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Executive Summary

Searle is no longer referring to myocardial infarction protection in its advertisements for the beta-blocker Kerlone (betaxolol HCI) after recently reaching an agreement with FDA on its promotions for the drug. In a March 29 response to a March 15 letter from FDA, Searle told the agency that it cancelled professional journal ads headlined: "Catecholamine surge in the A.M. -- Is today's working heart still protected by yesterday's beta-blocker?" Searle told FDA it would revise the Kerlone promotional campaign and that "all current promotional materials containing the representations described in your letter" would be discontinued "no later than June 15, 1991." FDA cited Searle for its ad practices based on the agency's conclusion that the ad headlines and chart listing the half-life ranges, bioavailability, and interpatient variations in plasma levels of Kerlone and four other beta-blockers "imply that Kerlone tablets 10 mg and 20 mg provide not only protection for the heart, but better early A.M. protection against myocardial infarction and sudden death than the other beta-blockers." The Searle chart included data on Tenormin, Lopressor, Corgard and Inderal LA in addition to Kerlone. The agency pointed out that "each of the other beta-blockers has been studied in and is indicated for other uses such as acute myocardial infarction, arrhythmias, hypertrophic subaortic stenosis, etc., which may be categorized by some as treatment related to protecting the heart." Kerlone, however, "has never been studied in a myocardial infarction setting, is not known to prevent myocardial infarction, is not known to improve survival, and has no post-infarction or any other labeling claims related to protecting the heart," FDA said. Therefore, FDA told Searle: "In the absence of adequate and well-controlled clinical studies which demonstrate one or more facets of 'heart protection' so that a labeling claim may be substantiated via the NDA process, Kerlone promotion must be limited to that which is circumscribed by the current approved package insert." The Searle antihypertensive was approved in October 1989 with a "3C" rating denoting little or no therapeutic gain over existing therapies. The Kerlone ad, which apparently was the first advertisement for the antihypertensive, ran in major medical journals. The ads last appeared in April issues of the Journal of the American Medical Association and The New England Journal of Medicine. Marion Merrell Dow has been in discussions with FDA over promotions for its calcium channel blocker Cardizem (diltiazem) for prevention of post-myocardial reinfarction. FDA was concerned about Marion sales reps who were referring physicians to published studies of the drug for the unapproved use of preventing reinfarction. Marion said that it has agreed with FDA to have its detail force refer physician inquiries about Cardizem's use in post-MI to the firm's medical department. FDA said it is still reviewing Cardizem promotions because other issues have been raised. The agency noted that it considers the prompting by the MMD sales reps for the unapproved use to be a promotional activity. FDA's concern lies in the fact that there is no evidence that Cardizem or other calcium channel blockers are beneficial in the population at risk of post-MI reinfarction in terms of morbidity and mortality. Calcium channel blockers are approved for treating hypertension and angina. During a June 11 hearing before Rep. Weiss' (D-N.Y.) House Government Operations/Intergovernmental Relations Subcommittee, FDA Commissioner Kessler revealed that the agency was examining a company for the post-MI reinfarction promotion of a calcium channel blocker ("The Pink Sheet" June 17, p. 9). Kessler said the unidentified company has, "in effect, encouraged physicians to substitute calcium channel blockers for beta-blockers, a class of drugs that have been shown to improve survival in certain patients who have suffered a heart attack." He also noted that patients "with pulmonary congestion who were given a calcium channel blocker showed a decrease in survival compared with those patients given a placebo." Promotion of another calcium channel blocker, Syntex' Cardene (nicardipine HCI), has also come under FDA scrutiny. In response to a May 3 letter from FDA, Syntex discontinued and withdrew journal ads and promotional materials that implied Cardene's superiority in treating angina and hypertension through the use of three descriptive claims. Syntex said in a May 23 reply that FDA's letter "clarified the agency's position and we now understand that pieces with any of the three components in question ('vasoselective,' 'without cardiac compromise,' or 'any variation of the Pepine chart') are unacceptable." The company said it immediately asked medical journals to destroy the four-page ad insert in question and another two-page ad insert that included the terms "vasoselective" and "without cardiac compromise." For the other promotional pieces, Syntex noted that it had instructed its sale force to stop distributing the materials and return them to the company. One of the Cardene ads had a picture of a heart being gripped and released by a hand and the headline: "Break the grip of angina -- Release the heart . . . without cardiac compromise." A May 14 letter from Syntex to FDA warned the firm that "if you proceed with revised materials without [an advisory opinion from FDA] those materials may be the subject of formal regulatory action, if deemed necessary."

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