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Executive Summary

Wyeth-Ayerst has been asked by FDA to review all of its promotional claims for the company's prescription drugs and all studies on which those claims are based to ensure their validity and compliance with FDA statutory and regulatory requirements. In a Dec. 15 regulatory letter to Wyeth-Ayerst Chairman Bernard Canavan, MD, FDA Office of Drug Standards Director Peter Rheinstein, MD, asked the firm to "submit a listing of all studies that are currently referred to in support of any promotional claim for any prescription drug product distributed or marketed by your firm." The letter also asks the firm to "identify those studies that are adequate and well controlled." For those studies not considered adequate and well-controlled, FDA asked the firm to discontinue all claims citing such a study "for any product distributed or marketed by your firm." In addition, FDA requested that the company submit English language copies of each study not considered adequate or well controlled as well as each promotional piece citing such a study. FDA accused Wyeth-Ayerst of having an "intolerable" record of noncompliance with FDA standards for drug promotions, particularly recent promotions for the firm's anti-arrhythmic Cordarone and transdermal nitroglycerin Deponit. * "An examination of your firm's current overall degree of compliance" with FDA law and regs shows "a series of actions by your firm that indicate a general and willful disregard for legal and regulatory limitations upon drug promotion," the letter states. Wyeth-Ayerst's reputation as an aggressive marketer, particularly versus generics, has given the company a reputation on Capitol Hill. The FDA letter could reinforce that reputation and whet any appetites for promotion investigations. Sen. Kennedy (D-Mass.), for example, has been stalking the issue of pharmaceutical marketing practices and sent a series of letters to the industry last summer. Rep. Dingell (D-Mich.) has also been keeping a close eye on the brandname industry, especially companies looking to capitalize on the generic scandal. FDA's tough language to Wyeth-Ayerst may represent an effort by the agency to assume the pose of a reinvigorated enforcement agency. "During calendar years 1988 and 1989, the Division of Drug Advertising and Labeling has issued 18 notices of violations" to Wyeth-Ayerst, FDA said. "In case after case, your firm has disseminated promotional materials that are clearly false and misleading, [and] in case after case, you have discontinued or extensively modified these claims at the insistence" of the division. Wyeth-Ayerst "has an intolerable record of compliance with the law, compounded by your recent promotion of Deponit and Cordarone," FDA said. Promotional campaigns "continue to present false and/or misleading information regarding the safety and/or efficacy of these products," the reg letter states. FDA accused Wyeth-Ayerst of "repeatedly" using "open-label studies without a concurrent control group as the basis for false and misleading substantive promotional claims, and after being specifically warned by FDA against such conduct." FDA noted that Wyeth-Ayerst "continues to promote Cordarone [amiodarone HCl], an extraordinarily hazardous drug, in a manner we consider clearly misrepresentative of its known hazards." The agency asked Wyeth-Ayerst to suspend all Cordarone promotional activities and to agree "not to employ any promotional materials or support any promotional activities for Cordarone until those materials and activities have been" precleared by FDA. The company also is being asked to take corrective action. FDA asked Wyeth-Ayerst to "draft and submit to FDA a letter to be sent to every person to whom promotional materials for Cordarone have been mailed or disseminated by your detail force during calendar years 1988 and/or 1989 to correct the false and/or misleading impressions conveyed by your promotional campaign for this product." The firm was given 10 working days after receiving the reg letter to respond. FDA's criticism of Cordarone promotion follows an October journal ad and the use of a promotional brochure by the Wyeth-Ayerst sales force, which, the agency says, minimize the hazards associated with the drug and encourage wider use of the drug than is indicated in labeling. Wyeth-Ayerst "has been warned repeatedly against promoting the drug in a manner inconsistent with" the product's "cautionary labeling," FDA said. As recently as Feb. 17, the company was advised by FDA "that the content and emphasis of then-current journal advertisements for Cordarone were fundamentally inconsistent with the content and emphasis of the approved labeling," the letter states. FDA noted that "Cordarone is indicated only for treatment of documented, life-threatening recurrent ventricular arrhythmias...when these conditions have not responded to documented adequate doses of other available anti-arrhythmics or when alternative agents cannot be tolerated. Cordarone is clearly labeled as an anti-arrhythmic of last resort." Further, the letter notes that approved labeling "makes clear that Cordarone should be administered only by physicians who are expert in the treatment of recurrent, life-threatening arrhythmias." Nonetheless, review of an October journal ad "indicates that our cautions have been ignored," the letter states. The ad "is clearly intended to minimize the hazards of the drug and emphasize the drug's efficacy." Cordarone brochures, submitted for agency review last May, "also minimize hazards associated with administration of Cordarone by suggesting that it is possible to administer the drug in a manner that eliminates the need for concern over these hazards," FDA said. Further, citing a statement that "an early decision for Cordarone...can improve the odds," the agency said the campaign "clearly fails to recognize the drug's unique role as a drug of last resort" and therefore constitutes "an unapproved use for Cordarone." FDA's objections to Deponit promotional activities include the use of brochures citing efficacy claims derived from an uncontrolled study conducted by Wyeth-Ayerst. The reg letter asks Wyeth-Ayerst to "suspend dissemination," recall, destroy, "and verify recall and destruction of" all Deponit brochures "and all similar promotional labeling pieces." It also asks that all similar Deponit journal ads be suspended. FDA said the claims are false and/or misleading because they are based on the study, which "was incapable by design of a valid assessment of efficacy of this product." For example, improvements of episodes of angina in the unblinded study "were attributed entirely to efficacy of the test drug, rather than to the numerous other likely sources." FDA said it had "specifically advised" Wyeth-Ayerst that "studies of this type cannot provide an adequate basis for any substantive promotional claim" of efficacy. In addition, "the manuscript of the Deponit study was received by the publisher for publication on Aug. 24, 1988, months after our discussion of the deficiencies inherent in a study of this type. Such disregard for accepted scientific/medical principals related to quantification of drug effect, as well as for clear agency standards, requires action on our part." Furthermore, use of the brochures began more than one month before they were submitted to the agency in October by Wyeth-Ayerst. FDA requires that promotional pieces be submitted "at the time of initial dissemination."

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