MARION MERRELL DOW CARDIZEM DECREASED REINFARCTION CLAIM WILL REQUIRE "CORRECTIVE CAMPAIGN" TO ALL MDs REACHED BY 1991 DETAIL PROGRAM, FDA SAYS

Marion Merrell Dow's post-MI reinfarction claims for the calcium channel blocker Cardizem (diltiazem) must be corrected through a campaign to doctors, FDA said in a Feb. 14 warning letter. The warning letter states that FDA is concerned that a "detailer" pamphlet distributed by 1,200 Marion Merrell Dow sales reps during three months of 1991 contains "statements, inferences and suggestions" that Cardizem "decreased the incidence of reinfarction and mortality in postinfarction trials." The agency is requesting that MMD run a "corrective campaign" addressed to all physicians exposed to the message that Cardizem can decrease the risk of a second heart attack. MMD has 15 working days from receipt of the warning letter to respond to FDA about the corrective campaign. The company said Feb. 28 that it expects to work closely with FDA to resolve the issue but has not yet formally responded to the warning letter. To put pressure on MMD to expedite its corrective action, FDA is using the threat of reduced Cardizem sales to other government agencies. "Until these violations are corrected," FDA noted, "federal agencies will be informed that FDA recommends against the award of contracts for Cardizem products." Behind the 15-day response deadline lies almost a year of discussions between the agency and the company. FDA references those discussions in the warning letter, noting that these issues were raised in a March 26, 1991 letter to the company and discussed at an April 11, 1991 meeting with the agency. During the past year, FDA has shown less patience with companies involved in protracted discussions over alleged promotional or manufacturing violations. MMD's dispute with FDA unfolded against the background of a high-visibility agency crackdown on unapproved indication promotions. MMD has been asked to run a similar corrective campaign previously -- three years ago for the ulcer drug Carafate. During discussions with the agency last spring, MMD told FDA that the detail piece in question was printed by mistake and had not been approved by MMD's review committee. The company's apparent failure to remedy its promotion vetting procedures may have contributed to FDA's decision to send a warning letter this far into the discussion. The warning letter points out to the company that when the agency made a plant inspection in October 1991, MMD had not yet modified the internal procedures that had allowed the detailer to be printed. "The failure by MMD to provide proper safeguards against inadvertent distribution of violative promotional materials does not excuse such violations and appropriate corporate officials may be held responsible," the letter states. Similarly, last summer, FDA took Ciba-Geigy to task for failing to include its Quality Control unit in manufacturing/production decisions, basically telling the firm that mistakes were not excusable solely because they were due to a lack of proper procedures. The Cardizem warning letter applies the concept of appropriate procedures to advertising clearance. A July 8 warning letter to Ciba-Geigy cautioned that "the use of semantical phrases such as 'process deviation correction' should not be used to bypass the authority of the organization unit charged with the responsibility for controlling quality," FDA wrote ("The Pink Sheet" Aug. 12, 1991, T&G-5). The Cardizem warning letter suggests several ways of disseminating the corrective promotional materials, including a "remedial labeling piece" mailed to each physician detailed on Cardizem during the three-month period in question. Regardless of how MMD eventually handles the dissemination of the corrective materials, FDA said the company must include full prescribing information and a boxed heading stating that it is a "'CORRECTION OF A PREVIOUS PROMOTION THAT THE FOOD AND DRUG ADMINISTRATION REGARDED AS MISLEADING.'" The agency is not asking MMD to preclear future Cardizem promotions. A preclearance requirement was exacted in promotion debates with Bristol-Myers Squibb and Syntex in 1991. FDA's concern with the Cardizem claims is that there is no evidence that any calcium channel blocker is beneficial for the population at risk of a post-myocardial infarction reinfarction in terms of morbidity and mortality. Calcium channel blockers are approved for hypertension and angina. FDA is also concerned with the comparison of calcium channel blockers with beta-blockers made in the MMD detailer. The Cardizem unapproved claims cited by the agency are numerous. The front page of the detailer, which made the reduced reinfarction claims, cited a study identified as "The Multicenter Diltiazem Postinfarction Trial." FDA said that "contrary" to how the study was being used by MMD, it "shows no overall benefit from the use of Cardizem in the postinfarction patient population studied." Moreover, the warning letter states, the detailer "raises serious public health and safety concerns because the study MMD cites demonstrated severe disadvantages in a subgroup of patients who also experienced congestive heart failure. This subgroup experienced a significant increase in mortality associated with postinfarction Cardizem use." The agency also objected to the use of the term "cardiovascular events" to refer to mortality when, in fact, the expression generally is used to "define a variety of outcomes that may be as mild as palpitations." FDA told MMD that this "mischaracterization raises serious safety issues that are not offset by providing the full labeling or a brief summary with the detailer." The second page of the detailer references the "Danish verapamil infarction trial." The warning letter states that this reference "raises concerns by (1) promoting the concept of using a calcium channel blocker to reduce cardiac events in post-MI patients; (2) suggesting a comparison between two calcium channel blockers, i.e verapamil and diltiazem, for the treatment of post- MI patients with pulmonary congestion; and (3) raising issues concerning the concomitant use of calcium channel blockers and beta-blockers in post-MI patients." FDA called the reference to the Danish verapamil study "misleading" and said the "suggested comparison" of diltiazem and verapamil "implies therapeutic superiority" of Cardizem in post-MI patients with CHF. "Such comparisons are not supported," the agency states. Furthermore, FDA said, "in regard to the concomitant use of calcium channel blockers and beta-blockers, the statement 'using verapamil and beta-blockers concomitantly can worsen patients with poorly performing left ventricles' suggests that calcium channel blockers in general, and Cardizem in particular, may be used alone in place of beta-blockers in the treatment of post-infarction patients." FDA said these beta-blocker comparison claims raised "serious public health and safety issues because calcium channel blockers have demonstrated no benefit in survival in the postinfarction population and no calcium channel blocker is indicated for the decreased incidence of reinfarction and mortality. However," FDA noted, in the same patient population, "beta-blockers have been shown to improve survival by at least 25% and some beta-blockers are approved for" the prevention of second heart attack. The Cardizem warning letter is one of a number of FDA run-ins with manufacturers of calcium channel blockers and beta-blockers over post-MI promotional claims in the last nine months. In July 1991, Searle dropped post-MI protection claims for its beta- blocker Kerlone (betaxolol HCl) in response to an FDA letter and Syntex discontinued descriptive superiority claims for its calcium channel blocker Cardene (nicardipine HCl) after the claims came under FDA scrutiny ("The Pink Sheet" July 15, 1991, p. 4). In November of 1991, professional journal ads for the beta-blockers Tenormin (atenolol) by ICI and Lopressor (metoprolol tartrate) from Ciba-Geigy were the subject of FDA warning letters. The agency cited ads suggesting that Tenormin provided protection from myocardial infarction and that Lopressor prevented first, nonfatal MIs ("The Pink Sheet" Nov. 25, 1991, p. 8). Both companies subsequently discontinued the ads. FDA also has been concerned about the promotion of antihypertensives for the treatment of left ventricular hypertrophy. The agency has sent letters over the last five years to all companies marketing antihypertensives to discuss LVH claims, and FDA's Cardiovascular and Renal Drugs Advisory Committee decided in March 1991 that LVH claims cannot be made for antihypertensives until clinical data is in showing long-term benefits ("The Pink Sheet" March 25, 1991, p. 9).