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Executive Summary

Merck's Losec (omeprazole) has the go-ahead from FDA's Gastrointestinal Drugs Advisory Committee for use in the treatment of both acute duodenal ulcers and refractory duodenal ulcers. Voting eight-to-one at its May 25 meeting, the committee recommended expanding Losec labeling for the treatment of duodenal ulcers. The vote was unanimous in favor of an indication for "treatment of acute duodenal ulcers poorly responsive to customary medical treatment, usually including a course of a histamine H2 receptor antagonist." Losec, the first acid pump inhibitor to reach the market, was approved in September for three limited indications: short-term treatment of severe erosive esophagitis, short-term treatment of symptomatic gastroesophageal reflux disease poorly responsive to customary medical treatment, and long-term treatment of Zollinger-Ellison syndrome ("The Pink Sheet" Sept. 25, T&G-1). The broad duodenal ulcer indication did not draw much discussion prior to the vote. The decision hinged primarily on updated safety information on the drug. At its previous March 15, 1989 review of Losec, the committee had recommended against approval of the general duodenal ulcer indication because of potential safety issues raised by carcinoid tumors seen in rat studies. At that time, the committee said the agent was clearly effective, but that the benefits of therapy might not outweigh the risks. The committee had been particularly concerned because of the potential for long-term use, given the recurrent nature of ulcers. In support of Losec's safety, Merck presented results from a number of studies with gastric biopsy data, including a long-term use trial with information on approximately 250 patients who had been treated with Losec for at least 11 months (at the previous meeting, the company only had biopsy data on 86 patients). The long-term use data showed that micronodular hyperplasia was the most advanced change in gastric cells and that the majority of patients (89%) had normal gastric biopsies. Merck also presented data showing that the rise in the number of ECL cells with Losec is similar to that seen with H[2] antagonists. Commenting on the updated safety information, committee reviewer Rosemarie Fisher, MD, Yale University School of Medicine, said: "I think that the safety data has been much better presented, and while I'm still a little bit concerned about the long-term effects of omeprazole on other organs,...I feel a little bit better about the effects of it on EC cells and ECL cells in the stomach. I'm more convinced than I was in March about that effect." Efficacy in acute ulcers was acknowledged by FDA in its prepared questions to the committee, which noted that "the efficacy of Losec delayed release capsules for the treatment of acute duodenal ulcers has been supported by substantial evidence from clinical trials." Among the central efficacy studies recapped by Merck at the May 25 meeting was a double-blind comparison of omeprazole 20 mg once-daily to ranitidine 150 mg b.i.d. in approximately 300 patients. The study found that after four weeks of treatment, ulcers had healed in 82% of the omeprazole-treated group and 63% of the ranitidine-treated group. The majority of committee members recommended that Losec be given in a once-daily dose of 20 mg for four weeks. However, the last two committee members commenting (Michael Gershon, MD, Columbia University College of Physicians and Surgeons and Committee Chairman Eugene Schiff, MD, University of Miami School of Medicine) contended there is no evidence that the drug is less safe when given for eight weeks and suggested that labeling not restrict use to four weeks. "I think that decision should be driven by efficacy; i.e., if there's a reason to do it for eight weeks it should be permitted," Gershon said. The committee's deliberations over the refractory duodenal ulcer indication were somewhat more complicated, in part because of study design questions and statistical issues. At its meeting a year earlier, the committee had recommended that the refractory duodenal ulcer indication be granted if preliminary results were confirmed by data that was soon to be submitted by the company. Merck submitted the final study results in November. Data in support of the refractory duodenal ulcer indication included two trials: a single-blind, single-center study in 34 patients randomized to receive either cimetidine 2 g daily or omeprazole 40 mg daily and in 16 patients randomized to receive either cimetidine 3 g daily or omeprazole 40 mg daily; and a multi-center, double-blind, double-dummy study in 107 patients randomized to receive either Losec 40 mg once-daily, ranitidine 150 mg b.i.d., cimetidine 400 mg b.i.d. or cimetidine 200 mg t.i.d. plus 400 mg at bedtime. The 107-patient study was originally designed to look at unresponsive peptic ulcers, so Merck retrospectively went back and analyzed data on the 88 patients with unresponsive duodenal ulcers. The single center study, which found that 87% of omeprazole-treated patients were healed at week four in comparison to 44% of cimetidine-treated patients, showed statistical superiority for omeprazole for both week four and eight. The study, however, was faulted by the committee for several design features, including limited compliance information. The committee members pointed out that cimetidine-treated patients may not have taken the many pills they were supposed to take, and that information was not available to assess that potential scenario. The larger, core multicenter study found statistical superiority for omeprazole over all cimetidine groups, but only showed numerical superiority to the ranitidine group. While the smallest treatment difference at four and eight weeks post treatment was 25%, the 16-patient ranitidine-treated group was too small to permit a showing of statistical significance. The committee also expressed concern with insufficient compliance information in the multicenter study, as well as some statistical issues related to Merck's pooled analysis. However, the committee agreed that the study supported efficacy of Losec in the treatment of unresponsive ulcers. Much of the debate over the refractory duodenal ulcer indication related to a comment by FDA Gastrointestinal and Coagulation Drug Products Division Director Stephen Fredd that the proposed indication ("poorly responsive" duodenal ulcers) implied a benefit over continuing treatment with H[2] receptor antagonists. The committee, which generally felt that a once-daily 40 mg dose of the drug is effective in resistant ulcers but was not proven to be better than ranitidine, decided to split its vote on the efficacy issue into two questions: whether Losec provides "unique benefit" in the unresponsive duodenal ulcer population and whether it provides "general benefit." The committee unanimously agreed that the drug does not provide unique benefit and that it does provide general benefit. The efficacy "question has to be very carefully phrased," committee member Thomas Burks, PhD, University of Arizona Health Science Center, explained. "If the question is simply one of efficacy in this particular population of patients, I think the answer is a definite 'yes'. If the question involves the term 'superiority' or 'unique benefit,' then I think what we're hearing is 'no'."

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