant patients. While recommending approval for use in schizophrenics refractory to other drugs, the committee left unclear whether the drug should also be indicated for patients who can not tolerate other drugs. A Sandoz representative said that the company plans to work out the definition of "treatment-resistant" with FDA. Following the February 1984 panel meeting, Sandoz worked out a study design with FDA to answer the questions raised at that advisory committee meeting. The trial, Study 30, involved patients who had failed at least three previous treatments. The study consisted of several phases, including a two-week placebo washout phase in which 319 patients entered; a second phase where 305 patients were treated with increasing doses of haloperidol for six weeks to determine if they were treatment-resistant followed by a one-week placebo washout; and an actual efficacy trial in which clozapine was compared to a combination of chlorpromazine and benztropine over six weeks in 16 centers. A total of 268 patients, those not responding and intolerant, were randomized to either therapy -- 126 to clozapine and 142 to the combination. Presenting FDA's review of the efficacy data, Karin Kook, PharmD, reported that "36 of the 126 clozapine patients or 29% were treatment responders . . . compared to 9 of 142 [chlorpromazine/benztropine] patients." Kook concluded that "clozapine appears to be effective in roughly 30% of the treatment refractory patients [and] it appears that for most patients four-to-six weeks of treatment was required to see a treatment effect." Of the four FDA reviewers, only one, the safety data reviewer Richard Kapit, MD, felt that clozapine's benefits did not justify the risks. Kapit noted that 112 cases of clozapine-related agranulocytosis have been reported in Europe and that 35% of those cases resulted in death. He added that use of clozapine was restricted in Denmark, Finland and Norway, following 36 cases of agranulocytosis in Europe in 1975. Sandoz reported that there have been 13 cases of agranulocytosis in clinical trials in the U.S., or a 1.65% incidence, and that none of the patients died. Sandoz presented a proposal for a "Clozaril Patient Management System" whereby a visiting nurse would take weekly blood samples from patients to be sent to a national laboratory for analysis. After drawing the blood, the nurse would give the patient a seven day supply of Clozaril. Several committee members felt that the program was unnecessary.
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