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Executive Summary

High-dose estrogen contraceptive products with more than 50 mcg estrogen should no longer be available for contraception, FDA's Fertility & Maternal Health Drugs Advisory Committee recommended at their Jan. 15 meeting. The committee agreed that all oral contraceptives containing 30 mcg or more of estrogen were equally efficacious for the prevention of pregnancy. Therefore, committee chairman Carolyn Coulam, MD, Methodist Hospital of Indiana, concluded that the continued availability of higher dose estrogen oral contraceptives is "unnecessary from an efficacy standpoint and may be less safe than lower dosage forms." Summarizing the committee consensus on the health risks from high-dose estrogen contraceptives, Coulam said "there is an association between oral contraceptive use and thromboembolic phenomenon and that within this association there is a trend to suggest a dose response relationship such that the higher the dosage of estrogen, the higher the risk of thromboembolic phenomenon." The committee voted eight to two to set the estrogen high-dose level for oral contraceptive products at 50 mcg. The two dissenters, James Schlesselman, PhD, Uniformed Services University of the Health Sciences, and Paul McDonough, MD, Medical College of Georgia, held out for a high-dose level of 80 mcg, citing potential use in controlling bleeding. Voicing the majority view, committee member Paul Manganiello, MD, Dartmouth-Hitchcock Medical Center, Hanover, New Hampshire, said he "would much rather err on the side of being too conservative due to the fact that there are other modalities available to treat these problems. [While] we may be splitting hairs with 50 mcg and 80 mcg, I would much rather err on the side of the lower dose and say that we recommend 50 mcg [as the cut-off level] . . . going up to 80, we run into problems with degradation of mestranol." FDAer Ridgely Bennett, MD, noted that during the past year, FDA has "had several distinguished clinicians tell us that it is their belief that high-dose oral contraceptives should be withdrawn from the market." Bennett said that the agency "has the same belief, but lacks the legal authority to withdraw approved drugs from the market unless there is a finding of an imminent hazard to the public health or a finding that the drug is unsafe for use for the condition for which it is approved, and then only after affording the sponsor the opportunity for a hearing." FDAer Dianne Kennedy reported that, based on IMS data, there were approximately 51 mil. prescriptions written in the U.S. for oral contraceptives, including approximately 36 mil. for low-dose estrogen pills, 13 mil. for the 50 mcg pill, and "a little under 2 mil." for the high-dose estrogen pill. Ortho's two high-dose pills, Ortho-Novum 1/80 and Ovulen, account for about 75% of the prescriptions written for high-dose pills, Kennedy said. Searle, Ortho, and Syntex continue to market oral contraceptives with estrogen levels above 50 mcg. Bennett noted that one company marketing high-dose pills told FDA that it believes that high-dose pills offer MDs "a valuable option for control of intractable or unacceptable intermenstrual bleeding without creating an increased danger of adverse experiences." McGraw reported that new prescriptions of Cardizem are "currently running about a quarter of a mil. per month, [giving the product a] market share of approximately 34%." Total prescriptions are "approaching one million per month," McGraw said, adding that "our market share is 36%." Discussing the patent status of Cardizem, Marion President and Chief Executive Officer Fred Lyons told the analysts that although the patent on Cardizem expires in February 1988, the company does not anticipate any diltiazem approvals until after Nov. 5, 1992. Cardizem, which was approved in November 1982, received 10 years protection from ANDA approvals of diltiazem under the Waxman/Hatch law provisions for products first approved between January 1982 and passage of the law in September 1984. Under the law, however, another company can obtain approval for a product before the exclusivity period expires if the full NDA process is used. Addressing rumors that a diltiazem product might be approved before the company's exclusivity expires, Lyons said: "Our interpretation is that it is very unlikely -- near zero percent -- with the time and the cost involved, that a product will come to market through the full NDA process prior to November of 1992, at which time ANDAs" will be eligible. "I know there has been a lot of question, a lot of misinterpretation," Lyons added, "but we think the law is very specific and very clear in the way it is written . . . and we think it is very unlikely that there will be competition to Cardizem generically before the exclusivity period goes." Marion's second largest product, Carafate (sucralfate), is expected to show 50% growth in fiscal 1988, with sales reaching $ 150 mil., McGraw reported. "These past two years," McGraw said, "Carafate has been the fastest growing antiulcer product in the nation. New prescriptions are currently running about 167,000 per month, with a market share of 12%." Total prescriptions, he added, are "now approaching a third of a million per month, at a market share of 11%." McGraw noted that the company will be submitting an NDA pending for ulcer maintenance in the next few months, and that filings for treatment of stomatitis, stress ulcers, and a suspension formulation will follow shortly. In the new product development area, Lyons predicted that Marion will be filing an IND this year for TA 3090, an analog of Cardizem. TA 3090 "has a longer half life [than diltiazem]," Lyons said, "and we think it may be a once-a-day dosage." TA 3090, like Cardizem, is licensed from Tanabe. "As I talk about Tanabe and Marion Laboratories," Lyons said, "the significance of this joint venture continues to grow." Marion is "working with them early on in the discovery stage. In addition to the calcium channel blocker [TA 3090], we're looking at many other types of products, [including] lipid lowering and gastrointestinal" drugs, Lyons added. Lyons noted that Marion is also in the early research phases with six cardiovascular compounds that have not been publicly discussed. "We're working very actively in a number of other areas in the cardiovascular" segment, Lyons reported. "We have six compounds licensed that have not been announced and will not be announced for some time because they're in the very early stage of development." Lyons noted that Marion will continue to rely on licensing compounds for new product growth, but that the company will be making increased commitments to R&D over the next two years. "We're going to double the size of our R&D operation over the next 18 to 24 months," Lyons said. "We'll have approximately 900 to 1,000 associates [employees] in that group, [with] $ 150 to $ 200 mil. in R&D." But, he added, "we're still not going to get ourselves into the discovery and synthesis phase, although we will work very closely with companies in that discovery phase." In a statement, Searle said it does not believe "the scientific evidence has shown a dose response relationship between estrogen content and any adverse cardiovascular effects. And, in view of the large though declining market for such products, we feel this indicates a need for the continued availability for these products to the medical profession."

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