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P&G PEPTO-BISMOL CLINICAL STUDY IN PEDIATRIC DIARRHEA

Executive Summary

P&G PEPTO-BISMOL CLINICAL STUDY IN PEDIATRIC DIARRHEA patients will focus on establishing efficacy of low dose Pepto-Bismol (bismuth subsalicylate) in approximately 260 three-to-six year olds with acute nonspecific diarrhea. At a Nov. 23 "OTC feedback" meeting, FDA gave Procter & Gamble the go-ahead for its proposed double-blind, placebo-controlled multicenter trial supporting the use of bismuth subsalicylate for OTC antidiarrheal use in children. To date, sites have been identified in Venezuela and Mexico, with additional centers to be named in the U.S., P&G says. P&G initially proposed a study protocol involving children aged three-to-12 years old. However, at the urging of FDA, the company agreed to limit the trial to three-to-six year olds. FDA Gastrointestinal & Coagulation Blood Products Division Director Stephen Fredd, MD, explained: "Ideally, I'd like to have data on all the groups, but if I had one question to answer," it would be whether "the three-to-six age group" can be treated effectively. After we "make sure that works," Fredd continued, "we can extrapolate that to the other" age groups. Office of Drug Evaluation I Director Robert Temple, MD, concurred, stating that "if you don't want to change the study size, then to get a definitive answer on the three-to-six [year old(] group, you have to make all of the people three to six or upsize the study." FDA's Gastrointestinal Drugs Advisory Committee recommended in July 1991 that bismuth subsalicylate be included in the antidiarrheal monograph as Category I (safe and effective) for treatment of diarrhea in adults but would not support use of the product in a pediatric population based on a statistical extrapolation of the data in adults ("The Pink Sheet" July 29, 1991, p. 3). Bismuth subsalicylate was listed in the 1986 tentative final monograph for OTC antidiarrheals in Category III (not proven safe and effective). An outside scientific panel convened by P&G at the request of the agency concluded that basing bismuth subsalicylate dosing for the six-to-12 year old population on a statistical extrapolation from the adult dose is "rational and supportable." However, the panel suggested that extrapolating a dosage for three-to-six year old children based on the adult dose could lead to use of too low a dose to be effective. FDA told P&G earlier this year that a double-blind, placebo- controlled study in pediatric subjects with acute nonspecific diarrhea would be necessary because of a paucity of controlled studies on the three-to-12 age group ("The Pink Sheet" Aug. 17, T&G- 13). * At the Nov. 23 feedback meeting, FDA okayed P&G's plans to admit patients into the treatment phase of the study after up to 48 hours of diarrhea contracted in their home area, as opposed to "travelers' diarrhea." After determining whether rehydration is necessary, subjects will be randomized and treated for two days. The Pepto- Bismol dose for each patient will be determined on a mg/kg basis. Patients will be followed for three days after treatment to determine outcome. According to a P&G letter to FDA dated Nov. 11, effectiveness will be determined by duration of diarrhea, defined as "the time from initial dose to passage of the last unformed stool prior to a formed stool during the observation period, or until the last unformed stool prior to the beginning of a 24-hour period when no further unformed stools are passed." Clinical significance is defined as a "30% reduction in duration of diarrhea." Duration of diarrhea prior to dosing will not be considered in estimating the overall duration of diarrhea but will be examined "for possible effect on duration of diarrhea, stool frequency, and stool consistency post-treatment," the letter states. FDAers at the feedback session emphasized that duration of diarrhea be monitored closely. Although P&G reps noted that diarrhea in pediatric populations does not tend to last more than 48 hours after treatment, Fredd suggested that "if we learn from this study that diarrhea lasts five days" or longer, the company should consider conducting "dose duration" studies in the future. In response to FDA inquiries, P&G also said that it would keep close tabs on whether patients are rehydrated to determine if there is any difference in clinical outcome. In addition, P&G and FDA agreed at the meeting that a separate pharmacokinetic study should not be conducted "at this time," referring to a previous FDA request that the company provide information "on studies in pharmacokinetic modeling (based on the disposition of bismuth and subsalicylate) utilizing doses in infants." P&G also is pursuing use of Pepto-Bismol for preventing traveler's diarrhea. In April, FDA rejected P&G's request to add a traveler's diarrhea prevention claim for bismuth subsalicylate to the monograph for OTC antidiarrheal products ("The Pink Sheet" May 4, T&G-1).
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