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Executive Summary

Marion Merrell Dow's Carafate superiority claims for duodenal ulcer patients who smoke require a corrective campaign, FDA declared in an Oct. 13 warning letter. FDA is requesting that the company prepare a "Dear Doctor" letter for publication in the 12 U.S. medical journals with the greatest circulation that "states explicitly the full indications" for Carafate and "emphasizes its comparative profile in both treatment of acute duodenal ulcers and in maintenance therapy." Carafate (sucralfate) is approved for the short-term treatment (up to eight weeks) of active duodenal ulcers. The drug is also approved for maintenance therapy of duodenal ulcer patients at reduced doses. The "Dear Doctor" missive, which must be vetted by FDA's Division of Drug Marketing, Advertising and Communications, should go out prior to any new or revised ads/promos for Carafate, DDMAC Acting Director Cheryl Graham, MD, said in the agency letter. Marion Merrell Dow has received the warning letter and is formulating a formal response to FDA, the company said Oct. 21. MMD has been given the standard 15 working days from receipt of the letter to respond to the agency. Marion Merrell Dow also is being requested by the agency to take "prompt action" to correct these violations by immediately halting "any and all aspects" of its Carafate ad/promo campaign deemed violative by FDA; submitting its intent to comply with the ad/promo ban and providing the agency with its corrective action plans; and by avoiding graphics or texts "in future" that "may connect or otherwise remind the target audience of the themes and materials found to be violative." FDA is still evaluating Carafate ads/promos and could find additional violations that may require further remedial actions, the letter warns. The warning letter, Marion Merrell Dow's second this year for a prescription drug and its second letter from FDA in three years on Carafate ads and promotions, again takes the company to task for its advertising and promotional review procedures. Marion Merrell Dow should "reassess its policies and procedures to assure compliance with" FD&C Act requirements and with federal regulations governing ads and promotions, Graham advised. "Failure to comply with this letter," she warned, "may result in further regulatory action, including seizure and/or injunction without further notice." The first 1992 warning letter, on Feb. 14, dealt with a detailer pamphlet for MMD's Cardizem (diltiazem) that claimed the calcium channel blocker could decrease the risk of second heart attack ("The Pink Sheet" March 2, p. 8). FDA requested a "Dear Doctor" letter and warned that, unless the violative ad/promo actions were corrected, it would advise federal agencies not to award contracts for Cardizem products. The agency also cautioned MMD then that corporate officials could be held responsible for the violations. FDA first had raised the Cardizem detailer pamphlet issue a year earlier when MMD said the pamphlet had not been approved by its internal review committee and had been printed by mistake. The failure of the company to remedy its ad/promo review procedures was noted during an October 1991 plant inspection by FDA. That failure, combined with an echo of the past problems with Carafate ads/promos, may have prompted the agency to write the February warning letter. However, after nearly seven months of negotiations on Cardizem, FDA agreed to far less action from MMD to close the matter than that originally warned of in the February letter. FDA advised MMD on Sept. 25 that no further corrective actions were required "in view of MMD's cooperation in receiving the issues raised...including the preparation of a draft manuscript for a possible [FDA] Drug Bulletin article" ("The Pink Sheet" Oct. 5, In Brief). Citing the previous agency letter concerning Carafate, Graham said "the issues discussed in this letter represent a repetitive course of conduct by MMD in its advertising and promotion of Carafate." Some of the same issues, including the use of Carafate by patients who smoke, were raised in a regulatory letter (the agency format that preceded warning letters) dated March 19, 1989. The current letter lays out in detail the "several themes that we consider violative" of the FD&C Act, including the suggestion or implication of "comparative superiority" in the treatment of duodenal ulcers "in patients who continue to smoke." The letter cites Carafate claims that the drug "is superior to other anti-ulcer medications, namely H[2] antagonists, in effectiveness." The promotional materials considered violative by FDA also "state, suggest or imply that Carafate is superior to other anti-ulcer products because it produces equal healing effects in smokers and nonsmokers. Third," Graham wrote, MMD's promotional materials "imply that Carafate is superior to H[2] antagonists with respect to the recurrence of duodenal ulcers in patients on maintenance therapy. Finally," the acting DDMAC director wrote, MMD "alleges that Carafate has comparable efficacy in maintenance therapy in smokers and nonsmokers." With regard to the specific claims that FDA finds violative, Graham wrote that the agency is "not aware of any clinical evidence that supports MMD's assertions" of Carafate's comparative superiority in the healing of duodenal ulcers in patients who continue to smoke. Studies used by MMD to support that claim "neither support [the company's] assertions" of Carafate's superiority over other anti-ulcer drugs "nor that it is superior because of its healing rates in ulcer patients who smoke," the warning letter states. For example, Graham pointed out, a 1987 study published in the journal Gastroenterology by S.K. Lam, et al. and "frequently" cited by MMD as support for its superiority claims in Carafate ads and promotions, uses a lower than recommended dose of cimetidine (SmithKline Beecham's Tagamet) for comparisons; was not designed to compare healing rates of smokers; was not randomized; and did not use smoking status as a stratum in randomization. Graham noted in a footnote that FDA told Marion Labs in 1988 that the comparisons to cimetidine made in Lam et al. were "inappropriate." Graham added that the study "suggests an interesting hypothesis," but said the hypothesis, to FDA's knowledge, has not been tested in support of the Carafate claims being made by MMD. Therefore, FDA considers the claims "misleading and potentially false." Moreover, the ad/promo references to Lam et al. "did not balance or provide for other prognostic factors which may affect healing rates including, but not limited to, sex, age, weight, use of NSAIDs [non-steroidal anti-inflammatory drugs], alcohol consumption, and size of ulcer crater between groups of smokers and nonsmokers," Graham said. "Thus," the FDAer added, "there is no basis for the claim of equal healing rates in smokers and nonsmokers." Therefore, MMD's suggestion of superiority "is misleading and, if the proper studies were conducted," Graham added, "it may prove to be false." Discussing MMD's claims that suggest or imply Carafate's superiority as a maintenance therapy, Graham wrote that the agency "is not aware of any persuasive evidence" to back up the company's claim. For example, Graham cited MMD's promoting Carafate as having "'an unsurpassed remission profile' compared to cimetidine and ranitidine [Glaxo's Zantac]" and noted that the company "provides graphics that allege clinical superiority." To support these claims, the warning letter states that MMD "relies upon published studies that do not meet the standard for trials designed to demonstrate comparable or superior efficacy. Moreover," Graham added, the company acknowledged that "'we agree that conclusions about equivalent efficacy may be premature.'" The statement appeared in a letter to the editor in the March 19 issue of the New England Journal of Medicine. "Finally," Graham wrote, a review of published literature "reveals no basis for MMD's claims, suggestions and implications that, for maintenance therapy for duodenal ulcer patients, Carafate has comparable effectiveness in smokers and nonsmokers."

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