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TOPICAL CORTICOSTEROID INTERIM BIOEQUIVALENCE GUIDANCE SHOULD BE READY BY JULY 1; PRE-APRIL 1992 GENERIC APPLICATIONS TO BE EVALUATED UNDER EXISTING STANDARDS

Executive Summary

An interim bioequivalence guidance for topical corticosteroids should be ready sometime around July 1, 1992, FDA Anti-Infective Drug Products Division Dermatological Group Leader Susan Alpert, MD, told industry members at a March 27 conference on bioequivalence issues related to topical corticosteroids. The interim guidance, which will spell out the assays needed to demonstrate bioequivalence between generic and innovator topical corticosteroid products, has been anticipated since March 1990 ("The Pink Sheet" April 16, 1990, T&G-10). While the imminent issuance of interim guidelines should be an encouraging step forward for generic topical corticosteroid makers, definitive requirements still appear to be far off. FDA Office of Generic Drugs Director Roger Williams, MD, noted: "We are no where near ready for any kind of final guidance." Williams and Alpert will discuss assays to be included in the interim guidance at upcoming meetings of the Dermatological Drugs Advisory Committee on April 10 and the Generic Drugs Advisory Committee on April 24. At the generics advisory committee meeting, Alpert said FDA will propose that ANDAs for topical corticosteroids submitted between March 1990 and April 1992 should be evaluated by the current set of standards for bioequivalence, i.e. the single-point vasoconstrictor assay developed in 1987 by University of California-San Diego researcher Richard Stoughton, MD. Generic topical corticosteroid drug applications with studies completed before July 1, 1992 also will be evaluated under the old standards. If any of the ANDAs from either of these categories are deemed nonapprovable, they will be required to meet the new interim standards, Alpert said. Studies begun after July 1 will be assessed by the new standards as well. The interim bioequivalence guidance will focus primarily on pharmacodynamic studies, Williams told the group. FDA is looking at multiple-point methods to replace the Stoughton assay, which provides information based on a single skin-blanching measurement taken two hours after the drug is washed off the skin. The drug remains on the skin for 16 hours. Of the Stoughton assay, Williams said: "You are getting just too limited data to make a statement that we would find compelling in terms of saying one product is equivalent to another." To achieve multiple endpoints, the pharmacodynamic studies proposed by Williams would require either variations in dosage strengths, duration of drug application or areas of application. Dose strength can be varied by diluting the product with vehicle (e.g. cream without active ingredient), Williams said. Duration can be altered by varying times of application and area may be changed by applying the same strength over different areas of skin. The Office of Generic Drugs is being assisted in its analysis of these various methods by University of Utah researchers Jerry Kruger, PhD, and Lynn Pershing, PhD. One University of Utah experiment in dilution of dose strength yielded a good dose-response relationship and peak measurements of vasoconstriction that fit the curve of the FDA's preferred maximum effect model. In the study, .005%, .01%, .025% and .05% strengths of betamethasone dipropionate each were applied to the skin for six hours. At the end of the six-hour period, the applications were washed off and a skin-blanching (vasconstriction) measurement was taken 24 hours later. Although the experiment showed a good dose-response relationship, Williams noted that the dilution method poses some problems. He maintained that "if you end up diluting an innovator product in a generic vehicle you would end up with something that looks very much like the generic product." Williams said that "dilution of drug in a vehicle...right now poses a serious problem to this particular methodology" and for this reason "[FDA] is not considering it as [the agency's] first choice." A second strategy outlined by Williams involves the application of drug over different time periods. In an example provided by the University of Utah researchers, betamethasone dipropionate cream .5% was applied to skin for .5, 2, 6, and 16 hours. This method "needs further work," Williams noted, since it did not yield an optimal dose-response relationship. The OGD director suggested that shorter durations of application may yield better data. "It may be that you have to go down to 10 minutes to develop this duration of a dose-response relationship." The variation in duration of topical drug application method "right now if I have to say is probably our first choice," Williams said, but he added that "we will need a lot of confirmation." The third strategy, which would involve varying the areas where the drug is applied to the skin, has not yet been explored, Williams reported. "That is some set of data we need to develop," he noted. Williams suggested to the audience: "Maybe we can work with you, industry, to make that possible." The generic drugs officer director indicated that FDA may ask different companies to volunteer to conduct each of the types of studies to help verify the utility of the methods. FDA is also considering using a Minolta chromameter as a more objective way to measure vasoconstriction, or skin blanching. FDA Office of Generic Drugs Acting Deputy Director for Science Vinod Shah, PhD, presented FDA's thinking on how to measure drug uptake and elimination from the skin. Dermatokinetic studies conducted by the University of Utah for FDA, Shah said, involved applying topical drug for six hours and then progressively stripping thin layers of skin with adhesive tape to collect and analyze the concentration of drug absorbed. Shah also outlined an in vitro release method that would use an apparatus called the Franz diffusion cell to measure diffusion of a topical preparation across a synthetic membrane. He said that such a system could serve as a quality control test to assure stability and quality of products and ascertain the effects of manufacturing and process changes. Williams noted during the meeting that the Title I regulations implementing the Waxman-Hatch Act would issue "very soon." The regulations contain a requirement that "the ingredients in a topical product have to be identical between the generic form and the innovator form," he said. The regulations currently are under review by the Office of Management & Budget.

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