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Executive Summary

TERFENADINE ANDA STUDIES SHOULD MEASURE QTc CHANGES, MMD MAINTAINS in a Nov. 22 citizen petition filed with FDA. The petition argues that FDA "should amend the terfenadine guidance to recommend a multiple-dose pharmacokinetic/pharmacodynamic crossover study comparing plasma concentrations of terfenadine, the active metabolite and QTc changes." The petition was submitted by Peter Safir of the D.C. firm Kleinfeld, Kaplan and Becker on behalf of Marion Merrell Dow. Marion Merrell Dow's terfenadine (Seldane) patent expires April 15, 1994. The nonsedating antihistamine has been associated with life-threatening cardiovascular side effects (torsade des points arrhythmia). "Due to the unique nature of terfenadine and the very real concern that minute differences in plasma levels can result in QTc prolongation in a few rare patients," MMD contends that generic bioequivalence trials should include electrocardiograph (ECG) comparisons of the change in mean and maximum QTc from baseline. FDA's Office of Generic Drugs has issued a terfenadine bioequivalence guidance recommending a "relatively standard bioequivalence protocol," the petition notes. The OGD guidance recommends one single-dose study in fasted and healthy subjects comparing plasma levels of terfenadine and its active metabolite. believes that the active metabolite (which the company is developing as a follow-on product) is responsible for the clinical efficacy of Seldane and is not associated with cardiovascular abnormalities, while the terfenadine parent molecule causes the side effect. "Marion Merrell Dow believes there is no adequate basis on which a comparison of blood levels of parent terfenadine between Seldane and generic versions, by itself, can assure that compounds will behave similarly in the body," the petition states. MMD points out that QTc prolongation has been seen with very low levels of terfenadine, including instances "where there are no measurable levels of parent terfenadine." The type of bioequivalence study proposed by MMD "will be more efficient to conduct" than the one recommended by FDA, the petition maintains. The use of ECG data means that generic firms would not have to assay very low levels of parent terfenadine, "an expensive and time-consuming process," MMD declared. However, "data from pharmacokinetic studies conducted by FDA show that [QTc] measurements can only be made at therapeutic doses once steady state levels are achieved," the petition adds. Hence, MMD recommends that bioequivalence trials require multiple dose crossover designs to compare data at steady-state plasma levels.

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