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Executive Summary

Glaxo's Zantac (ranitidine) should be approved for use in a 300 mg, single bedtime dose for the treatment of duodenal ulcer, FDA's Gastrointestinal Drugs Advisory Cmte. recommended at its Aug. 16 meeting. The cmte. based its decision on three double-blind, randomized trials comparing the 300 mg once-a-day dose to the standard 150 mg b.i.d. dose. Glaxo reported that the healing rates with the two regimens were "not significantly different." Glaxo presented the results of three major studies included in its NDA for the 300 mg daily dose. In a U.K./Canada study, which involved 102 evaluable patients, 85% of those receiving 300 mg ranitidine once-a-day were healed at four weeks compared to a healing of 96% in patients receiving 150 mg b.i.d. In another internatl. multicenter trial, involving 625 evaluable patients, healing rates at four weeks were 79% for the once-a-day dose and 85% for the b.i.d. dose and at eight weeks were 88% (once-a-day) and 93% (b.i.d.). In a German study, with 96 patients, healing rates were 91% and 96%, respectively, for the single v. b.i.d. regimens. Summarizing the company's efficacy and safety results, Glaxo VP-New Product Development Peter Wise, MD, concluded that "overall 83% of evaluable patients had their ulcers healed by four weeks when receiving ranitidine 300 mg in a single bedtime dose." He said "this rate of healing was neither statistically nor clinically different from the 86% seen with 150 mg b.i.d." Thus, he maintained, the data "support the conclusion that a single daily 300 mg dose of ranitidine given at bedtime is an efficacious and safe alternative to the standard 150 mg b.i.d. regimen for the short-term treatment No Difference Between Regimens At Four Weeks, At Eight Weeks b.i.d. Dose May Be Better -- Cmte. Reviewer Although the cmte. agreed that the 300 mg, single dose regimen is effective, FDA and several cmte. members questioned whether the efficacy of one 300 mg dose is equivalent to the b.i.d. regimen. Cmte. reviewer Donald Castell, MD, Duke University, concluded that the studies show that at four weeks there is no difference between the two dosage regimens. However, he added that there seems to be a trend "or even a significant effect that maybe, as we look to the eight week healing effect, the b.i.d. dose" may actually be better. In its questions to the cmte., FDA suggested that the absence of placebo controls in the studies casts doubt on the studies' ability to substantiate the efficacy of the once-a-day dose. "Rigorously, the only conclusion one can draw from this positive control study of ranitidine is that 300 mg h.s. is not as effective as 150 mg b.i.d.," the agency declared. "Without some assumptions about how large the placebo response would be, and whether the 300 mg regimen result can be distinguished from that [unknown] response, we cannot say whether the 300 mg dose is effective." Asked whether the data can "produce evidence that the 300 mg dose is effective," the cmte. chairman Eugene Schiff, MD, University of Miami, told the agency: "The answer is not yes, but we won't say the answer is no." During the discussion, FDA Cardio-Renal Div. Acting Director Raymond Lipicky, MD, declared: "How can you vote for [recommending approval] if you cannot justify" that the dose is effective. "How in the world can you ask us as an agency to approve a noneffective dose?" Since there is no placebo control, Lipicky said, "if there is a 5% difference in healing rates [between the two dosage regimens], you can't really rigorously say you know that 300 mg once a day is better than placebo," though "you can argue very strongly that it is." The FDAer asserted that "there is an enormous logical jump here of saying, okay, 'I can't tell that this one regimen is less good than the other,' and to now say, 'but I am going to allow this less good regimen to be used because I know it's going to work." He said he would be "perfectly happy to say I don't think a 5% difference is meaningful clinically, or in terms of outcome." However, he asked: "On what data is one going to make a decision that this less performing regimen in fact works at all?" A once-a-day regimen would give Zantac a further labeling advantage over Tagamet (cimetidine), which currently is labeled for four times daily dosing. Last December the cmte. recommended cimetidine for twice a day dosing, and the company is preparing to ask the agency to approve a once-a-day regimen

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