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Executive Summary

Rhone-Poulenc Rorer's Calcimar (synthetic salmon calcitonin injection) should have its labeled indication for osteoporosis altered to reflect a lack of evidence that calcitonin therapy prevents osteoporitic fractures, FDA's Endocrinologic and Metabolic Drugs Advisory Committee agreed at its July 24 meeting. The committee unanimously concurred with a suggestion from chairman Lewis Kuller, MD, University of Pittsburgh, that Calcimar's labeled indication for osteoporosis should include a statement to the effect that "there is no evidence at the present time that calcitonin prevents fractures, or that it is useful in the treatment of people with fractures." The recommendation, if adopted by FDA, will leave Wyeth- Ayerst's Premarin (conjugated estrogens) as the only drug product in the U.S. that can claim to prevent or reduce the risk of osteoporitic fractures. The advisory committee recently rejected an osteoporosis indication for Norwich Eaton's Didronel PMO (etidronate) after the product failed to show long-term efficacy against fracture ("The Pink Sheet" March 11, p. 3). The committee considered withdrawing Calcimar's indication for osteoporosis altogether: Rhone-Poulenc Rorer dodged that bullet by a four-to-two vote against withdrawal of the indication. Under the proposed change, Calcimar would retain an indication for postmenopausal osteoporosis limited to "prevent(BRACKET)s] the progressive loss of bone mass." However, the committee also voted that the bone mass maintenance claim should be followed by a new qualifier that evidence of Calcimar's effect on bone density is inadequate to predict its long-term efficacy beyond two-to-three years of use. Calcimar has never possessed an outright claim to reduce the risk or incidence of osteoporitic fractures: current labeling, after stating Calcimar's effect on bone mass, simply says that the trials used as the basis for its approval for osteoporosis "were not designed to detect differences in fracture rates." Calcimar's annual sales first topped the $ 100 mil. level in 1988 on the strength of the rapidly expanding osteoporosis market ("The Pink Sheet" June 26, 1989, p. 8). Calcimar labeling is likely to be weakened because of two issues: FDA's efficacy requirements for osteoporosis drugs are more stringent now than they were 10 years ago; and the Calcimar Phase IV studies failed to live up to expectations. The committee's recommendation was reached after Rhone-Poulec Rorer presented the results of a six-year Phase IV study of Calcimar in women with previous osteoporitic fractures that found no superiority of Calcimar over placebo in reducing the rate of new vertebral fractures. However, the study, plagued by enrollment and protocol violation problems, was considered so flawed that it "could not be regarded as an adequate and well-controlled trial," FDA medical reviewer Leland Pierce said. The Phase IV study was a placebo-controlled, randomized multicenter trial in post-menopausal women treated daily with Calcimar and an adequate diet including Vitamin D and calcium. The trial enrolled less than half the 300 subjects called for in the protocol -- 86 patients received Calcimar and 65 were on placebo. A high drop out rate in both drug and placebo arms left only 35 patients on Calcimar and 30 on placebo. Analysis of new fractures in the study found a rate of 23.1% for Calcimar versus 11.6% for the control regimen of placebo, calcium and vitamin D (p value = 0.14). Time until first fracture analysis also favored the control over Calcimar, with the drug showing a relative risk of 1.15 (p value = 1.35). The agency and the company agreed that the overall number of new fractures occurring during the trial (5 in the control, 12 in the Calcimar group) was too small to make the results statistically significant. Rhone-Poulenc Rorer argued that the treatment arm contained more patients with advanced illness (those with 3 or more fractures at baseline). "Statistically, it's a wash," FDA consultant Henry Bone, MD, Henry Ford Hospital, said of the Phase IV data. The inadequacy of the study made it difficult for the committee to conclude that Calcimar had no efficacy in osteoporosis because it "provided no basis for analysis," according to Bone. He said the study "demonstrates basically neither an advantage nor a disadvantage from the drug" in the patients' risk of fractures, but that evidence remained that the drug provides "a modest increase in bone density." Calcimar's problems are also due to changing standards for evaluating efficacy and clinical endpoints in osteoporosis. The original approval for the osteoporosis indication, based on pivotal trials in 170 patients and utilizing a single surrogate endpoint for efficacy, "probably broke the limit of the absolute minimum NDA package," Bone suggested. The trials were performed in the late 1970's by Armour, later acquired by Rorer. The drug was approved in 1978 for Paget's disease and in 1980 for hypercalcemia. When the osteoporosis indication was granted in December 1984, four years after an advisory committee recommendation for approval, evidence of the drug's efficacy consisted of improvements in the mass and mineral density of patients' bones as measured by changes in their total body calcium, Pierce told the committee. However, given rapid improvements in bone evaluation technology, an increase in total body calcium is no longer considered by itself to be "an acceptable primary endpoint for establishing the efficacy of a drug for osteoporosis," the FDA reviewer said. As a condition of approval, FDA required Armour to conduct the Phase IV study to substantiate calcitonin's efficacy against fracture. As chairman Kuller summed up FDA's current dilemma, "given the fact that in 1981 the requirement was to do a Phase IV study, and that the Phase IV study basically was not done, what do we do now?" The committee unanimously recommended that FDA request an entirely new, rigorously monitored Phase IV trial for Calcimar. Committee member Barry Bercu, MD, University of South Florida, suggested that a new trial might "focus on a younger group which will be more highly motivated . . . the ones who haven't had had fractures yet, women maybe between 45 and 50." Bercu also recommended that at least part of the study go beyond three years. The panel also voted in support of an FDA proposal to hold a consensus conference on clinical endpoints for future osteoporosis trials, tentatively to be held in the spring of 1992. From FDA's perspective, commented committee executive secretary John Gueriguian, MD, Division of Metabolism and Endocrine Drug Products, Calcimar points up an ongoing "situation, where on the one hand, at the tail end of an approval process, the FDA is encouraged to go into Phase IV studies, and ten or eleven years later, several different companies haven't kept their promises. Something has to be done. Unless we do it, something will give. That is to say, FDA will become very reluctant to give early approvals with Phase IVs and will cite these examples to prove its point."

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