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Executive Summary

Searle's Cytotec (misoprostol) 200 mcg q.i.d. should be approved for the prevention of NSAID-induced gastric ulcers in "high risk" patients, FDA's Gastrointestinal Drugs Advisory Committee agreed by a nine-to-one vote at its Sept. 15 meeting. The committee did not specifically identify subsets of chronic NSAID users as acceptable Cytotec populations. However, the majority of the committee members recommended that use be targeted to those patients at risk of serious events arising from NSAID-induced gastric ulcers. For example, committee member Stephen Hanauer, MD, University of Chicago, in voicing his vote of approval, said: "I do not believe it is important to treat every patient receiving NSAIDs with a prophylactic agent. However, I do believe there is a subgroup of patients -- those who are at increased risk from complications of ulcers, such as the aged population, patients with previous peptic ulcer disease, and patients with concurrent illnesses -- who may benefit." The meeting marks the second time the advisory committee has reviewed Cytotec and the second recommendation for its approval. Over three years ago, in June 1985, the committee endorsed approval of the drug for the treatment of duodenal ulcers. FDA has not acted on the committee's earlier advice. The drug has received a close review because of its abortifacient potential. The NSAID-induced peptic ulcer indication may, however, be an easier decision for the agency. NSAID-related ulcers are thought to be associated with high morbidity and mortality in certain patient populations, and no therapy is currently approved for their prevention. FDA signified the importance of the indication with a grant of "1-A" fast-track review status in March ("The Pink Sheet" May 9, "In Brief"). Searle also indicated in its presentation to the committee that the company believes that FDA has deferred approval of misoprostol pending discovery of a "unique" indication. Referring to the committee's earlier approval recommendation, Searle Senior VP-R&D Paul Nicholson told the committee that since that time "many consultations have been conducted with the agency to define subgroups of patients in whom misoprostol is specifically and uniquely beneficial and to discuss the implications, obviously, of its uterotonic activity." At the 1985 advisory committee meeting, Searle has proposed addressing the abortifacient issue in the drug's labeling with a contraindication for pregnant women and a warning against use for women who might become pregnant. The company has proposed a much more comprehensive warning for the NSAID-induced ulcer indication, recommending that the drug be contraindicated in all women of childbearing age. To permit use in women of childbearing age who might be good candidates for the drug, Searle suggested setting up a post-NDA compassionate use protocol that would include written informed consent forms, mandatory pregnancy testing, and an education program. The advisory committee concurred that a contraindication in all women of childbearing age would be too restrictive and should not be used. The committee did, however, recommend a strong warning about use in pregnant women, or women who might become pregnant, and supported Searle proposals for packaging features that would alert patients to the warning. Explaining his reasoning in voting against an across-the-board contraindication for women of childbearing age, committee member Melvin Schapiro, MD, University of California at Los Angeles, said: "I would not like to see [misoprostol] contraindicated or restricted in a patient in whom it might be of value. I think there needs to be a very intensive and broad campaign about its abortifactive potential . . . and I would lead the sponsor to do everything they possibly can, including labeling, in that regard, but not put the primary [physician in a liability] position because he gave it to a needing patient." FDA Office of Drug Evaluation I Director Robert Temple, MD, noted that the agency would also not favor the proposed contraindication. "When we realized that the proposal was to contraindicate use in women of childbearing age, I have to say we were quite uncomfortable," Temple said. "Plainly [Searle's] very proposal to make it available under some other arrangement belies the sincerity of that contraindication. There are alternatives: one can say it is not for people who are or may become pregnant, and you can provide appropriate warnings on how to avoid it." Among the packaging features proposed by Searle are colored sections to highlight warnings, a symbol of a pregnant woman with a slash through it, and warnings on the top of bottle caps or back of unit-use packages. Commenting on the proposals, Temple said that FDA "likes the approach [of] putting stuff on the packaging." My bias, he continued, "is to say that [misoprostol] should not be available except in unit-of-use packaging that contains all the appropriate warnings and perhaps even a patient insert." The committee recommended approval of the NSAID-induced ulcer prophylaxis indication on the basis of two pivotol studies that were halted early because of promising results. The studies, which had almost identical protocols, were scheduled to run for one year, but were discontinued after a three-month interim analysis found a highly significant difference between ulcer rates in the placebo and misoprostol treatment groups. The studies compared misoprostol 100 mcg q.i.d. and 200 mcg q.i.d. to placebo in a total of 420 osteoarthritis patients taking either naproxen, ibuprofen or piroxicam. The protocols called for enrollment of gastric pain patients who were shown, through an endoscopic evaluation, not to have ulcers. Patients were endoscoped every four weeks after beginning therapy. At the three-month endoscopy, peptic ulcers were observed in 30 of 138 patients in the placebo group (21.7%), compared to 8 of 143 (5.6%) in the 100 mcg misoprostol group and 2 of 139 (1.4%) in the 200 mcg misoprostol group. Formation of duodenal ulcers, however, was not significantly different in the misoprostol and placebo groups: five ulcers were seen in the placebo population, compared to three in the lower dose misoprostol group and four in the 200 mcg group. Despite agreement by the committee that misoprostol was clearly effective in preventing peptic ulcers, a number of committee members said they were concerned that ulcer prevention may not necessarily correlate with prevention of serious ulcer complications. Schapiro, for example, commented: "I'm very torn, as is everybody else. I don't think there's an endoscopist out there that doesn't realize that older people who take these drugs are in serious difficulty, but what we're looking at today is addressing the topic of something that may not [be], and has not been proven to be, related to this clinical problem." Several committee members suggested that Searle conduct post-marketing studies to examine long-term (i.e., more than three months) safety and efficacy of the agent, specifically looking at occurrence of serious ulcer complications. Responding to one committee member's remark that such studies would be valuable, but ethically and logistically difficult once the drug is approved, Temple commented that such a study "might be doable." He suggested that a large enough population could be obtained if low-risk patients were studied, with the occurrence of bleeding as the major endpoint. "There may be lessons in the cardiovascular area where very large studies have been mounted using a sort of 'keep it simple' approach, asking relatively few questions and randomizing large numbers of people." he said. Some committee members also suggested additional post-marketing studies. Committee member Rosemarie Fisher, MD, Yale University School of Medicine, said she would "like to see some surveillance mechanism set up, or some individual studies, on these patients long-term [to look at] bone metabolism, perhaps by looking at CT exams of the . . . bone thickness, and perhaps even some biliary motility studies." The request for bone metabolism data was based, in part, on the results on a mouse study that found some changes in bone metabolism. Searle noted that because of the mouse findings it looked at the the effect of misoprostol on serum levels of calcium, phosphorous and alkaline phosphatase in human studies and "concluded [that there is] no apparent effect." Committee Chairman Eugene Schiff, MD, University of Miami School of Medicine, also recommended that post-marketing studies look for effects on the gallbladder. "Prostaglandins could stimulate mucus in the bile, which could precipitate stones, etc., and that ought to be looked at," he said. The committee, in considering the appropriate patient population for misoprostol, also considered whether use should be allowed in patient groups not looked at in the prophylaxis studies, i.e., asymptomatic patients, NSAID users without osteoarthritis, patients with a prior history of gastric ulcers, and patients using NSAIDs other than prioxicam, naproxen and ibuprofen. The committee agreed that Searle's data could be extrapolated to support usage with all NSAIDs and in chronic NSAID users without osteoarthritis. With regard to patients that had previously had gastric ulcers and patients who were not experiencing pain, the committee agreed that misoprostol, although not proven, might be particularly useful. Commenting on use in patients with prior gastric ulcers, Schapiro said: "If a patient had previously had gastric ulcer disease secondary to salicylate therapy, for example, he is a prime candidate for another recurrence when you put them on the NSAIDs, so he's somebody I certainly want to approach" about use of misoprostol. Addressing use in asymptomatic patients, Schiff pointed out that that population is specifically at risk of ulcer complications. Given that the central side effect outside of abortion was transient diarrhea (seen in 11% of patients), benefit in that population could be expected to outweigh risks. "I think what we're talking about here is particularly a group of people who are elderly, who when they develop a complication it could be life-threatening and they may not have paid precede that, and we're really trying to prevent that type of problem from happening," Schiff said. "On the risk side, in that group it doesn't sound like it's very risky. The diarrhea we're hearing about doesn't sound like a diarrhea that's going to cause volume depletion, etc." Advisory committee members, however, were somewhat divided on whether or not misoprostol should be used in individuals who would be receiving NSAID therapy only for relatively short periods of time, such as two weeks. One committee member said that he would use misoprostol in patients who were receiving NSAIDs for only one week, citing studies that have shown even such limited use in health patients may lead to ulcers. First marketed in 1985, misoprostil is approved in 41 countries, primarily for use in the treatment of duodenal ulcers. The drug is approved in seven countries for coadministration with NSAIDs, most recently the U.K.

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