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Executive Summary

VERSED ADR REPORTS SUGGEST NO DIFFERENCE BETWEEN CONCENTRATED AND DILUTE formulations of the product, Hoffmann-LaRoche contended in an Aug. 1 statement. The statement responds to renewed charges from Public Citizen's Health Research Group that Roche delayed in moving from the concentrated dosage form of the injectable benzodiazepine sedative product (midazolam), approved in December 1985, to the more dilute concentration, introduced in 1987, despite knowledge of serious side effects and deaths associated with the higher strength formulation of the sedative. "Based on spontaneous reporting of serious cardio-respiratory events associated with Versed," Roche stated, "there is no evidence to indicate any difference between the 5 mg/ml and the lower 1 mg/ml concentrations." Roche said also that it has complied with all reporting requirements. HRG Director Sidney Wolfe, MD, wrote FDA Commissioner Kessler on July 31 requesting that FDA open a new investigation of Versed. Enclosed with the Wolfe's letter are nine company documents discussing Versed, including internal Hoffmann-LaRoche memos and correspondence between the U.S. unit and the headquarters office in Basle, Switzerland and the firm's U.K. subsidiary, Roche/Welwyn. The HRG letter contends that "there is evidence that these documents have been criminally withheld" from FDA. A press conference held July 31 by HRG was briefly interrupted by a call from Kessler to Wolfe to acknowledge receipt of the information. With the flurry of renewed attention, Rep. Weiss (D- N.Y.) is also expected to request a Justice Department investigation of whether information was withheld from FDA, although the House Government Operations/Human Resources Subcommittee chairman has not yet formally done so. Weiss held a hearing in May 1988 to look into whether Roche provided FDA with all relevant Versed safety data. At that time, Weiss alleged that European reports linked six deaths to Versed during 1984 and 1985, and those cases should have been reported to FDA. HRG's Wolfe suggested that the 5 mg/ml formulation was pushed in an effort to appeal to physicians using a similar formulation of Roche's own injectable Valium, which was approaching patent expiration. However, HRG says that physicians were not informed when data became available that the product was more potent than expected and difficult to titrate. Wolfe noted also that Versed was frequently used in procedures such as oral surgery and endoscopy where a patient is given "conscious sedation" but an anesthesiologist is not always present. By the time the more dilute formulation was launched, HRG said, "there were more than 20 U.S. deaths from cardiac or respiratory depression which had been reported to the FDA, meaning that the actual number was probably three times higher" due to the frequent underreporting of adverse events. The documents were provided to HRG by an individual described as a former Roche employee; Roche said they are authentic but "stolen" from the company. The earliest is an April 1980 letter from the U.S. unit to Basle, stating that safety issues will be "of greatest concern when midazolam becomes available for direct intravenous administration for minor medical and dental procedures in situations in which there usually is neither resuscitation equipment available nor personnel trained in the use of these measures. There is clear agreement that these problems can best be avoided by prompting the use of a dilute intravenous solution of midazolam." The other documents span the years 1983 through 1988, including a 1984 memo between Roche/Welwyn and the U.S. office stating that the British "success at winning" business away from competing injectable sedatives "has often been short-lived as users experience difficulty in titrating the dose of Hypnovel, resulting in oversedation. In some cases this has led to prolonged apnea and death." Hypnovel is the British trade name for midazolam. None of the other documents specifically mentions deaths linked to Versed; the others discuss oversedation and respiratory depression generally but do not discuss details of individual cases where these occurred. In its response, Roche says it "complied with all FDA reporting requirements concerning adverse drug events associated with the use of Versed. This includes both domestic and foreign adverse drug reaction reports associated with the drug, whether or not they are considered to be drug-related, during clinical trials and after market introduction." Routine, general discussions by company employees concerning products need not be reported, a company spokesperson pointed out. Overall, HRG's allegations are "false, misleading, and medically unjustified," Roche maintained in a separate July 31 statement. According to the company, there have been fewer than half a dozen product liability lawsuits concerning Versed. Roche states that the drug has been used in more than 50 mil. patients and the 5 mg/ml formulation "continues to be a formulation preferred by many physicians." A company spokesperson said the two strengths presently are used about equally as often in the U.S. Much of the recent flurry of news reports on Versed has focused on whether Roche bowed to pressures from its Swiss parent to minimize safety concerns about the concentrated formulation. Those suggestions are based in part from a 1988 analysis prepared for Roche by the law firm Arnold & Porter. The memo reviews a series of events suggesting Roche/Nutley favored early introduction of the 1 mg/ml formulation in contrast to Basle's preference for the stronger formulation. But subsequently, "new data were presented to completely reverse Nutley's opinion," the Arnold & Porter memo continues. "Nutley's safety concerns about apnea and respiratory depression were dismissed because apnea had been found to occur less than with thiopental . . . The new data leading to the change in opinion were from use in induction of anesthesia, even though the safety concerns had been expressed in the context of conscious sedation as well as induction." It adds: "One interpretation possible from these documents is that Roche/Nutley disregarded its own concerns from safety of the drug in favor of the marketing and political pressure from Roche/Basle." Roche's July 31 statement asserts: "It is absolutely wrong to suggest that potential safety concerns were overruled by marketing considerations in the development and marketing of Versed. As a reputable company, Roche would not knowingly market a prescription drug that may put patients are risk."

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