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Executive Summary

Knoll's Rhythmonorm (propafenone) is effective in suppressing ventricular arrythmias, but additional data on the dose-response relationship, drug interaction and symptom prevention should be supplied before the drug is approved, FDA's Cardio-Renal Drugs Advisory Cmte. concluded at its July 26 meeting. Cmte. Chairman Jeffrey Borer, MD, New York Hospital-Cornell Medical Center summarized the cmte.'s conclusion that "the drug is clearly an effective agent in suppressing ventricular arrythmias of various types, and therefore is potentially approvable, but that we do not recommend approval at this time because we believe that additional data should be made available to the FDA." Additional data that the cmte. would like to see included with the Knoll NDA, Borer said, would involve the "relationship of plasma concentration to drug effect, both therapeutic and toxic; drug interaction data in addition to what has been presented; clear dose-response relationships in non-selected populations; and data regarding the effectiveness of the drug in preventing the development of symptoms for which the drug was given to prevent." The cmte. concluded that association of the drug with rare or unusual side effects such as agranulocytosis or impotence was not clear, and that post-marketing surveillance would be sufficient to clear up any remaining questions in that regard. Cmte. member Bertram Pitt, MD, University of Michigan, noted that some of the missing data, such as that involving symptomatic improvement "already exists and it just hasn't been presented." Pitt cited the case of Ive's amniodarone: "We really didn't have any better data, and maybe somewhat less data," Pitt said. However, the fact that "there were a number of people who were clearly symptomatic with syncopal episodes and they were well defined, and after administration of the drug the number of syncopal episodes clearly were reduced. . . was one of the things that swayed us" to recommend amniodarone's approval. In regard to the need for additional dose-ranging information, cmte. statistician Lloyd Fisher, PhD, CASS/CAPS Coordinating Center, stated that "it's not a question of rearrangement, but that somebody will have to collect some more data." In its questions to the cmte., FDA noted that the majority of clinical trial experience comes from trials where only patients who responded to propafenone were studied. This does not necessarily represent a serious problem with respect to conclusions regarding drug efficacy, the agency noted, but does not give information about likelihood or response in a general population of patients. Cmte. member Philip Reid, MD, Sinai Hospital, commented that more information was needed on dose-response relationships "which would then permit a dose-range development in a rather unselected, as opposed to a selected population." Reid also maintained that additional information was needed with respect to the relationship of the plasma concentrations/kinetics "to both the desired response and side effects." Cmte. members also pointed to the need for additional evidence concerning drug interactions, particularly with beta-blockers.

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