Executive Summary

Glaxo has undertaken a "repetitive course of conduct" to disseminate misleading information about its ulcer drug Zantac in advertising and promotions, FDA charged in a Jan. 13 warning letter to the company. Signed by FDA Drug Marketing, Advertising and Communications Division Acting Director Cheryl Graham, the warning letter maintains that in spite of earlier warnings to the company, Glaxo continues to use drug interaction and adverse reaction data to imply superiority over other gastrointestinal drugs. Glaxo, Graham asserts, also persists in running ads that suggest efficacy for unapproved uses of Zantac. Glaxo said that it has responded to the warning letter and requested a meeting to discuss the issues with FDA. The company said it has discontinued promotional materials making claims referred to in the letter. The FDA warning letter cites numerous incidences in which Glaxo has used drug interaction data to suggest superiority over H[2] receptor antagonists, despite a Notice of Adverse Findings letter sent to the company in May 1986 on the matter. The letter alleges that some Zantac promotional materials contain drug interaction sections that present data "in such a manner as to falsely suggest that Zantac has fewer drugs interactions" than other H[2] antagonists. FDA specifically objected to Glaxo's use of a drug interaction chart with two categories captioned: "Documented: Clinically Significant Drug Interactions"; and "Documented: Significant Effect on Blood Level." The agency asserted that "Glaxo has selectively used certain clinical reports to provide information for the drug interaction chart" to suggest a greater number of clinically significant drug interactions with other H[2] antagonists as compared to Zantac. The drug interaction information included in promotional materials does not appear in approved labeling and is not supported by "substantial clinical experience," FDA said. Glaxo cosponsorship of "mock trials" simulating the decision- making process of hospital formulary committees is also cited by FDA for "grossly exaggerate[ing] the clinical significance of drug interactions with [SmithKline Beecham's] Tagamet, and as a result compel[ing] the conclusion that Zantac is a much safer product than Tagamet." After FDA warned Glaxo about holding mock trials that made similar false and misleading suggestions, the company subsequently conducted another mock trial, the letter maintains. FDA noted that certain Zantac promotional materials discuss patients in the intensive care unit. "By showing these [intensive care unit] patients in promotional materials, the implication is made that they are at risk for bleeding from stress ulceration," the agency maintained, adding that "there can be no suggestion or implication in promotional materials that Zantac may be used in these clinical settings for such uses." Tagamet is approved for prevention of upper gastrointestinal bleeding in critically ill patients, while Zantac is not. Glaxo has been "repeatedly warned against making claims of suggestions for the use of Zantac in critically ill patients in any manner which would suggest or imply an indication for the treatment and/or prevention of stress ulceration," the letter states. FDA is asking Glaxo to issue "Dear Doctor" letters and place ads in 12 medical journals to correct the "false and misleading" information. The agency said it is evaluating "other aspects of Glaxo's promotional campaign" and may determine that "additional remedial measures will be necessary to fully correct the false and/or misleading messages." The "Dear Doctor" letters, which must "explicitly" correct all misleading information included in Zantac promotions, are to be "mailed and published before the dissemination of any new or revised advertising or promotional materials," the warning letter states. In the corrective letter, FDA said "there should be particular emphasis on the fact that Zantac is not approved for prevention of stress ulcer and gastrointestinal bleeding in the critically ill patient." Other advertising and promotional materials distributed by Glaxo have focused on "alleged adverse hemodynamic effects" associated with other H[2] antagonists and have maintained that the same side effects do not result with Zantac therapy, the warning letter states. FDA noted that the data on famotidine [Merck's Pepcid] "are conflicting" regarding such side effects and that cimetidine (Tagamet), "in its approved dosing regimen for prevention of gastrointestinal bleeding in critically ill patients, has not been associated with adverse hemodynamic effects." For Glaxo to make comparative hemodynamic claims, FDA says the company would be required to "submit comparative adverse reaction data from randomized studies with various histamine H[2] receptor antagonists in patients in [ICU settings]." Without such data, FDA remarked, "Glaxo cannot suggest comparable or superior safety to other" H[2] antagonists in cardiovascular patients. FDA objected to the assertion in a July 1992 letter to physicians that Zantac is "unsurpassed" as a treatment for endoscopically diagnosed erosive esophagitis. The agency said it has "no evidence that Glaxo has conducted comparative trials of Zantac versus [Merck's] Prilosec, Tagamet, [Lilly's] Axid, or Pepcid for erosive esophagitis. Without such evidence, it is misleading for Glaxo to promote Zantac as demonstrating unsurpassed efficacy." Glaxo's July letter to physicians also suggests that Zantac has a better safety profile compared to other gastrointestinal agents because the drug is effective "without total inhibition of normal physiologic patterns of acid secretion." FDA said the statement implies that other drugs cause such total inhibition. The agency added that "Zantac, itself, can produce prolonged and profound hypochlorhydria at certain doses, and the differences in antisecretory effects between drugs cannot be assumed to be clinically meaningful." The agency also referred to a brochure distributed by Glaxo, entitled "The Data Base of Documentation: Published References Regarding Ranitidine and Famotidine in Humans." The brochure "suggests superiority of Zantac [over other drugs] based merely on the number of published 'references' in which the product is cited," FDA observed. Glaxo promotions of the use of Zantac for "rapid" and "early" relief of pain due to reflux esophagitis also are cited by FDA as misleading. The agency noted that approved labeling for the treatment of GERD with Zantac states that "symptomatic relief commonly occurs within one or two weeks after starting therapy," not immediately as suggested by the ads. In addition, FDA noted that Glaxo has made "explicit, as well as implied, claims that Zantac is 'equally effective in smokers and nonsmokers.'" The agency maintained that the "data presented do not support the claim that healing rates are equal in smokers and nonsmokers in either duodenal ulcer disease or reflux esophagitis when patients are treated with Zantac." The studies that Glaxo used to support the claim are inadequate, FDA said, because "they do not rule out or control for influences, other than smoking, that may affect healing rates." Marion Merrell Dow received a warning letter in October 1992 for making similar claims for Carafate (sucralfate) in the treatment of duodenal ulcers in patients who smoke ("The Pink Sheet" Oct. 26, 1992, p. 8). FDA requested that the company send Dear Doctor letters as part of its corrective campaign. The Glaxo warning letter may be the DMAC acting director's last corrective action request as she leaves FDA for private industry at the end of February. In addition to Carafate, Graham issued 1992 warning letters on promotional campaigns of Lemmon's Orap, Parke-Davis' Lopid, Hoechst-Roussel's Lasix, and Upjohn's Glynase. Other warning letters issued by DMAC in 1992, signed by Graham's co-acting director Ann Witt before she left on detail to the device center, were for Miles Nimotop, ICI's Zestril and Astra's Yutopar.