KAY-FRIES' WITEPSOL COCOA BUTTER SUBSTITUTES STUDY OBJECTIVE should be better defined, FDA OTC Div. Director William Gilbertson, PharmD, told the company in a Feb. 3 letter. "Clarification is needed as to whether the objective is to demonstrate that certain grades of Witepsol are Category I protectants or that certain grades behave like cocoa butter," he explained. "If the objective is the former we do not see the necessity of having a cocoa butter treatment group. If the objective is the latter we see no reason for untreated control" Gilbertson noted the agency would accept two alternative means for establishing efficacy as an anorectal protectant: a demonstration that "specific grades of Witepsol are as effective as cocoa butter" or test data based on guidelines recommended by the OTC Hemorrhoidal Panel. The OTC division directed also said FDA questions "the need for 18 grades of Witepsol." With "the same number of subjects but fewer grades, the study would be logically simpler and have greater statistical power," Gilbertson observed. The FDA letter was in response to a proposed protocol submitted by Kay-Fries in August ("The Pink Sheet" Sept. 5, T&G-9). The firm proposed to assess efficacy by measuring electrical resistance to the skin immediately following application of the substitutes and one half hour later. In his letter, Gilbertson questioned why the "initial measurement of skin resistance [is] taken after the application rather than before." He also asked "what is the purpose of the pretreatment measurements?" Gilbertson took issue with the company's assertion that the ratio of the change in resistance reflects effectiveness "with almost no effects of initial moisturization levels." Noting that "the corresponding ratio for the transepidermal moisture loss does not appear to be independent of the initial level," Gilbertson asked: "Why should the ratio of the change in skin resistance to the initial skin resistance be independent of the initial resistance level?" The FDAer also asserted that because "half of the treatment by site combinations will be tested on two subjects [and] half on one subject," the study design is "not balanced." As a result, Gilbertson said, "if there is a site effect, the difference between two treatment means will not estimate the true difference between the treatments." He also said the proposed statistical test, the Newman-Keuls procedure, "would not be valid." This "problem could be avoided," he advised, "if the number of subjects were an integral multiple of the number of treatments, with the treatments arranged so as to form a number of complete Latin Squares."
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