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This article was originally published in The Tan Sheet

Executive Summary

KAOLIN EFFICACY FINDING BY FDA ADVISORY COMMITTEES QUESTIONED by Public Citizen's Health Research Group in a June 16 letter to FDA Center for Drug Evaluation and Research Director Carl Peck, MD. The letter, signed by HRG Director Sidney Wolfe, MD, and Peter Durie, MD, University of California-San Francisco, recommends that FDA "reject the findings" of the joint OTC Drugs and Gastrointestinal Drugs Advisory Committees "with respect to kaolin" and calls the committees' decision "insupportable" based on the data presented. The advisory committee voted 8-6 in support of kaolin's efficacy as an OTC ingredient for treating diarrhea in adults after considering the results of four clinical trials presented at the meeting ("The Tan Sheet" April 12, p. 1, and April 19, p. 6). In two of the clinical trials conducted by Upjohn (studies #302 and #303), patients in the kaolin group showed improvement in stool consistency and a modest improvement in the length of acute diarrhea episodes. In a third Upjohn trial (study #295), improved stool consistency was found in patients taking kaolin and pectin. At the same meeting, the committee decided by a 14-1 vote that attapulgite has not been shown to be effective for treating diarrhea. HRG questioned the committee's decision regarding kaolin on the grounds that the studies considered by the panel are unpublished and because one of the studies (#302) that served as the basis for the decision was inserted into the deliberations at the last minute and was given only "a very cursory presentation" at the meeting. HRG noted that FDA, in correspondence with Upjohn prior to the meeting, listed "only studies #295 and #303 as 'pivotal information' in the evaluation of kaolin." Thus, HRG concluded that "study #302 was not to form part of the committee's deliberations." HRG also suggested that the panel was given information on the study "perhaps only in summary form" prior to the meeting and that the public was not given sufficient opportunity to review the study. After reviewing study #302, HRG maintained the the randomized double-blind trial comparing kaolin/pectin, kaolin, pectin, and placebo in 232 adults with acute diarrhea "fails to support kaolin's efficacy." HRG contended that "the more notable finding [of the study] is not the minor differences between placebo and kaolin . . . but the major decrease in watery stools between baseline and day 1 consistency in all four treatment arms." HRG pointed out that at baseline subjects in the study experienced 4.6 watery stools per day compared with day 1 results of .98 for kaolin and 1.3 for placebo. "In other words," HRG asserted, "the most remarkable finding was the degree to which diarrhea spontaneously improved, not the minor cosmetic benefit conferred by kaolin." HRG noted that there was no statistically significant difference between kaolin and placebo with respect to duration of diarrhea episodes, mean number of stools or time from drug administration to change in bowel movement consistency. In addition, HRG suggested that because "about one-quarter" of the subjects did not provide a stool sample at each point in the study period, study #302 "is unable to properly assess fluid balance," which HRG argues is "the true outcome of interest for any antidiarrheal drug." HRG also maintained that committee members "ignored" two published placebo-controlled kaolin trials with unfavorable findings (Watkinson et al. and Nalin and Cash). "Even using the 'cosmetic' endpoints relied upon by the committee in making its finding of efficacy (endpoints which we reject)," HRG declared, "both of these studies show no difference between kaolin and controls." The consumer group noted that the two studies were brought up during HRG's presentation but not during the advisory committee presentations. HRG said it could could not understand "why published articles with unfavorable findings are ignored, while unpublished data is used to assert findings of efficacy." Finally, HRG asserted that study #295, which compared a kaolin/pectin combination to placebo, "cannot be used in a finding of efficacy for kaolin alone." The advisory committee wrestled with the issue of stool consistency as a valid endpoint for efficacy before the split vote in support of kaolin's effectiveness. Several committee members felt that an improvement in stool consistency translated into less incontinence and improved quality of life and is, therefore, valid as an endpoint. Speaking at a Food and Drug Law Institute meeting on May 19, OTC Monograph Review Staff Director William Gilbertson indicated that the agency is leaning toward including kaolin in the antidiarrheal final monograph as a Category I (safe and effective) ingredient "with limited claims." He suggested that attapulgite probably will not be included in the final monograph ("The Tan Sheet" May 24, p. 1).

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