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SUPERPOTENT TOPICAL CORTICOSTEROID ANDAs BASED ON VC ASSAYS

Executive Summary

SUPERPOTENT TOPICAL CORTICOSTEROID ANDAs BASED ON VC ASSAYS should be denied FDA approval, Glaxo maintained in a June 29 petition to the agency. The petition, submitted by Glaxo's Washington, D.C. attorneys Arnold & Porter, requests "that no ANDA for [a] generic version of superpotent topical corticosteroids be approved when that application contains only a VC [vasoconstrictor] assay, or only a [VC] assay in conjunction with an [Hypothalmic-Pituitary-Adrenal] Axis Suppression Test as the means to demonstrate bioequivalence with an innovator product." Innovator of the superpotent corticosteroid Temovate (clobetasol propionate), Glaxo objected to the Office of Generic Drugs' new policy allowing topical corticosteroid ANDAs submitted before July 1, 1992 to be reviewed under the old standards of a single-point vasoconstrictor assay ("The Pink Sheet" July 6, T&G- 5). In addition, Glaxo requested "that FDA not approve any ANDA for any superpotent topical corticosteroid product that has not undergone clinical trials to establish bioequivalence...until FDA establishes bioequivalence guidelines outlining well-validated bioequivalence tests for such products and the pending ANDA complies with such guidelines." Glaxo argued that FDA "has acknowledged that there is no established method of determining the bioequivalence of topical corticosteroids and that [the agency] is searching for an appropriate methodology." The company maintained that the agency should require clinical testing for generic superpotent topical corticosteroids just as the agency requires of generic topical antifungal products. The Glaxo petition focuses on superpotent topical corticosteroids such as clobetasol, not regular potency products, because the superpotent products pose certain concerns such as suppression of the HPA Axis and scarring of the skin, the company said. "Because topical corticosteroids that are absorbed may be recognized by the body as endogenous cortisol, the HPA Axis may react by reducing the body's own cortisol production, thus affecting the stress response of patients," the petition maintains. Potent corticosteroids may also cause thinning of the skin that can lead to permanent scarring, the company said. "Bioequivalence may only be shown by a combination of tests that would include, at a minimum, clinical studies comparing the new formulation against the approved innovator formulation and, for the more potent topical corticosteroids...a crossover HPA Axis study," the petition states. The petition also raises the issue that FDA appears to require different tests for product formulation changes sought by generic firms and supplements filed by NDA holders. Glaxo cited FDA's response to an ANDA suitability petition filed by Kross, Inc. seeking to submit an ANDA for clobetasol propionate .05% lotion rather than cream. FDA asked Kross to test for HPA Axis suppression and conduct a vasoconstrictor assay, Glaxo noted. For a similar type of formulation change filed through the NDA process, Glaxo pointed out that FDA required animal and human toxicity studies, a multi-point vasoconstrictor assay, an HPA Axis Suppression crossover test, and a 30-patient Phase III clinical trial. The innovator company contended that its "line extension situation [for Temovate] is directly analogous to formulation of new generic products." Therefore, changes in topical corticosteroid formulations by generic applicants warrant "full testing" according to the new drug division standards, Glaxo argued. "The Office of Generic Drugs should use the same requirements, not lesser ones," the petition maintains.
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