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Executive Summary

BURROUGHS WELLCOME's SEPTRA: NEW INDICATION FOR TRAVELER's DIARRHEA treatment was recommended for approval by FDA's Anti-Infective Drugs Advisory Committee at its Nov. 29 meeting. In an unanimous vote, the committee passed a motion by panel member Calvin Kunin, MD, Ohio State University to recommend: "approval for the indication for the use of this combination product in the treatment of traveler's diarrhea." FDA and the advisory committee considered only one of two studies presented by Burroughs Wellcome's Kathryn Pattishall on Septra (trimethoprim/sulfamethoxazole) as acceptable for evaluating the drug's efficacy for the indication. The committee determined, however, that one study was enough to support an approval recommendation. The study accepted by the advisory committee was conducted in 1981 by Herbert DuPont, MD, University of Texas. The study was a double-blind, placebo-controlled trial with American volunteers who had contracted diarrhea in Mexico. The study compared trimethoprim 160 mg/sulfamethoxazole 800 mg twice a day with trimethoprim alone 200 mg twice a day or placebo for a five-day period. "By the end of the first day of therapy, it was quite clear that in 37 students receiving the combination, [and in] 38 students receiving trimethoprim alone, statistically fewer stools were passed than in 38 students receiving placebo," Pattishall said. In the second study, conducted by Myron Levine, MD, University of Maryland School of Medicine, acute diarrhea was induced in healthy adult volunteers by challenging them with a strain of enterotoxigenic Escherichia coli isolated in Bangladesh. The volunteers were randomized to the same regimen of treatment as the other study. "Both the active drugs substantially decreased the duration and the severity of the diarrhea compared to placebo," Pattishall noted. At the end of the five-day study period, the volunteers were given the antibacterial neomycin to assure that the enterotoxigenic (ITALICS)E. coli strain was eliminated. Previously, FDA had determined, in March 1988, that Burroughs Wellcome's application for the traveler's diarrhea indication was not approvable due to concerns with the use of neomycin in the Maryland study. FDA believed that the use of neomycin prevented a post-therapy follow-up on the efficacy of the study drug, Pattishall explained. FDA Division of Anti-Infective Drugs reviewing medical officer Anna Standard, MD, told the advisory committee that in "looking at these two studies, trimethoprim and trimethoprim/sulfamethoxazole appear to be essentially equivalent in the therapy of diarrhea" caused by enterotoxigenic E. coli. She added that "both of these entities are superior to placebo with regard to decreased duration, decreased number and volume of diarrhea stools" and in clinical improvement. Bruce Burlington, MD, who is currently serving as both deputy director of Office of Drug Evaluation II and acting director of the Office of Generic Drugs, pointed out that the Maryland study indicated that the combination of ingredients may effect the development of resistant organisms. Burlington noted that because resistant enterotoxigenic E. coli developed in trimethoprim-only patients and not in the group receiving Septra that Levine's study "provides the only data that would allow us to conclude that emergence of resistance is suppressed by using a fixed dose combination rather than a single agent."

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