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Executive Summary

Bristol-Myers Squibb's Betapace (sotalol) anti-arrhythmic beta-blocker was recommended for approval by FDA's Cardio-Renal Advisory Committee at its Dec. 13 meeting. The vote for the approval recommendation was 5-3. The relatively close vote and concerns about the status of results from a major ongoing NIH-sponsored study, however, appear to temper the approval recommendation. The advisory committee made its decisions contingent on confirmation of existing clinical results by interim data from the multicenter ESVEM trial. Members of the advisory committee were unanimous in praising Betapace's performance as an anti-arrhythmic agent in several early small-scale trials conducted by the company. "I'd love to be able to write a prescription starting tomorrow," commented Edward Pritchett, MD, Duke University Medical Center. Three different studies -- a comparison of Betapace with procainamide, a study of the effect of Betapace on refractory arrhythmias, and the company's dose ranging trials -- have all demonstrated that the drug can reduce the rate of inducible ventricular arrhythmias by as much as 35%. However, the committee agreed that the database provided by these trials was too limited to justify a clear approval recommendation. The key to final approval, the committee believed, will be the results from the ESVEM (Electrophysiologic Versus Electrocardiograph Monitoring for Selection of Antiarrhythmic Therapy for Ventricular Tachycardia) Trials. ESVEM is a National Heart, Lung, and Blood Institute-sponsored multicenter trial comparing the effects of Betapace and six other anti-arrhythmic agents on patients suffering from ventricular tachycardia. The study has been underway for more than five years, has treated over 1,000 patients, and is expected to reach its conclusion sometime in 1992. Interim results are expected sooner. "ESVEM is the most critical piece of information about [Betapace's] approvability," said Peter Kowey, MD, committee reviewer and Chief of the Division of Cardiology at Lankenau Hospital in Philadelphia. "I don't think we have much else...the other studies are corroborative," he said. The results of ESVEM to date are favorable to Betapace. Response rates (measured in terms of non-inducibility of tachycardia) were unusually high in the Betapace arm of the trial, with 38% of the 208 Betapace recipients becoming non-inducible within four weeks. The average ESVEM response rate for all other drugs -- including procainamide, quinidine, imipramine, and mexiletine -- was only 21%. The next best drug, an unidentified compound administered to 198 patients, attained a 24% non-inducible rate. In addition, Betapace patients involved in the study have demonstrated the lowest incidence of treatment withdrawal and the lowest rate of recurrence of arrhythmias. The question of how to incorporate data from the ESVEM trial into the decision to approve became a central issue of debate at the Dec. 13 committee meeting. Ray Lipicky, MD, director of FDA's Cardio-Renal Drugs Division, attempted to discourage committee members from making a recommendation based on interim ESVEM trial data. He described the incomplete study as "nonexistent" in the eyes of FDA. Kowey and Pritchett also claimed that accepting interim data would be setting a dangerous precedent. Defending the minority opinion, which advocated withholding approval of the compound until the completion of the ESVEM trial in 1992 Kowey said: "I think we've tried to set a standard for what is and what is not approvable, and the standard currently is that we'd like to see some information relating to outcome. I don't think that that's an unreasonable expectation...It would be inconsistent with what we've said before to say that we're willing to accept [a trial] before its done." The majority of committee members favored approval of Betapace if satisfactory interim data concerning study protocols were made available upon completion of ESVEM enrollment in early 1991. The committee was interested in a breakdown of which ESVEM patients had been tested with EKG monitoring and which in the PES labs. The type of test procedure is believed to influence significantly a patient's rate of responsiveness. Despite evidence that the drug is a negative inotrope, the committee did not recommend special precautions on labeling. Betapace patients have a 4% mortality rate. No special warnings concerning combination therapies were suggested. The committee did suggest that more information be made available in this area. At present, only digitalis/Betapace combinations have been investigated. Taken in combination with digitalis, the drug has produced no significant side effects. The committee's single safety concern with Betapace involved appropriate dosing of the drug. Several committee members suggested that the high incidence of pro-arrhythmias evident among Betapace patients could be attributed to the extremely high dosing ranges used to test the drug.

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