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This article was originally published in The Tan Sheet

Executive Summary

NDMA ATTAPULGITE STUDY PRIMARY EFFICACY VARIABLES TO BE DISCUSSED at an upcoming meeting between FDA and the Nonprescription Drug Manufacturers Association's Attapulgite Study Group, according to a Nov. 29 letter from FDA to the trade association. Commenting on NDMA's Oct. 18 proposed protocol to study the effectiveness of attapulgite in the treatment of acute non-specific diarrhea, the agency said it "would like to discuss [with NDMA] the optimal selection of a primary efficacy variable(s) in our meeting." FDA also suggested that statistical methods for measuring "multiple endpoints and comparisons for secondary endpoints . . . need to be considered and prespecified." In addition, FDA recommended that "for results comparisons, statistical tests should include confidence limits around the selected value, not simply p values." A date for an OTC feedback meeting on the attapulgite protocol has not yet been set. Because of concerns about the design of the study outlined in the letter, FDA suggested that "the protocol may not be designed to present the best evidence of the effectiveness of attapulgite for treating acute diarrhea." Another potential problem with the protocol -- a single- center, randomized, double-blind, parallel and placebo-controlled comparison of up to 250 subjects suffering from acute, mild-to- moderate non-specific diarrhea -- is the time to first dose, the agency said. Noting that NDMA's protocol would allow 48 hours of diarrhea prior to entrance into the study, FDA pointed out that "if some participants are 48 hours into their illness before beginning treatment, they may have experienced up to 50% of their illness (and be up to 50% improved) prior to study entry." This would cause "variability in the time from onset of diarrhea to the first dose," FDA said. Therefore, the agency concluded, "consideration should be given to stratification of participants by duration of illness prior to study entry." Diarrhea is defined by the protocol as three or more stools per 24 hours. NDMA had requested an expedited review of the attapulgite protocol in order to begin a clinical study to support a Category I (safe and effective) classification of attapulgite in the antidiarrheal products final monograph ("The Tan Sheet" Oct. 25, p. 21). Following an April determination by FDA's Nonprescription Drugs and Gastrointestinal Drugs Advisory Committees that the existing efficacy data do not support attapulgite's classification in Category I, NDMA asked the agency to defer action on the ingredient in the impending antidiarrheal final monograph until additional studies were conducted. However, FDA denied the association's request but said that if "relevant data" were submitted before the final monograph's effective date, action on the ingredient might be deferred while the agency reviews the new data ("The Tan Sheet" Oct. 4, p. 1). FDA also expressed concern about the attapulgite dose administered, particularly that the "maximum number of doses in a 24-hour period needs to be clarified." FDA observed that the protocol had alternately stated that six doses or four doses are not to be exceeded during a 24-hour period. The agency also suggested that NDMA provide an analysis of dose and response, and that "all randomized patients should be analyzed in addition to the evaluable analysis." FDA also recommended that NDMA "clarify assignment of participants who drop out early, are excluded due to positive culture results or take rescue medication." Observing that the protocol allows the use of Lomotil or other medication if relief is not obtained, the agency said that "it is not clear whether patients taking this rescue would exit the study and how they would be counted in the analyses." FDA suggested that, "if possible, no rescue should be offered for most patients." In cases "where a patient is too sick to continue, he or she should exit and be counted as a treatment failure in the intention-to-treat analysis," the agency offered. FDA also declared that "based on the inclusion and exclusion criteria in the proposed protocol, we do not feel that the study is adequately designed to assess acute non-specific diarrhea." One potential problem, the agency explained, is that study participant ages are listed as 12 through 70 years and that "adolescents (ages 12 to 18) and the elderly (ages 60 to 70) represent significantly distinct populations." If both groups are enrolled, FDA continued, a "subgroup analysis must be performed and shown to have comparable results to each other and the overall group." Another suggestion offered by the agency is that the presence of E. coli, Campylobacter and Yersinia should be considered as exclusion criteria in addition to Salmonella and Shigella. Moreover, taking a single oral temperature of more than 40 deg. Fahrenheit "may not be a sufficient screening tool" for the presence of invasive enteric pathogens, FDA concluded. "Miscellaneous" FDA suggestions to NDMA dealt with diary entries, subject demographics and the physical examination procedure. NDMA said that it intends to submit a revised protocol to FDA in the near future that would address some of the concerns outlined by the agency. The revised submission is expected to be provided to FDA prior to a feedback meeting.

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