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Executive Summary

TOPICAL CORTICOSTEROID BIOEQUIVALENCE TESTS: CHROMAMETER USE ENCOURAGED by a July 1 interim guidance prepared by the FDA Office of Generic Drugs' Bioequivalence Division and Division of Anti- Infective Drug Products. Current bioequivalence testing uses human observers to evaluate skin blanching. "In an era with increasingly sophisticated methods to detect changes in light, temperature, pressure and other physical and chemical changes, the use of a human observer to assess the magnitude of a pharmacologic effect becomes increasingly unacceptable," the document says. "Sponsors are therefore incorporate the use of a chromameter into their vasoconstrictor assay bioequivalence study designs to be used concurrently with visual scores." The content of the interim guideline follows closely the outline presented by OGD to an industry workshop in March and to FDA's Dermatologic and Generic Drugs Advisory Committees in April. The July 1 release of the guidance meets the timetable set by OGD Director Roger Williams, MD ("The Pink Sheet" March 30, p. 19). The guidance recommends modifications to the current standard bioequivalence test, the Stoughton-McKenzie vasoconstrictor assay. As previously described by Williams, those modifications include determination of a dose response by varying either the strength, duration of treatment, or skin area tested. The guidance includes a sample 36-patient two-day trial protocol. "Despite expectations that the current vasoconstrictor assay can be validated and assessed according to modern standards," the guidance says, "scientists in the Divisions of Bioequivalence and Anti-Infective Drug Products also believe that a measure of bioequivalence based on the vasoconstrictor assay will not be sufficient as a single test and should be supplemented by other studies." Proposed supplementary studies include "dermatopharmacokinetic studies" of the penetration of the corticosteroid into the skin and in vitro release analysis. A second July 1 guidance prepared by the Division of Bioequivalence addresses statistical procedures for standard two- treatment crossover design bioequivalence trials. The guidance stems from recommendations of the Generic Drugs Advisory Committee in September ("The Pink Sheet" Oct. 7, 1991, p. 7). The statistical guideline addresses three specific topics: logarithmic transformation of pharmacokinetic data, sequence effect and outliers. In keeping with the advisory committee's suggestions, the guideline "recommends that the pharmacokinetic parameters AUC [area under the concentration curve] and C[max] [peak drug concentration] be log transformed." The guidance also sets conditions for handling sequence effect and outliers. * OGD also released an analysis of its new criteria for issuing refuse-to-file letters for ANDAs that are not complete at the time of submission. The division looked at 35 letters issued between December and May and found that the top reasons for refusal to file were "no executed batch records" and "no authorization of a U.S. agent for the [drug master file]," with nine citations apiece. Overall, the division lists 22 different reasons cited a total of 77 times in the 35 letters. Other top reasons for refusal-to-file were "no certificate of analysis for ingredients" and "no master production batch records."

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