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Executive Summary

The European Community's Committee for Proprietary Medicinal Products will decide whether to recommend a change in the marketing status of Upjohn's Halcion (triazolam) in December after a two-month review of safety data for the drug. In an Oct. 16 position statement issued after a same-day meeting in Brussels, the CPMP decided that, "given the large volume of information supplied [by Upjohn on Oct. 11], the committee considers it necessary to review these data, as well as data in the application dossier and information" from the CPMP's pharmacovigilance committee. "Rapporteurs" from France, Germany, Greece and Italy "have been appointed and will report in December 1991," the CPMP said. "The committee will formulate its opinion in December 1991, taking into account the full review of all existing data." The CPMP action was precipitated by the marketing withdrawal of triazolam in the U.K. on Oct. 2. That decision followed a reanalysis of Halcion safety data that was prompted by Upjohn's disclosure of a "transcription error" in one of its clinical trials, protocol 321 ("The Pink Sheet" Oct. 7, p. 11). French and Dutch regulatory officials requested a CPMP meeting, and the CPMP pharmacovigilance committee heard presentations from Upjohn and the U.K.'s Medicines Control Agency on Oct. 16. "Upon preliminary consideration of the available data, evidence of new risks at recommended doses does not seem to be available," the CPMP said in the position statement. While awaiting full analysis of the data, the CPMP recommended labeling changes, small packs, and a postmarketing study for the benzodiazepine sleep inducer. CPMP recommendations are not binding on member states. The CPMP agreed that the Halcion label "be immediately strengthened" to include: (1) a statement in the indication section that "triazolam is only indicated when the sleeping disorder is severe, disabling or causing extreme distress"; (2) a statement that "triazolam should not be used for more than two to three weeks, and treatment thereafter requires a complete re- evaluation of therapy"; (3) a warning statement that "triazolam should not be used in patients with any major psychiatric disorders"; and (4) statements that "the lowest effective dose should be used," that "a dose of .25 mg should not be exceeded," that a dose of .125 mg should not be exceeded in the elderly and patients with liver/kidney impairments, and that "safety and efficacy of triazolam have not been established for patients younger than 18." "To emphasize that the product is for short-term use, the company has proposed introducing small pack sizes," the CPMP position statement says. "The committee considers that small packs (not more than seven tablets) should be made available immediately." Finally, Upjohn will "perform an extensive pan-European controlled comparative postmarketing safety and efficacy study immediately, and a draft protocol should be submitted to the committee before December 1991," the position statement reads. The labeling changes recommended by the CPMP "currently exist in some countries," Upjohn reported. Package sizes also vary in Europe; Upjohn said it intends to offer the small packs in addition to other sizes. U.S. labeling does not include any of the statements recommended by the CPMP, nor are small packs available. FDA representatives were present at the CPMP meeting and the agency indicated that all the CPMP recommendations would be considered during its ongoing review of Halcion data. Upjohn said it is "encouraged by the action of the EC." The company "is satisfied that today's decision will enable the CPMP to make a fair and measured review of Halcion data and to avoid what the company has maintained was a precipitous action by U.K. authorities." The CPMP action may take some of the steam out of the momentum toward worldwide withdrawals of the product. Norway and Finland, which are not members of the CPMP, withdrew Halcion from the market soon after the U. K. Outside of Europe, Argentina and Jamaica followed suit, and New Zealand has removed the .25 mg dose, although the .125 mg dose is still available. At least one country that was considering withdrawing the product (Germany) is now awaiting the CPMP decision, Upjohn observed. Public Citizen's Health Research Group called for FDA to initiate a criminal investigation of Upjohn's handling of Halcion safety data on the same day as the CPMP meeting. "It now appears that at least two out of 13 long-term studies on the drug Halcion contain fraudulent or misrepresented data, and that for the past two decades, Upjohn has systematically misrepresented Halcion's serious behavioral and psychological adverse effect to FDA, to expert panels of physicians assembled to review the data on Halcion, and to the public," HRG Director Sidney Wolfe, MD, and Researcher Ida Hellander, MD, said in an Oct. 16 letter to FDA Commissioner Kessler. HRG bases many of its allegations on an Oct. 14 BBC television documentary, "Panorama," which discussed Halcion. According to a BBC transcript of the program, Panorama "obtained the official summary prepared by Upjohn of protocol 321" which, according to the transcript, showed that a key underreported adverse event was paranoia. Panorama also charges that there are "irregularities which suggest that some serious side effects were left out of the report entirely." That allegation is based on BBC interviews with several prisoners who participated in the 1972 trial who remember different reactions than were allegedly recorded in the case reports. Upjohn maintains that the "transcription error" in the summary of protocol 321 did not seriously mischaracterize the safety profile of the drug. The company questions the validity of patient statements almost 20 years after the study. The second clinical trial which HRG refers to as containing false or misrepresented data is Protocol 6415. Upjohn acknowledges that this 1978-9 trial resulted in an investigation of the lead researcher when FDA discovered in 1983 that he apparently had faked the data. "Two panels of scientific experts (one an advisory committee to the FDA) have been misled by incomplete presentations of the data on Halcion by Upjohn," HRG alleged. The first panel, HRG said, was composed of experts convened by Upjohn to answer reports from a Dutch investigator of a high incidence of adverse effects from the drug which led to Halcion's withdrawal in Holland in 1980. (Halcion was reinstated in that country in August 1990.) Panorama quoted a member of that panel saying he was "misled" by not having the data at the time, and that the panel would not have written a letter to the British medical journal The Lancet discrediting the reports if they had seen it then. HRG also alleged that Upjohn's presentation before FDA's Psychopharmacologic Drugs Advisory Committee on Sept. 22, 1989 was misleading because the company knowingly did not present all adverse reaction data it had at its disposal. "Because of the widespread use of Halcion in the U.S., and the discredit a scandal of these proportions might bring to the entire drug regulatory process, we urge that FDA launch an immediate criminal investigation of Upjohn and conduct a thorough review of all longterm clinical trials used to support Halcion's approval," the HRG letter says. HRG also reiterated its call for a stronger warning label on Halcion in the Oct. 16 letter; HRG originally requested the warning in a citizen petition filed April 19, 1990. "An outright ban may be warranted should further evidence of serious adverse reactions emerge from a reexamination of the longterm clinical trial data," HRG said. Upjohn responded to the Oct. 16 letter by saying it is "outraged" by HRG's allegations. The company called the BBC television program "biased and one-sided" and accused the program of showing a "blatant disregard for accuracy and balance." FDA did not have any comment on the allegations.

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