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Executive Summary

FDA's REVIEW OF HALCION CLINICAL DATA WILL BE COMPLETED "SHORTLY," the agency said in a Feb. 14 "Talk Paper" on Upjohn's benzodiazepine hypnotic triazolam. Despite questions about the validity of some of the studies, the balance of trial data "are well designed and appear to support the effectiveness of Halcion as a sleep aid," FDA said. The agency began its "special review" of Upjohn's clinical data for Halcion following the company's submission of Phase I data omitted from the NDA due to what Upjohn claimed was a "transcription error" ("The Pink Sheet" Oct. 7, p. 11). Upjohn since has agreed to a number of labeling and packaging changes, which FDA is seeking for all benzodiazepine sleep aids ("The Pink Sheet" Nov. 25, p. 11). FDA emphasized that, while the drug's "adverse reactions have been widely discussed, Halcion's effectiveness in short-term use has not been called into question." The "Talk Paper" was prompted by the discovery that the role of a Halcion clinical investigator disqualified for fraud, William Franklin, may have been larger than the agency was told by Upjohn at the time of Halcion's approval. "FDA has recently become aware that a clinical investigator who contributed important data to studies of the effectiveness of Halcion...had been disqualified by the agency prior to the drug's approval in November 1982," the "Talk Paper" says. Franklin's role in the Halcion approval was questioned by Public Citizen's Health Research Group in an Oct. 16 letter calling for the withdrawal of Halcion ("The Pink Sheet" Oct. 21, p. 9). HRG based its petition on allegations raised by an Oct. 14 episode of the BBC TV documentary "Panorama." HRG noted that a 1978-1979 pivotal trial for Halcion, Protocol 6415, was conducted in part by Franklin, who was discovered to have faked the data. In the "Talk Paper," FDA reports that Franklin was, in fact, part of two of the "pivotal" Halcion trials. The agency believes, however, that the balance of the studies included in the NDA and "many others carried out since 1982" support the efficacy of the drug. "Furthermore, the studies in which Dr. Franklin participated do not have important implications for the drug's safety, and he contributed only a minor portion of the overall safety data," the "Talk Paper" says. "More troubling," FDA said, "are statements made by Upjohn to the effect that Dr. Franklin had not played a material role in studies leading to Halcion's NDA." "These statements were made in response to an FDA inquiry shortly after Halcion was approved," the "Talk Paper" says. "Upjohn's statements were incomplete, inaccurate and misleading, in that they addressed only his contribution to the safety data and ignored his potentially important role in the evaluation of Halcion's effectiveness. FDA is continuing to investigate this matter." Upjohn has acknowledged that its statements to the agency at the time were not satisfactory. The agency noted that its own files "would not have identified the specific studies nor the importance of the studies in a marketing application" in which a disqualified investigator was involved. "Asking Upjohn to identify the studies Dr. Franklin had carried out and their importance to the NDA was standard practice ...Depending on the response, FDA's review staff might have been asked to carry out further evaluation," the agency noted. "It is clear that this system was not adequate, and it has now been changed," FDA said. "When a clinical investigator has been disqualified, all drugs he or she worked on will now be identified and the role of the studies assessed. In addition, the review divisions will be asked to examine all recently approved and pending NDAs to identify the participation of the clinical investigator."

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