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BERLEX' QUINAGLUTE SUPERIORITY CLAIMS OVER GENERIC QUINIDINES SPUR WARNING LETTER FROM FDA; ROULETTE WHEEL, D.A.W. AND B.I.D. DOSING INSTRUCTIONS ARE AT ISSUE

Executive Summary

Berlex promotional claims that its Quinaglute Dura-Tabs (quinidine gluconate sustained-release tablets) are superior to generic quinidine products drew an April 2 warning letter from FDA. The company's "current promotional labeling contains representations that Quinaglute is superior to generic brands of sustained-release quinidine gluconate 324 mg tablets," the warning letter states. "The materials show a graphic of a roulette wheel that appears to contain generic sustained-release quinidine gluconate products in the roulette slots." The promotional materials -- brochures and fliers used by Berlex sales reps to detail Quinaglute Dura-Tabs -- contain the statements: "Don't gamble with substitution variables" and "Specify 'Dispense as Written' in accordance with your state's regulations." Other statements in the materials are: "Prescribe Quinaglute: The reference standard by which all long-acting quinidine gluconates are measured; BID [twice-daily] dosing to enhance compliance; more than three decades of therapeutic reliability; [and] The Berlex commitment to cardiovascular medicine." These statements, the warning letter asserts, "suggest or imply that 1) Quinaglute is superior to its generic competitors; 2) that to prescribe and to use generic quinidine gluconate 324 mg sustained-release products is a gamble, i.e., is a greater risk than to prescribe and use Quinaglute; and 3) that generic products are not safe or effective." The promotions "conflict with FDA's determination that all 'AB'-rated generic versions of quinidine gluconate 324 mg sustained-release tablets are therapeutically equivalent to Berlex' product," the warning letter states. "Moreover, Berlex has not presented any evidence that substantiates its superiority claims or that establishes that the generic products are not therapeutically equivalent to Quinaglute." Furthermore, the letter continues, "Berlex' emphasis on BID dosing is misleading, not consistent with the approved labeling and may pose significant safety issues for patients who may receive inadequate dosing regimens because of Berlex's promotional message." FDA also took exception to promotional labeling in which Berlex cites an uncontrolled, retrospective study "to support Berlex' claims that Quinaglute is 'less likely to cause GI side effects' in comparison to Quinidex Extentabs (extended-release quinidine sulfate; A.H. Robins Company) and that is has the 'lowest total discontinuation rate among all Class I antiarrhythmics.'" FDA said that such comparative claims "must be based on adequate and well-controlled comparative trials [and] Berlex has not referred to such trials and [the Division of Drug Marketing, Advertising and Communications] is not aware of any trials that support such claims." Berlex "has previously attempted to generalize the results of a single retrospective review to claim a lower discontinuation rate for quinidine versus other Class I antiarrhythmic agents," the letter reminds Berlex. FDA sent a letter to the firm Oct. 15, 1992 about that claim. Moreover, the agency wrote, Quinaglute promotions contain "claims in regard to 'quality of life' and 'cost-effectiveness' [and] in the absence of definitive, adequate, and well-controlled trials that use Quinaglute and that assess 'quality-of-life' issues, such claims are unsupported." The promotions also say that Quinaglute is "cost-effective" in comparison to Quinidex. "However, mere reference to average wholesale price (AWP) information is inadequate to support such claims," the FDA letter states. FDA has asked Berlex to prepare "corrective" messages for healthcare personnel about the Quinaglute promotions and to "cease immediately the use of any and all aspects of its advertising and promotional campaign that are violative." Berlex said April 6 that it is cooperating with FDA but is still in discussions over some points of disagreement. Among the actions requested by FDA is a "'Corrective Message' letter that states 1) there is no therapeutic difference between Quinaglute and any other 'AB'-rated generic 324 mg sustained- release quinidine gluconate tablet; 2) that Quinaglute should be dosed every 12, 8, or 6 hours depending upon the need; and 3) that there are no adequate and well-controlled studies to suggest that Quinaglute has a lower gastrointestinal adverse reaction or discontinuation rate than any other Class I antiarrhythmic." The "Corrective Message" letter "is to be disseminated both by direct mail to all healthcare personnel to whom Berlex promoted Quinaglute during the 24 months prior to the date of this warning letter and through a paid advertisement in at least 12 medical, pharmacy or other healthcare journals," the warning letter states. The journals should include those that have run ads for Quinaglute "within the 12 months prior to the issuance of this warning letter." FDA said it wants to ensure the message is seen by a large audience since it is not sure how widely the materials were disseminated. The letter seems to go beyond previous warning letters by emphasizing the need for the sales team to be informed about alleged violative claims in promotions. Berlex should "disseminate a copy of this warning letter to all Berlex sales managers and representatives and to all sales managers and representatives that promote Quinaglute pursuant to co-marketing agreements or contracts for services within 15 days of receipt of this letter," FDA said. Recently appointed DDMAC Acting Director Janet Rose signed the letter. Before joining FDA, Rose was a sales exec with Mead Johnson Pharmaceuticals ("The Pink Sheet" March 15, T&G-5). Alleged false and misleading superiority claims for a brandname drug versus a generic product resulted in a June 1992 warning letter to Hoechst-Roussel concerning its promotions for Lasix (furosemide). The warning letter said that Hoechst made unsubstantiated claims that Lasix is superior to generics and that switching to or between generic furosemide products could result in undesirable outcomes. Hoechst had been cited by FDA in 1986 for similar claims for Lasix. The warning letter pointed out that all furosemide products are therapeutically equivalent. The company also made price comparisons to generics without submitting data on how the prices were derived, FDA said. At FDA's request, Hoechst ran ads in the form of a "Dear Doctor"/"Dear Pharmacist" letter to correct those messages in January issues of 10 medical and pharmacy journals ("The Pink Sheet" Jan. 11, T&G-4). Claims of superiority for drug products versus other products within the same therapeutic class also have been cited by FDA in recent warning letters. In January, Glaxo received a warning letter for a "repetitive course of conduct" to disseminate drug interaction and adverse reaction data implying that Zantac (ranitidine) is superior to other gastrointestinal drugs ("The Pink Sheet" Feb. 8, p. 21). FDA requested that Glaxo send a "Dear Doctor" letter and issue a corrective ad in 12 medical journals. The letter is expected to be issued soon. Marion Merrell Dow received a warning letter in October for misleading claims that Carafate (sucralfate) is superior to other antiulcer drugs, namely H[2] antagonists, for treating active duodenal ulcer in patients who smoke and for treating recurrence of duodenal ulcers in patients on maintenance therapy ("The Pink Sheet" Feb. 22, T&G-9). MMD issued a "Dear Doctor" letter to 225,000 physicians and ran the letter in March issues of 12 medical journals to correct those promotional messages.
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