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OTC SMOKING DETERRENTS MUST SHOW LONG-TERM DECREASE IN SMOKE EXPOSURE

This article was originally published in The Tan Sheet

Executive Summary

OTC SMOKING DETERRENTS MUST SHOW LONG-TERM DECREASE IN SMOKE EXPOSURE in order to gain monograph status, FDA said in the final monograph for OTC smoking deterrent drug products. Published in the June 1 Federal Register, the final rule explains that "follow- up data on changes in smoking behavior have indicated that most smokers . . . [who] reduce their smoking without totally stopping, return to baseline smoking levels." Consequently, the agency concluded "that a study in support of a claim of reduction in smoking must demonstrate long-term reductions in total smoke exposure." FDA added that "if the only dependent variable to be measured is the 'number of cigarettes smoked per unit time,' applying data analysis to only this variable may not be sufficient to support a reduction claim because individuals may compensate for changes in nicotine levels." In general, FDA declared that "if sufficient evidence is provided demonstrating that a reduction in smoking leads to cessation or results in a significant health benefit to consumers, the agency will consider reduction claims for smoking deterrent drug products." The final monograph does not place any ingredients in Category I (safe and effective) ("The Tan Sheet" May 31, In Brief). The agency emphasized in a June 2 press release, however, that it has told companies that it is "anxious to work with them to develop new products in this area." "Several manufacturers" of OTC smoking deterrent products "have discussed with FDA the possibility of conducting clinical trials on lobeline sulfate and silver acetate" as smoking deterrents, the release says. If adequate data become available through well-controlled clinical trials, FDA explained in the monograph, "such data may be submitted in a citizen petition to establish a monograph." In the meantime, FDA noted that prescription smoking cessation drugs are available. Marion Merrell Dow, which manufactures Nicorette chewing gum, "has expressed interest in gaining FDA approval for switching the product to nonprescription status," FDA noted. However, prior to an Rx-to-OTC switch, the agency noted that it would "need to consider carefully Nicorette's own potential for addiction, since it contains nicotine." Also available with a prescription are a number of nicotine patches, including MMD's Nicoderm, Ciba's Habitrol and Warner-Lambert's Nicotrol. The monograph becomes effective on Dec. 1, 1993, but smoking deterrent products "may continue to be sold until supplies are exhausted," the agency said. As in the July 1985 tentative final monograph for OTC smoking deterrent products, FDA said there were inadequate data to allow lobeline sulfate and silver acetate as Category I ingredients under the monograph. For lobeline sulfate, FDA said it agreed with an OTC panel determination that data do not show effectiveness of the ingredient for smoking cessation -- the only claim recognized by the panel as appropriate for OTC smoking deterrents. Data on lobeline sulfate that were subsequently resubmitted to support a claim for "reduction in smoking leading to cessation or lowering the health risks associated with smoking" were also deemed insufficient by FDA because they measured "only short-term [smoking] reductions" of four months to one year. "If reduction- in-smoking claims are to be considered acceptable, criteria similar to those needed to establish 'cessation' should be used to establish 'reduction' in smoking as a viable goal," FDA said. The agency suggested that "the smoking status of the subjects should be evaluated at the end of four months" because "recidivism is greatest within four months" and the "follow-up period should adequately indicate long-term effectiveness of the treatment." The OTC review panel suggested that smoking deterrent studies should span at least four weeks, and include one week of pretesting and a three-week study period, FDA pointed out. "An evaluation of effectiveness should take place at least three weeks after the drug is started." Any difference between the drug and placebo for periods shorter than three weeks is not "clinically significant," FDA added, although it may be "statistically significant." Regarding studies submitted on silver acetate, FDA said data do not support the inclusion of the ingredient in the monograph. Although one double-blind, placebo-controlled study that was submitted had sufficient design and methodology, FDA said that an inappropriate criterion of "treatment success" was used. The study defined treatment successes as individuals who stopped smoking as measured by self-reporting, and confirmed by blood carboxyhemoglobin levels and urinary nicotine metabolites; treatment failures were subjects who had not stopped smoking by day 18 of the 21-day study, according to the notice. "The assessment of the data collected to determine the effectiveness of the drug was, therefore, limited to a three-day period (days 18 to 21)," FDA said, declaring that "the agency does not consider a three-day period of abstinence from smoking to be sufficient predictor of the effectiveness of a drug that is intended to result in smoking cessation." In a study with this objective, "subjects should stop smoking within the first 24 to 48 hours after beginning the drug and should be considered 'treatment successes' only if they abstain from smoking for the remainder of the study," the notice states. FDA added that "even if this criterion were not applied," the study results on silver acetate were "marginally significant, at best," with 15 of 136 subjects in the silver acetate group and six out of 146 subjects in the placebo group quitting smoking. The study also lacked case report forms and subject diary cards, and failed to provide the point at which each subject quit smoking during the study and follow-up periods, FDA stated. Another study evaluating silver acetate chewing gum in an open-label, parallel group setting also contained "major flaws in design, conduct and analysis," FDA said. The agency noted that a placebo group was "virtually nonexistent." No studies were submitted to support the efficacy of povidone- silver nitrate as an OTC smoking deterrent ingredient. A November 1990 notice, effective May 1991, removed 11 other ingredients from consideration as smoking deterrents: clove, coriander, eucalyptus oil, ginger, lemon oil, licorice root extract, menthol, methyl salicylate, quinine ascorbate, silver nitrate and thymol.

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