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TOPICAL CORTICOSTEROIDS BIOEQUIVALENCE TEST METHODOLOGY IS UNDER REVIEW BY FDA; TWO STUDIES BY SAN DIEGO RESEARCHER STOUGHTON SHOW BRAND/GENERIC DIFFERENCES

Executive Summary

FDA is reviewing the vasoconstrictor tests for showing equivalence between different brands and formulations of prescription topical corticosteroids. The agency is looking at the test methodology in the wake of two sets of results by the developer of the test, University of California, San Diego researcher Richard Stoughton, MD. On March 9, Stoughton presented to the agency the results of a study evaluating the equivalence of generic and brandname formulations of corticosteroids. Attending the meeting from FDA were representatives from the Office of Drug Standards, the Division of Generic Drugs and the Division of Anti-Infective Drugs. The study results discussed on March 9 were from a second study on the subject by Stoughton. FDA had requested that Stoughton do a follow-up to confirm the results of a study published in the October 1987 issue of the Archives of Dermatology. In the published study, brandname corticosteroid formulations of triamcinolone acetonide, fluocinolone acetonide, and betamethasone valerate were compared to their generic counterparts. Vasoconstrictor assays were used to evaluate the clinical activity of both the cream and ointment formulations. Thirty volunteers were used for each group evaluation, with formulations applied to forearms on a randomized basis. The creams and lotions were left on for 16 hours and later washed off. Two hours later the readings were taken on a blind basis by an investigator and quantified as: 0, no vasoconstriction; 1, mild vasoconstriction; 2, moderate; or 3, intense vasoconstriction. Stoughton's found that Squibb's "Kenalog cream 0.1% was significantly more potent than any of the generic triamcinolone creams. One of the generic triamcinolone acetonide creams [Geneva] at 0.1% was inferior to all the other generic triamcinolone acetonide 0.1% creams." Lederle's Aristocort A ointment 0.1%, the study found, "was dramatically superior to the two generic triamcinolone acetonide 0.1% ointment formulations [Goldline and Rugby]." Schering's Valisone cream was "more potent than all the generic betamethasone valerate 0.1% creams [but] there was no difference between Valisone ointment 0.1% and the two generic betamethasone valerate ointments [Fougera and URL]." Syntex' Synalar cream fluocinolone acetonide 0.025% was found stronger than Rugby's cream but equivalent to the other generics containing the same concentration. Stoughton reported no difference in potency between Kenalog 0.025% cream, Kenalog 0.1% cream and Kenalog 0.5% cream. He concluded that "the lowest concentration of Kenalog cream (0.025%) was statistically superior to all the generic triamcinolone acetonide 0.1% creams." FDAers who met with Stoughton on March 9 conferred on March 21 to discuss the researcher's second corticosteroid study. Agency staffers believe it will take about three months to analyze Stoughton's work and come up with recommendations. One issue for FDA to decide is whether the vasoconstrictor assay is the appropriate test for the comparison of therapeutic equivalence of topical corticosteroids. Stoughton developed the vasoconstrictor assay as a potential indicator of clinical activity. Last September FDA adopted Stoughton's test as part of the criteria for ANDA vehicle changes. At that time, FDA decided that topical corticosteroid vehicle changes would be ANDA-able, if the companies perform a biostudy in patients and a vasoconstrictor assay for each change ("The Pink Sheet" Sept. 21, T&G-8). Previously, a full NDA was required for any change in dosage form.
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