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Executive Summary

ICI must send "Dear Doctor" letters to cardiologists and other physicians as part of a corrective action relating to its promotion of the angiotensin converting enzyme inhibitor Zestril (lisinopril), FDA told the company's Stuart Pharmaceuticals subsidiary in a March 2 warning letter. In the "Dear Doctor" letter, Stuart is required to inform physicians of the "violative nature of its previous promotional activities," correct any "resulting misconceptions," and apprise physicians of Zestril's labeling, FDA stipulated. The warning letter was signed by FDA Division of Drug Marketing, Advertising and Communications Acting Director Ann Witt and Office of Drug Evaluation I Director Robert Temple, MD. In addition to ceasing distribution of misleading advertising, detail pieces and press releases, ICI must "submit all promotional materials to [FDA's Division of Drug Marketing, Advertising and Communications] prior to distribution for pre-clearance for a six- month period," FDA added. The requirement could throw a wrench in some of ICI's promotional plans for the upcoming annual meeting of American College of Cardiology, scheduled for April 12-16 in Dallas. FDA is requiring ICI to submit a list of Zestril materials that may contain any promotional violations. Detail pieces identified by FDA in the letter already have been distributed to cardiologists and primary care physicians. ICI maintains that all the materials cited by FDA are in accordance with Zestril labeling. The company plans to work closely with FDA to resolve the issues raised, an ICI spokesman said, and is expected to respond to the FDA letter by March 27. The warning letter identifies three primary violations in ICI's promotion of Zestril: "that Zestril [lisinopril] is distinct from other ACE inhibitors in being able to control all patients with a single daily dose, whereas others sometimes need twice daily dosing; that Zestril is not a pro-drug and that this is a clinically meaningful distinction in contrast to other ACE inhibitors; and that Zestril is uniquely able to reduce cardiac hypertrophy, stroke, and other complications of hypertension because of its once daily dosing (24-hour effect) and ACE- inhibiting properties." FDA maintained that it is "not aware" of any clinical evidence supporting the the ICI claims for Zestril. "In fact, there are no clinical studies that distinguish the effectiveness of Zestril from any of the ACE inhibitors that are approved and labeled for once daily or twice daily use," FDA asserted. The agency finds "no adequate data" to support an advantage of Zestril "or other ACE inhibitors" with respect to morbidity or mortality related to hypertension. "Indeed, unlike agents such as thiazide, diuretics and beta-blockers, no ACE inhibitor has been shown to reduce stroke, mortality, or congestive heart failure in hypertensive patients," FDA asserted. Further, the use of the name Zestril in ICI materials on the mechanisms of heart failure "suggests that Zestril is valuable in the treatment of congestive heart failure," when in fact the drug, "unlike other ACE inhibitors," is not indicated for that use, FDA said. Bristol-Myers Squibb's Capoten (captopril) is indicated as a second-line therapy for congestive heart failure patients. The warning letter notes that while the Zestril labeling only recommends once-daily dosing, as opposed to either once or twice daily for other ACE inhibitors, "this difference exists -- not because twice daily dosing has been shown to be less helpful for Zestril than for other agents, but because Zestril was never studied in a twice-daily regimen." Nor is there evidence from controlled studies that Zestril provides better 24 hour-blood pressure control than other ACE inhibitors, the warning letter states. "In fact, some patients on every ACE inhibitor evaluated to date, including Zestril, show a loss of effect toward the end of the 24-hour dosing interval," the letter observes. FDA noted that in the recent approval of Bristol- Myers Squibb's Monopril (fosinopril), based on studies of a once- daily dosing regimen, the agency labeled the new ACE inhibitor as once-a-day or twice-a-day therapy, presumably to eliminate comparative claims. Addressing promotional suggestions that Zestril is superior to other therapies in the areas of hypertension and mortality, FDA said that "some ACE inhibitors, like enalapril [Merck's Vasotec], are effective in enhancing survival in certain patients with [chronic heart failure]"; however, "lisinopril has never been studied in that setting." FDA asserted that Stuart's detailing pieces attempt to link Zestril's once-daily dosing claim "to the putative value of ambulatory monitoring in prediction of left ventricular hypertrophy and stroke, and to the possible relation of 'BP load' to prognosis, in absence of any outcome data." The detail pieces leave "the clear and clearly misleading implication" that Zestril reduces the rate of silent stroke and left ventricular mass index and does so better than other agents, FDA said. The warning letter cites a press release issued by ICI during the 1991 American College of Cardiology meeting, entitled "The Role of ACE Inhibitors Following Myocardial Infarction," as containing a "lengthy discussion" of the role of ACE inhibitors in preventing left ventricular hypertrophy after myocardial infarction. However, the press release "barely" mentions that fact that Zestril has not been shown to be useful in this setting, FDA said. The agency noted that ICI's Stuart and other marketers of antihypertensive drugs were warned against suggesting that their drugs may modify LVH in a Sept. 25, 1991 letter to the firms from FDA Cardio-Renal Drug Products Division Director Raymond Lipicky, MD. An excerpt from the letter states that the Cardiovascular and Renal Drugs Advisory Committee concluded at a March 15, 1991 meeting that "at present there were no controlled clinical trial data that allowed any conclusion to be drawn regarding the effects of any single drug, or any class of drugs on left ventricular hypertrophy" and that all promotions relating to this topic should cease ("The Pink Sheet" March 25, 1991, p. 9). Violations cited by FDA are not necessarily exhaustive, the letter concludes. The agency is "evaluating other aspects of Stuart's campaign and additional violations may be identified." Until ICI takes corrective action, "federal agencies will be informed that FDA recommends against the award of contracts for Zestril products," FDA warned. Zestril ads have run into trouble before. In December 1990, a Trenton, N.J. court ordered ICI to run corrective ads in medical journals and send "Dear Doctor" letters to 100,000 physicians retracting safety claims the company had made for Zestril compared to Bristol-Myers Squibb's Capoten ("The Pink Sheet" Feb. 4, 1991, T&G-3). ICI's ads stated that Zestril was associated with a lower incidence of rash and taste disturbance than Capoten. The comparative ads also declared that once-daily Zestril controls blood pressure better than b.i.d. Capoten. The same court denied Bristol-Myers Squibb's motion for a preliminary injunction on the efficacy claims. However, the companies settled their dispute out of court in April 1991 after ICI agreed to discontinue its comparative efficacy claim ad campaign, which had been based on a study that appeared in the December 1990 issue of the Journal of Clinical Pharmacology. The Zestril letter marks the second time in three weeks FDA has taken on cardiovascular drug claims. On Feb. 14, FDA sent a warning letter to Marion Merrell Dow for claims of decreased post- myocardial reinfarction with Cardizem ("The Pink Sheet" March 2, p. 8). The letter also is the second warning in four months that FDA has issued to ICI regarding cardiovascular claims. In November, the company received a warning letter concerning myocardial infarction protection claims for Tenormin (atenolol) ("The Pink Sheet" Nov. 25, 1991, p. 8).

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