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Executive Summary

Bristol-Myers distributed promotional materials touting Enkaid use in patients with mild arrhythmias despite FDA's attempts to persuade the firm to revise the materials, according to documents released by Rep. Weiss' (D-N.Y.) Intergovernmental Relations subcommittee at an April 10 hearing. The primary focus of the hearing was a review of the approvals of Enkaid and 3M Riker's Tambocor (flecainide) and FDA's awareness of the drug's pro-arrhythmic effects ("The Pink Sheet" April 15, p. 16). Although the two products were approved for both life- threatening and mild arrhythmia, they were later relabeled when results from the CAST study showed an increased risk of death in mild arrhythmia patients taking the agents. Weiss cited an estimate, based on an informal survey of cardiologists, that up to 3,000 patients with non-life-threatening arrhythmias died while taking Tambocor or Enkaid. "Certain promotional materials minimized the risks of the drugs while exaggerating their safety," the subcommittee chairman said. "Clearly, Tambocor and Enkaid were overprescribed for mild arrhythmias." Office of Drug Evaluation I Director Robert Temple, MD, testified at the hearing that FDA's problem in regulating the promotional campaigns for both products was that they were approved for the broader indication of non-life-threatening arrhythmias. The promotional campaigns "did not accurately convey the proper place of the drug in therapy," Temple acknowledged, but the indication "we thought was overemphasized was, in fact, an approved indication." FDA documents released after the Enkaid/Tambocor hearing show that Bristol-Myers sought FDA preclearance of a "visual aid" to be used by the firm's detail force during the spring 1987 launch of Enkaid. The drug was approved in December 1986. Bristol-Myers Regulatory Affairs Associate Director Duane Morrow, PhD, asked the agency in a Jan. 16, 1987 letter to review the promotion "within 10 days" in order to give the company time to have the final material ready for the product's scheduled launch. However, FDA documents indicate that the agency had "serious problems with the material." According to the visual aid, Enkaid is "an alternative to quinidine" that provides "the anti-arrhythmic benefits of quinidine without significant GI distress." The material also declares that "classic anti-arrhythmic therapy is now improved," Enkaid "controls symptomatic nonsustained ventricular tachycardia more effectively than quinidine -- with fewer therapy-limiting side effects," and results in a "significantly greater proportion of patients controlled" and "significantly less diarrhea." Notations on an FDA copy of the brochure indicate that the agency felt that the visual aid, in referring to Enkaid as an improvement over quinidine, provided "no adequate fair balance," "distorted" the "serious nature" of the disease for which the drug was indicated, and ignored the "different levels" of precautions applicable to the drugs. According to an official FDA memorandum of an internal agency review of the proposed brochure, S.K. Chun, MD, at the time one of the Cardio-Renal Division's medical officers, indicated that "the material needed modification" in that it "needed more balance," "more emphasis about the drug's limitations of use (efficacy)," and information on "worsening arrhythmias, malignant arrhythmias and its pro-arrhythmic effects." In her own memo of Feb. 2, 1987, Chun wrote that the visual aid "is totally unbalanced and unacceptable." Despite FDA's problems with the promotional material, Bristol- Myers was told by agency staffers that FDA was "unlikely" to take regulatory action against the company if the material were to be distributed. An FDA memo of an April 1987 meeting between representatives of Bristol-Myers and FDA regarding the revised brochure states that the company representatives "asked about possible remedial action if they proceeded with their present campaign." Drug Advertising & Labeling Division Acting Director Kenneth Feather replied that Enkaid "could be declared misbranded and all material and drug would be seized," the memo states. "He acknowledged, however, after an inquiry from [Cardio-Renal Division Director Raymond Lipicky, MD,] that this was probably unlikely." Several weeks earlier, Bristol-Myers had made several minor revisions in the promotional material: "Classic therapy is now improved" was changed to "An alternative to classic therapy." According to an FDA memo of a meeting between agency and company officials, Lipicky stated that he and Temple "agreed the material was completely unacceptable as modified." The memo reports FDA told the firm that "the revised material did not address or correct the issues or concerns" raised earlier by the agency. According to the memo, Bristol-Myers was also told by FDA "that the detail aid could not be used as proposed." The memo of the April 1 meeting reports that Lipicky "was upset" by the brochure "because he felt the overall thrust of the campaign was wrong." The memo said that Lipicky's "initial reaction after reading the first nine pages of the flyer is that anyone now on quinidine should be switched to encainide." Lipicky, the memo said, "felt that imparting this general thought to the medical community would be a tragedy." Rather than redraft and reprint a totally new brochure, Bristol-Myers proposed adding a cover letter or a new first page to highlight the appropriate limits of use and precautions. At an internal FDA meeting on April 2, Temple "recommended that the firm prepare a new replacement first page that clearly sets out the indications and limitations," according to a memo of that meeting. Bristol-Myers responded that it was facing competitive marketing pressures from Riker. According to an FDA memo, Lipicky "agreed that [3M Riker] also targeted the same [less seriously ill] patients" However, Lipicky noted that the Tambocor manufacturer "did not base the bulk of their campaign on their quinidine positive controlled trial." Bristol-Myers also told FDA the ad was "caught at the worst possible time . . . in the initial launch stage for the drug. The material is printed up, and it is the only material they have," the memo states. Regarding the material, "the firm asked about 'rescuing' the ad" since it was already printed. An FDA memo also says that Bristol-Myers "reaffirmed that their statements in the ad are not inaccurate" but "simply may lead some people to the wrong conclusion." The memo of the meeting closes with the question and answer regarding the likelihood of regulatory action if Bristol- Myers used the revised material despite FDA's continued objections. An Oct. 30, 1987 letter from FDA to Bristol-Myers indicates that the ad campaign proceeded essentially unchanged. Subsequent Enkaid advertising was "either the same or that closely resembling the initial campaign" and continued to raise "concerns with Drs. Temple and Lipicky," the letter states. Although FDA permitted Bristol-Myers to simply add a new first page to the launch material, the agency said it had agreed to the measure as "only an interim measure to salvage prepared material" for the initial launch. The hearing record also includes an Enkaid ad that ran in the April 1989 issue of the American College of Cardiology journal and indicates that FDA failed to effect substantial changes in the campaign. The ad claims: "The anti-arrhythmic benefits of quinidine with fewer noncardiac side effects."

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