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CIBA-GEIGY's LOPRESSOR ANTI-ARRHYTHMIC DATA

Executive Summary

CIBA-GEIGY's LOPRESSOR ANTI-ARRHYTHMIC DATA needs further analysis, and possibly additional studies, before a decision on approvability of the drug can be made, FDA Office of Drug Evaluation I Director Robert Temple, MD, determined at FDA's Cardio-Renal Drugs Advisory Committee meeting Nov. 3-4. The committee was to evaluate approvability of the new indication. However during the course of the meeting the committee raised several questions about the firm's two pivotal studies. Based on the panel's questions, Temple advised that further analysis of existing data would be needed before the committee could recommend whether or not additional studies might be necessary. Specifically, the committee and FDA were concerned that the confidence intervals in a positive controlled trial (Lopressor v. propranolol) were insufficient to show Lopressor (metroprolol) significantly better than placebo. The committee was also concerned that the dose of propranolol, the approved 40 mg anti-arrhythmic dose, was not large enough given recent studies showing that a larger dose is necessary for anti-arrhythmic effect. In addition to concerns that FDA's two-study requirement would not be met if the active controlled trial turned out to be unsupportive, the committee also cited the small size (30 patients) of the placebo-controlled trial as an issue. "I have a feeling that we need to come back to you with a surer analysis of the effectiveness question on ]arrhythmia[ rates before we ask you these questions ]about approvability[," Temple said. Noting that a Swedish mortality study with Lopressor might also yield efficacy data on arrhythmias, Temple said: "We need to form an impression and provide an analysis of the Stockholm study . . . and I don't see how the committee can reach a conclusion on whether it's an effective anti-arrhythmic until we have some agreement on what those studies show." The committee's specific discussion of metoprolol for treating premature ventricular contractions (PVCs) digressed into the larger question of what is necessary for approving a class of drugs like beta blockers, with their established safety record, for an anti-arrhythmic indication. Would the committee "entertain a ventricular arrhythmia indication for something like a beta blocker with a clinical development program that was short of a total new chemical entity anti-arrhythmic development program?" FDA Cardio-Renal Division Director Raymond Lipicky, MD, asked. "The second question is whether it would be adequate to obtain that on the basis of chronic PVC trials in the absence of measuring symptoms." While the committee agreed that it would consider some type of modified approach in evaluating beta blockers for arrhythmias, it voted six-to-one against their approval without symptomatic data. "We will come back to you with a plan and plan it seems to me . . . is to remove all claims related to PVC," Temple remarked. "This needs to be treated quite seriously. Current drugs have no symptomatic data."
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