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Executive Summary

PROCTER & GAMBLE's METAMUCIL PSYLLIUM CHOLESTEROL-LOWERING CLAIM, if approved, "would fall into a somewhat different category than our usual biochemical approval," FDA Division of Metabolic and Endocrine Drug Products Director Solomon Sobel, MD, said at a July 25 feedback meeting between the agency and P&G. The meeting was held to discuss a clinical protocol proposed by P&G in March for testing its OTC psyllium laxative Metamucil's effectiveness in lowering cholesterol. FDA is hoping the study will shed some light on whether and how the agency could formulate an acceptable cholesterol-lowering claim for the OTC product. There is not yet enough data available to decide whether such a claim would be justified and practical for either consumer labelling or professional labelling, according to the agency. Sobel pointed out that the relatively modest reduction in cholesterol that P&G is attempting to demonstrate for Metamucil probably "would not meet the biochemical criteria for a drug indication...The typical cholesterol lowerer has a much higher effect." A claim for reduced risk of arteriosclerosis or heart disease, such as in Lopid (gemfibrozil) labeling, would not be appropriate for psyllium, Sobel suggested, but a claim limited to psyllium's biochemical effect on serum cholesterol might be. P&G Associate Director of Regulatory Services Doug Bierer, PhD, concurred that "we wouldn't want to imply that the reactions that you can expect [with Metamucil] were typical of those other agents" approved specifically as cholesterol-lowering products. According to a presentation by P&G biostatician Tim Balm, Metamucil currently is estimated to reduce LDL cholesterol by 5% to 9%, and total cholesterol by 4% to 6%, with no significant effect on levels of HDL cholesterol or triglycerides. The estimates are based on five previously completed clinical studies. In comparison, Merck's prescription cholesterol-lowerer Mevacor (lovastatin), is described in its labeling as reducing LDL and total cholesterol by 20% to 40%. However, OTC psyllium with an approved claim for lowering cholesterol might fulfill a different role than prescription cholesterol drugs, FDA indicated. "We've been talking for some time now [about whether] we would consider relaxing" the criteria for agents that have "a particularly solid safety record...which are not absorbed and have more modest benefits," Endocrine and Metabolics Division medical officer Russ Pierce, MD, remarked. "There could be a place for that in dietary treatments." Procter & Gamble is proposing a multicenter, six-month study of 5.1 g Metamucil twice daily in 200 patients, ages 21-75 years and including both sexes, with "moderately elevated" cholesterol of 130-190 mg/dL, plus a 50 person control group. The patients will also be on the American Heart Association Step I low-fat diet, with an eight week lead-in period on the diet preceding the drug treatment period. The study will measure sustained reduction in total and LDL cholesterol, the effect of psyllium on HDL-cholesterol, and effect on serum levels of minerals and fat-soluble vitamins from long-term psyllium treatment. FDA already informed P&G in a May 11 feedback letter that its proposed study "should provide adequate data for statistical analysis of endpoint efficacy and safety variables" ("The Pink Sheet" June 6, "In Brief"). At the July 25 meeting, the agency also requested that the study focus on median percentage changes from baseline in individual patients' cholesterol levels as the primary efficacy endpoint. The protocol originally proposed to focus on numbers of patients moving from levels defined as "higher risk" to "moderate risk" and "lower-risk," endpoints "which may lack clinical significance," the agency said. In addition, FDA suggested a separate study to establish the dose response parameters of psyllium, using a minimum of three dosage levels between 0 and 20 g of the compound. A "wash-out" study to find out how long the cholesterol-lowering effect of psyllium continues when the drug is stopped is also on the agency's "wish-list," FDA's Pierce indicated. Division of OTC Drug Evaluation staffer Michael Kennedy remarked to the P&G representatives that "one of our main objects is to try to get enough data to perhaps someday create a monograph on this sort of thing," apparently referring to a possible future monograph specifically for OTC psyllium as a cholesterol-reducing agent. P&G and Ciba-Geigy, for its psyllium laxative Fiberall, have been attempting to have the cholesterol-lowering claim for psyllium added through the OTC Laxative Monograph since 1987.

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