ANTIDIARRHEAL STUDY ENDPOINTS SHOULD INCLUDE INDIVIDUAL PATIENT RESPONSES

ANTIDIARRHEAL STUDY ENDPOINTS SHOULD INCLUDE INDIVIDUAL PATIENT RESPONSES, FDA Office of OTC Drugs director-designate Michael Weintraub, MD, suggested during the April 9 joint session of FDA's OTC Drugs Advisory Committee and Gastrointestinal Drugs Advisory Committee. "In the OTC area, when were dealing with studies, we are very much interested in individual patient responses rather than mean changes in a measured parameter such as time and number of stools," Weintraub noted. Commenting on the efficacy studies submitted on behalf of attapulgite and kaolin, Weintraub added: "I think these studies, which of course were done more than ten years ago, did not have that outlook. That's an advertisement for the design [of] future studies for OTC products." The joint advisory committee was asked to consider the efficacy of attapulgite and kaolin as OTC antidiarrheal ingredients. The joint committee voted in support of kaolin's efficacy in adults but did not believe that the attapulgite data was sufficient to support the ingredient's efficacy ("The Tan Sheet" April 12, p. 1). Much of the joint committee's discussion, particularly regarding kaolin, revolved around whether committee members believed that improvement of stool consistency was a valid endpoint. The committee's morning session included presentations of four clinical studies on kaolin and four on attapulgite. In three of the four kaolin studies, hardening of the patient's stool was the only consistent clinical benefit seen. Summarizing the committee's discussion, OTC Drugs Advisory Committee Chairman Randy Juhl, PhD, University of Pittsburgh, noted: "We have hypothesized that getting back to school, getting back to work would certainly be a useful endpoint. We've hypothesized that the one good evaluation from the patients if they feel better is to actually ask the patients. It's a revolutionary idea. It would be a useful endpoint, but we don't have studies that have given us those pieces of information." Several committee members indicated that they wanted to see clinical benefit measured in terms of a shorter duration of illness. FDA Gastrointestinal and Coagulation Drug Products Division Director Stephen Fredd, MD, observed that the joint committee is "trying to get a handle [on] the time the episode ended . . . to see if we're really doing something to shorten the diarrheal period to create . . . some clinically relevant benefit." He added: "It is hard when you only have an effect on consistency and there is nothing else to consider how clinically relevant that might be for a patient as a benefit." G-I advisory committee member Peter Banks, MD, Brigham and Women's Hospital, suggested that a "valuable parameter" from the patient's perspective "might be called 'improvement,' which might be defined as a reduction [in] liquid stool." Banks pointed out that "when a patient is having a certain number of watery stools and is made very uncomfortable, improvement is much welcome and could be a valid endpoint." Several committee members supported stool consistency as a valid endpoint because it could be associated with less incontinence and improved quality of life. G-I committee member Mary Jeanne Kreek, MD, Rockefeller University, declared that "watery stool is not a sign, it's a symptom that is debilitating. It keeps people from working, from going to school, from being able to get out of the bathroom frequently and it also does contribute to fluid and electrolyte imbalance." Based on a general agreement that kaolin's efficacy was supported by data in two clinical trials that showed a stool hardening effect and a mean 10% effect in shortening acute diarrhea episodes, the joint committee voted 8-6 that kaolin was effective in adults. The committee was not so sanguine about the attapulgite data, voting 14-1 against a finding of effectiveness. Commenting on the general quality of the clinical data presented to the OTC advisory committee, Juhl advised OTC drug companies "to pay attention to this nonrecommendation." He also warned that "if your product is one for which the scientific data doesn't hit you between the eyes and knock you off your seat, one that's been debated for the last 20 years, there's a good likelihood that a committee like this will swoop down on your product at some point in time." He predicted that "there is a progression that is going to occur, and regardless of what decisions the agency has subjected your products to in the past, when this group of scientific advisors come in here, they'd like [some] standards." OTC companies marketing attapulgite-containing antidiarrheals will have one year from the publication of the final monograph to reformulate their products should FDA accept the committee's recommendation. Pfizer and Upjohn, which both market products with attapulgite, said they will wait to see if FDA agrees with the committee before they make any decisions regarding active ingredients. Upjohn reformulated Kaopectate with attapulgite instead of kaolin/pectin after the TFM, in April 1986, placed attapulgite in Category I (safe and effective) and put kaolin/pectin in Category III (safety and efficacy data insufficient to permit classification). During the meeting, the Nonprescription Drug Manufacturers Association presented a voluntary labeling change for attapulgite products. Labeling for attapulgite-containing products already includes the statement, "Do not use for more than two days unless directed by a doctor." Under NDMA's voluntary initiative, "this statement will be the first warning listed and printed in all capital letters to give it prominence." The new labeling will include additional language: "Do not use if diarrhea is accompanied by fever or if blood or mucus is present in stool. Do not use in infants or children under three years of age unless directed by a doctor. If you are taking prescription medicine, consult your doctor before taking this product." The joint committee agreed that FDA should not require information on oral rehydration therapy in OTC antidiarrheal labeling. Calling the ORT/OTC debate "semantic," Gastrointestinal Drugs Advisory Committee Chair Rosemarie Fisher, MD, Yale University School of Medicine, maintained that "it's a matter of whether we're saying that the oral rehydration solution is for treatment of the diarrhea, which it is not [in] itself; but is for the complication of the diarrhea, which is the dehydration." "It seems that what we're looking at with the clays that we've seen today is for the comfort level . . . quality of life standard and the ability to get back to work in a non-life-threatening, mild, self-limited, acute diarrheal episode," Fisher continued. She added: "I would hope that we're not going to give every adult who develops a little bit of G-I virus [advice to] go out there and start drinking oral rehydration solution instead of taking something else . . . to get [them] back to work or let [them] sleep through the night." Columbus (Ohio) General Hospital Pediatric Gastroenterology Chief Juhling McClung, MD, told the committee that the "majority of children in the U.S. have viral diarrhea" and that "ORT does not treat viral diarrhea." McClung added that ORT "must be directed to the proper patient population"; specifically, children with severe diarrhea who "require skilled observation and advice for all the parts of their illness" in a "controlled environment." McClung asserted that "the primary treatment for about 95% of all children with diarrhea [in the U.S.] is to make sure that they receive adequate and wholesome nutrition throughout the illness. Oral rehydration therapy and antidiarrheals are of little significance to them getting well." The joint committee decided that neither kaolin nor attapulgite have been proven safe and effective in children, though there was some question about where to draw the line in labeling between children and adults. OTC committee member Marcus Reidenberg, MD, Cornell Medical Center, New York City, suggested that the committee define "child" as being under the age of six because the studies presented to the committee showed that most deaths occurred before age six. Reidenberg said he believed that "the decision that age 12 receive the cutoff is too old." "For this particular, highly focused, narrow mandate, we can say whatever we want because the database says that our data -- 12 and under, under 12, and 12 and over -- [allows us to] deal with [age 12] as the cutoff," Kreek said. However, she qualified the committee determination, noting that "all drugs should not have the same cutoff" and that the committee would like to see more age-specific studies in the future.