DRUG ADVERTISING WARNING LETTERS HAVE DOUBLED IN FY 1992

DRUG ADVERTISING WARNING LETTERS HAVE DOUBLED IN FY 1992 from the number issued in the previous two years, FDA Division of Drug Marketing, Advertising and Communications Acting Director Cheryl Graham, MD, said at a Sept. 14 Food and Drug Law Institute meeting on advertising and promotions. Nine warning letters have been issued in this fiscal year to date; however, five of those are still considered open files according to an update provided by DDMAC's Regulatory Counsel Norman Drezin. Asked if protracted discussions between companies and FDA over compliance with warning letters indicates that the regulatory tool is losing its impact, Drezin replied: "No, not at all." Discussing the length of negotiations with five companies, Drezin said: "I think the issue is that each one of these cases is very unique and goes back and forth as far as what the text should be for a 'Dear Doctor' letter or some other type of remedial campaign." He noted: "In each instance, the campaign or materials ...had ceased and been removed from distribution. And any other type of remedy is part of the negotiation process, and I don't think that you can really say that that process should take two weeks or four weeks or two months." The five cases still pending resolution are for promotions of: Marion Merrell Dow's Cardizem, Miles' Nimotop, Stuart's Zestril, Lemmon's Orap and Hoechst-Roussel's Lasix. Almost seven months after receiving a warning letter, Marion Merrell Dow is still in discussions with FDA over a detailer pamphlet for Cardizem (diltiazem) that claimed the calcium channel blocker can decrease the risk of second heart attack. FDA had first raised the issue with MMD a year earlier, at which point the company assured the agency that the pamphlet had been printed by mistake ("The Pink Sheet" March 2, p. 8). FDA sought a corrective campaign addressed to all physicians who had received the pamphlet; the agency did not request preclearance for future Cardizem ads. MMD met with FDA to explain why it felt a corrective campaign was unnecessary; no letter has been sent. MMD said both the company and FDA are anxious to get the matter resolved. Drezin noted that the detailer "was an unusual circumstance because it was, we understand, prepared to be a backgrounder...and somehow wound up in a detailing pouch and going to doctors' offices." Miles received a Feb. 21 warning letter for a journal ad that promoted Nimotop (nimodipine) for the unapproved use of preventing or treating cerebral ischemia not specifically related to the approved indication of subarachnoid hemorrhage. At the time, Miles maintained that the ads were "well within the approved indication" ("The Pink Sheet" March 2, p. 12). In a May 22 letter from Miles to FDA's Graham, the company noted that it has complied with many of the requests made by FDA in the warning letter. However, Miles said "the request to impose a one-year preclearance of Miles promotion and advertising seems unnecessary in light of Miles' actions to cooperate with [DDMAC]." Drezin said that revised ads for Nimotop have the approved indication "right up front, on top." FDA said the case is still an open file. Six months after getting a warning letter for Zestril (lisinopril), ICI's Stuart Pharmaceuticals is still talking with FDA about ads and promotions, which made superiority claims over other angiotensin-converting enzyme inhibitors based on Zestril's once-daily dosing. FDA requested that the firm send out "Dear Doctor" letters and submit to six months of preclearance for all future promotions ("The Pink Sheet" March 23, p. 12). ICI has not sent out a "Dear Doctor" letter. The firm said that it is involved in ongoing discussions with the agency "to resolve the issues raised in the warning letter." At the FDLI meeting, Drezin noted that "we're still in negotiations on the remedy." Lemmon received a warning letter May 7 for Orap (pimozide) promotions that FDA felt did not sufficiently emphasize the drug's risks or indication as a second-line therapy for Tourette's syndrome. FDA requested a "Dear Doctor" letter and one-year preclearance for all future promotions ("The Pink Sheet" May 25, p. 6). Lemmon said it does plan to issue a letter to physicians but is still "working to resolve the matter with FDA." Drezin noted that "after the warning letter, the firm came out with a new ad and all of the indications and warnings are presented [in] full disclosure and fair balance." Hoechst-Roussel has been in negotiations with the ad division for about three months over alleged false and misleading superiority claims for is loop diuretic Lasix (furosemide). In a June 24 warning letter, FDA said that numerous promotional materials for Lasix contained false superiority claims over generic products. FDA requested that the firm issue a "Dear Doctor" letter via direct mail and through paid ads in 12 medical journals having the greatest U.S. circulation ("The Pink Sheet" July 13, p. 8). Hoechst said the company "continues to work with FDA to resolve the issues raised in the warning letter." Warner-Lambert, in contrast with these protracted negotiations, complied quickly with FDA's June 4 warning letter concerning ads for Lopid (gemfibrozil) that the agency believed were false and misleading and promoted the drug for unapproved uses ("The Pink Sheet" June 22, p. 13). At a June 16 meeting with FDA, Warner-Lambert agreed to send out 225,000 "Dear Doctor" letters. The letter began to appear as an ad in the Aug. 13 issue of The New England Journal of Medicine. Concerns raised in three warning letters issued in fiscal 1992 have been resolved. ICI and Ciba-Geigy drew Nov. 6, 1991 warning letters for Tenormin myocardial infarction protection claims and Lopressor first nonfatal MI prevention claims ("The Pink Sheet" Nov. 25, 1991, p. 8) Astra got a warning letter Feb. 12 for a misleading promotional brochure for its preterm labor drug Yutopar that discussed an unapproved use ("The Pink Sheet" Feb. 24, T&G- 9). FDA discussions with ICI and Ciba lasted for several months. FDA's Drezin said that the Tenormin and Lopressor ads "were both stopped at that time, and as far as I know, those matters are resolved." Astra responded in a Feb. 24 letter to FDA, saying it previously had suspended use of the brochure and would commit to ad preclearance for one year.