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BRISTOL-MYERS SQUIBB’s PRAVACHOL SET FOR FDA ADVISORY COMMITTEE OCT. 23: PHASE IV REQUIREMENTS AND CARCINOGENICITY REVIEW ARE KEY QUESTIONS

Executive Summary

FDA's Endocrinologic & Metabolic Drugs Advisory Committee is scheduled to review Bristol-Myers Squibb's Pravachol (pravastatin) lipid-lowering drug at the second day of its next advisory committee meeting, Oct. 22-23. The meeting will be held in Bethesda, Maryland at the Ramada Inn. According to a preliminary agenda for the advisory committee, FDA has concerns about the conduct of carcinogenicity lab studies. However, the agency is willing to consider an approval recommendation with further animal studies after approval. FDA's advisory committee review for pravastatin comes one year and nine months after the filing of the NDA in January 1989. "The carcinogenicity studies that have been completed with pravastatin indicate that high doses are carcinogenic in the female rat liver and possibly produce malignant lymphomas in mice (no dose-response relationship)," FDA observes in a short backgrounder for the committee. The agency further notes that a mouse study on pravastatin "is not considered a valid carcinogenicity study since it was done at the 'maximal-no-effect dose' and not the maximum tolerated dose (MTD)." FDA assumes that "a repeat mouse study is therefore needed." The agency also questions the doses in rat carcinogenicity studies and points out that "if is is found that the MTD was not used, the rat carcinogenicity study will need to be repeated as well." The importance of the carcinogenicity review is highlighted in the agenda for pravastatin by a separate presentation from a BMS consultant on "carcinogenicity issues." That presentation will be delivered by a Johns Hopkins Professor of Comparative Medicine Robert Squire, DVM/PhD. National Institutes of Health researcher Richard Greisemer, DVM/PhD, is also scheduled to discuss "dose setting in [National Toxicology Program] long-term animal studies." Greisemer is director of the Division of Toxicology and Research Testing at the National Institute of Environmental Health Sciences. The advisory committee also has two expert pathology consultants scheduled to attend the meeting: Margarita McDonald, Phd, (National Institute of Environmental Health Sciences) and Ronald Moch, DVM, (FDA's Center for Food Safety and Applied Nutrition). The questions about lab studies, however, will not necessarily stand in the way of an approval recommendation. FDA notes in its questions to the committee that an affirmative determination of pravastatin's benefit-to-risk ratio "implies that the repeat carcinogenicity studies may be conducted in Phase IV (post-approval)." FDA's summary of the clinical trials in the pravastatin NDA put the product's ability to modify lipid levels (at 40 mg daily) at similar levels to Mevacor. "In most studies," FDA summarized, "a 40 mg/day dose resulted in about a 30-35% reduction in LDL-cholesterol and a 5-10% increase in HDL-cholesterol." During development, Squibb said that pravastatin was being studied with 40 mg once daily and 20 mg b.i.d. FDA noted that clinical efficacy has been "assessed only in terms of effects on lipids, not on vascular endpoints." The agency wants to know whether the advisory committee suggests Phase IV studies of "cardiovascular and total mortality with long-term use of HMG-CoA reductase inhibitors." Other Phase IV recommendations for specific patient populations (such as premenopausal women) are also being solicited by FDA. At the time of the Mevacor approval in September 1987, the National Heart, Lung and Blood Institute said that it was trying to encourage Merck and Squibb to participate in a long-term $60 mil. study of HMG-CoA drugs. NHLBI plans to begin a pilot study of the long-term trial in early 1991. The institute said it is still in the midst of designing the protocol and has not yet decided which HMG-CoA reductase inhibitor or inhibitors will be selected for the study. Mevacor and Pravachol are both being actively considered as well as Merck's Zocor (simvastatin), which is pending review at FDA. The pilot study may enroll about 400 men and women age 65 and older into five clinical centers, NHBLI said. The pilot should show whether its possible to recruit and retain a significant number of women and minorities, and whether quality of life improvements can be measured. The institute said it should also be able to estimate the cost of carrying out the full trial. The objective of the long-term study will be to see whether a lowering of cholesterol can reduce the incidence of fatal and non-fatal heart attacks over a period of five to six years. Pravachol's safety profile, FDA observes, is similar to that of Mevacor. The agency points out that "no detectable increase in the incidence of lens abnormalities has been observed." A high incidence of lenticular opacities was reported in clinical trials of Mevacor and is still reflected in labeling for the Merck drug. Labeling for Mevacor notes, however, that the "causal relationship" of the lens findings to lovastatin has "not been established." The effects of Mevacor on the eyes as well as liver are expected to be gleened from six Phase IV studies that are underway and one completed study. Merck said that information from the studies will be used to support changes in Mevacor's labeling regarding eye and liver abnormalities. The completed study was a 48-week, multicenter, placebo-controlled study of 8,245 patients with cholesterol levels between 240-300 mg/dl. According to Merck, initial results of the Expanded Clinical Evaluation of Lovastatin (EXCEL) were not able to demonstrate a causal relationship between Mevacor and lens opacities. The study did show a low incidence of liver enzyme elevations. Merck said that the final results have been submitted to a major medical journal for publication. One of the other studies, the Air Force Coronary Atherosclerosis Prevention Study, is a five-year trial that began in February to recruit 8,000, 45-70 year-old Air Force and military retirees and dependents. The participants must not have evidence of heart disease but have mild-to-moderate elevated cholesterol levels. The objective of the double-blind, placebo-controlled study is to see whether Mevacor decreases the incidence of fatal and non-fatal heart disease. Because of the long gap between the Mevacor and Pravachol reviews, the FDA advisory committee reviewing the second entry into the HMG-CoA class will be quite a different group of people. Only one individual who was on the committee when Mevacor was reviewed still remains on the committee. That is Barry Bercu, MD, Professor of Pediatrics, University of South Florida College of Medicine, All Children's Hospital. Four other committee members who had been on the panel in 1987 stepped down from the committee when their terms expired in June. QUESTIONS FOR FDA ADVISORY COMMITTEE ON PRAVACHOL REVIEW The four questions below are taken from a draft agenda for the committee dated Sept. 26. FDA prepares these questions to focus the advisory committee discussions. (1) Do the available clinical and non-clinical data permit a favorable benefit-to-risk assessment for use of pravastatin in primary hyperchlesterolemia? A 'yes' answer implies that the repeat carcinogenicity studies may be conducted in Phase IV (post-approval). (2) Does the proposed labeling provide appropriate information for the safe and effective use of the drug for the treatment of hyperlipidemia? If not, what additional information should be incorporated? (3) Does the Committee recommend any Phase IV formal clinical trials designed to collect data on cardiovascular and total mortality with long-term use of HMG-CoA reductase inhibitors? If so, what trials are recommended? (4) Does the Committee recommend additional Phase IV clinical studies with pravastatin in particular areas, e.g., its usage in the elderly, premenopausal women, or pediatric populations; its usage in patients with renal insufficiency; drug interaction studies? MEVACOR QUESTIONS FROM FEB. 19, 1987 FDA FAVORABLE REVIEW These questions are reproduced from two-and-a-half years ago to highlight the differences in the basic questions asked about the similar lipid-lowering compounds. As first in its class to be reviewed. Mevacor presumably faced some issues that will diminish with familiarity. (1) Is the safety data adequate to ensure that the benefit-to-risk ratio is not likely to be adverse for lovastatin with regard to carcinogenicity? Liver injuries? Lens abnormalities? (2) Do you recommend approval of lovastatin for reduction of cholesterol in patients who do not adequately respond to diet and other measures? (3) If approval is recommended, should further restrictions be placed on the population for which lovastatin is recommended? (4) What precautions, if any, do you recommend to ensure safe use of lovastatin?(ITEM 150)[EDITORS' NOTE: See box for FDA's preliminary questions to the committee for the pravastatin review. "The Pink Sheet" is also reprinting the questions from the Feb. 19, 1987 review of Merck's Mevacor (lovastatin) for comparison. Mevacor was recommended for approval at that meeting.]

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