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CHOLYBAR's TRIGLYCERIDE DIFFERENCE

Executive Summary

CHOLYBAR's TRIGLYCERIDE DIFFERENCE v. QUESTRAN in Warner-Lambert's bioequivalence study resulted from a dosing bias in one center, W-L maintained in a March 7 letter to FDA. Warner-Lambert submitted the letter in response to Bristol-Myer's Dec. 9 citizen's petition requesting that FDA withdraw approval of the Cholybar ANDA pending further studies by the company. The Bristol-Myers petition alleged that the bioequivalence of the two products has not been established, since Warner-Lambert's studies show higher increases in triglycerides and very low density lipoproteins with Cholybar ("The Pink Sheet" Jan. 2, T&G-9). The Warner-Lambert trial was a four-week randomized crossover study comparing its Cholybar to B-M's Questran. Six centers completed the study. However, Warner-Lambert said that patients in one center were not given the required doses of Questran, receiving less cholestyramine than the Cholybar group. While the medical reviewer in FDA's metabolism division excluded this center in her analysis of the data, the reviewer from the bioequivalence division included the center, thereby skewing his data, Warner-Lambert maintained. The analysis by the bioequivalence division reviewer determined that "on a six-center, four week basis, the difference in triglyceride elevation was significantly different" with an adjusted mean percentage change of 40.5% for Cholybar and 18.2% for Questran, the firm noted. However, Warner-Lambert maintained that this result is "inconsequential," because the reviewer "did not take into account the statistically significant center interaction [and] it is generally recognized that there is a dose related and temporally variable increase in triglycerides with cholestyramine resin use." Warner-Lambert pointed out that the five-center analysis shows "there was no statistically significant difference in elevation of triglycerides." The letter asserts that "additional statistical analyses of triglycerides confirms that there is no difference between the two products" in that "median values for triglyceride elevations were virtually identical (Cholybar 21.5 mg/dl and Questran 21.6 mg/dl)." In response to Bristol-Myers' argument that Cholybar may be unsafe because of the higher rate of gastrointestinal adverse effects among the patients taking Cholybar, Warner-Lambert submitted an analysis of adverse events for all 98 patients exposed to cholestyramine to FDA. "The differences in adverse events during crossover and in dropouts do not mean, as Bristol contends, that patients are at a higher risk of 'severe gastrointestinal complications' with Cholybar," the company stated. Warner-Lambert attributed the differences to several possible biases: "more patients were exposed to Cholybar during crossover; Cholybar users who dropped out during initial treatment would likely have had a similar reaction to Questran had they been crossed over; and 60.2% of the patient population were prior powdered resin users . . . these patients were more likely to be intolerant of a new dosage form."
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PS015334

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