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Executive Summary

TOPICAL DRUG "LOCAL" ABSORPTION AT SITE OF ACTION is an important parameter to be measured in applications for FDA approval, Schering argues in a May 23 filing with the agency. In the continuing debate before FDA over approval criteria for non-systemically effective drugs (NSEDs), Schering maintains that "with respect to an NSED administered to the skin, two quantities must be determined: (i) the quantity that is locally absorbed at the site(s) of action but not systemically absorbed, and (ii) the quantity that is systemically absorbed." Schering's focus on local absorption counters a test method for topical generic products suggested by a group of manufacturers earlier this year. The generic manufacturers group, which calls itself the Topical Drug Products Task Force, urged FDA to permit the measurement of rate and extent of topical absorption through the collection and assay of "equal amounts" of a generic and the listed product from the skin of a test patient. That assay, the generic firms believe, could determine whether "comparable" amounts of active drug remain in the topical drug to show by inference a similar rate and extent of absorption for the two compounds. The task force submitted its proposal to FDA on Jan. 22 ("The Pink Sheet" Feb. 5, T&G-12). "Because the Task Force's proposed procedure does not measure local absorption at the site of local action," Schering argued, "it does not measure local effectiveness or local safety." As part of its arguments to FDA, Schering commissioned a study of bioequivalence testing for NSEDs by the consulting firm Environ. "A crucial consideration in developing a model of percutaneous absorption is that what needs to be measured is local skin absorption, not absorption into blood after the drug passes through the skin," Environ said. Critiquing current skin tests, Environ stated: "For some topical products, a skin bioassay has been used that is based on a visual cutaneous vasoconstrictive response, known also as the blanching test." Environ faults that test for not measuring mechanism of action. "This test is not a measure of the pharmacologic mechanism of action of these drugs and has not been directly correlated with any measure of rate and extent of drug absorption in humans." A "true measure of pharmacologic response" to topicals applied to the skin, Environ contended, "would require detailed knowledge of the receptor-effector interaction within skin for the various classes of dermal agents. Such knowledge does not currently exist." FDA has been leaning toward requirements of clinical trials for non-systemically effective drugs. For example, in recent antifungal generic guidances, FDA would require a three-way (generic, reference product, vehicle) study for topicals and a two-way (generic vs. reference) study for vaginal antifungals. Schering, which has major products or pending projects in the three of the non-systemically effective drug classes, has pressed its case with FDA to maintain full NDA criteria for generic products coming into those classes. The classes of NSEDs include tropical skin products, inhaled bronchodilating agents, topical ocular products, gastrointestinal products (sucralfate and some lipid-lowering agents) and inhaled anti-protazoals (pentamidine).

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