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REP. WEISS' INVESTIGATION OF MERITAL APPROVAL FINDS EFFICACY DECISIONS IN NEUROPHARMACOLOGY DIV. A FERTILE GROUND FOR SECOND-GUESSING: BUSPAR TOO

Executive Summary

FDA's efficacy standards for antidepressants and anxiolytics are getting close attention from Chairman Weiss' (D-NY) House Intergovernmental Relations Subcommittee. The Weiss subcommittee staff has pursued recent approval standards in FDA's Neuropharmacologic Division as an outgrowth of the investigation into the approval and eventual market withdrawal of Hoechst-Roussel's Merital (nomifensine). A report on that investigation, issued by the House Government Operations Committee on July 14, questions FDA approval standards for at least one key approval subsequent to the Merital experience. [EDITORS' NOTE: The House report also urged FDA to make an effort to keep up to date on foreign regulatory activities by requiring additional submissions to the NDA. See related story in "The Pink Sheet" July 20, page 11]. "In approving [Bristol-Myers'] new drug Buspar (buspirone hydrochloride)," the House report maintains, FDA "disregarded several negative efficacy studies submitted for the drug." The House report, prepared by the Weiss subcommittee staff, cites an exchange of memos between Office of Drug Research & Review Director Robert Temple, MD, and Neuropharmacology Drug Division Director Paul Leber to question the buspirone efficacy decision. On May 27, 1986, Temple observed that two of four buspirone studies which did not clearly support the efficacy of the product "may actually provide some evidence against buspirone." Temple wrote at that time, four months prior to final approval of Buspar, that "it . . . seems possible that we need another supportive U.S. study prior to approval." In response to that memo, Leber wrote back to Temple in mid-July of 1986, objecting to what he found as an implicit argument in Temple's analysis that "studies failing to provide statistical support for the efficacy of a new drug . . . are evidence against the efficacy of a new drug." He House report quotes Leber as stating "the studies failing to provide evidence of efficacy must not persuasively contradict the conclusions of the studies identified as positive. I believe there are relatively few results that can be interpreted as convincing evidence of a lack of efficacy." The Weiss subcommittee interprets the dialogue between Temple and Leber as showing that FDA's review staff is searching for positive efficacy results and will ignore studies with less than clear efficacy results. "If FDA can find two 'positive' studies that it regards as acceptable," the House report charges, "it appears that [FDA] will disregard, in almost all circumstances, numerous studies in which the drug was not shown to be superior to a placebo." The House report further reads Leber's memo in the Buspar approval as "subtly" shifting "the burden of proof for demonstrating efficacy from the NDA sponsor" to the agency. Generalizing from Leber's July 1986 memo, the House report declares that "a sponsor need not submit 'convincing evidence' that a drug is effective, even when in most trials it has not been shown to be superior to a placebo. Instead, FDA has the burden for providing 'convincing' or 'persuasively contradictory' evidence that large numbers of negative studies do evince a 'lack of efficacy.'" While the House subcommittee's reading of the significance of the Leber memo may be exaggerated, the close attention to the efficacy standards in the relatively difficult area of psychopharmacologic drugs may telegraph further approval second-guessing in that area in the future. The Weiss subcommittee further pressed its continuing allegations that FDA's heavy end-of-the-year approval lists in recent years indicate a bias toward approvals. Specifically, the House report maintains that FDA dropped a requirement for labeling which would have identified Merital as second-line therapy in order to get the product approved by the end of December 1984. The House report alleges that FDA dropped that requirement after a Dec. 21 teleconference with the company. FDAer Temple testified at the Weiss subcommittee hearing on the Merital situation (in May 1986) that the agency had decided prior to that conference that FDA "didn't have a basis" for requiring the second-line therapy labeling.
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