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Executive Summary

HRG CALLS FOR HALCION WITHDRAWAL, maintaining that data on Upjohn's benzodiazepine hypnotic were "not adequately reviewed" by an FDA advisory committee convened in May to discuss the continued marketing of Halcion (triazolam). "We believe that the benzodiazepine hypnotic, triazolam (Halcion), should be removed from the market immediately based on new data not previously made public and/or presented without being considered adequately at the Psychopharmacologic Drugs Advisory Committee meeting on May 18, 1992, as well as data previously available in prior petitions but not adequately considered," Public Citizen's Health Research Group asserted in a July 22 petition filed with FDA. The petition argues that the committee did not consider all of the data about Halcion "in an integrated manner." Among "serious omissions" in the committee's deliberations, the petition contends, were: a lack of discussion of Upjohn's Protocol 321 for which results were inaccurately reported in the NDA; a lack of discussion of the U.K.'s rationale for banning Halcion last October; and a lack of discussion of actions by other regulatory bodies before and since the U.K. action. In a July 17 letter to Upjohn, the U.K. Medicines Control Agency told the company that it is proposing permanent revocation of Upjohn's triazolam license; the October suspension was temporary, pending a final ruling. However, Upjohn said it was "encouraged" that an advisory body to the MCA recommended that Halcion be returned to the market. The MCA overruled that opinion; Upjohn said "it will proceed with the appeal process." The advisory committee's May meeting, which focused on a reanalysis of the clinical trial database for Halcion, was prompted by the U.K. action to suspend the drug. The move in Britain followed Upjohn's admission that it had made errors in its NDA submission relating to protocol 321. FDA and Upjohn agreed in November to relabel and repackage Halcion to encourage short term use and lower doses ("The Pink Sheet" Nov. 25, p. 11). The committee unanimously agreed that Halcion is safe and effective when used according to the new labeling ("The Pink Sheet" May 25, p. 9). HRG Director Sidney Wolfe, MD, announced the filing of the petition at a July 22 press conference in Washington, D.C. Also signing the petition and appearing at the press conference were two members of Pennsylvania State University's psychiatry department: Chairman Anthony Kales, MD, and Research Director Edward Bixler, PhD. Kales, who conducted an early study of Halcion for Upjohn, submitted a petition calling for the withdrawal of the drug last year. Upjohn responded to the press conference by noting that Wolfe and Kales both presented to the advisory committee and that their views were "not persuasive to the committee....It seems to us that Wolfe and Kales are carrying their case back to the media." The company added that when "the science is considered, the safety and efficacy of Halcion is upheld." HRG previously has filed petitions calling for boxed warnings in Halcion's label and for a criminal investigation of Upjohn in connection with its Halcion NDA. Wolfe testified at the May advisory committee that in light of the data made available to him for that meeting, he was now prepared to call for the withdrawal of the drug. After reviewing the data "omitted" from the committee discussion and FDA's reanalysis of the clinical trial database, HRG's petition concludes that "triazolam has an unacceptable benefit-to-risk ratio." This conclusion "is based on: frequent and severe CNS and psychiatric adverse reactions at all doses; a very narrow margin of safety; and, limited efficacy" at the recommended dose of .25 mg. "Until triazolam is banned, FDA should require Upjohn to send a warning letter to all physicians and to warn patients regarding triazolam's low benefit-to-risk ratio," the petition adds. HRG included a copy of an Oct. 3 letter sent by Upjohn to U.S. physicians after the U.K. suspension of Halcion; HRG maintains that the letter provides a "limited, incomplete and erroneous interpretation" of the U.K. action. In a July 22 "Talk Paper," FDA said that its "ongoing review of the available evidence has led the agency to conclude that Halcion's benefit outweighs the reported risks."

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