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Executive Summary

FDA will take another look at OTC antihistamine labeling claims for treating cough/cold symptoms, Center for Drug Evaluation & Research Director Carl Peck, MD, declared at an April 8 hearing before the House Government Operations/Intergovernmental Relations subcommittee. Although "there has been no change" in the status of cold claims in the current draft of the antihistamine OTC monograph, Peck said "there has been no final decision." Calling the OTC Review an ongoing "process," he added: "I can assure you that the agency is expecting to take a careful look at that section of the proposed monograph and determine, on the basis of all currently available information, whether antihistamines are effective in the common cold." Emphasizing that the OTC antihistamine tentative final monograph, which allows cold claims for antihistamines, is a proposal and does not represent a final conclusion by FDA, Peck said: "Evidence that was presented" during the hearing to suggest that antihistamines, regardless of their anticholinergic effects, have no effect on cold symptoms "will certainly be taken into consideration" before the agency publishes its final monograph. University of Florida Pharmacy and Pediatrics Professor Leslie Hendeles expressed skepticism on the role of antihistamines. Patients may think antihistamines are effective in treating colds because they experience symptomatic relief from the decongestant component of OTC cough/cold products but not from the antihistamine component, Hendeles told the Weiss hearing. Patients also may be confused by the fact that a cold is self-limiting and mistakenly attribute to the OTC drug any improvement in the cold after a few days. "Scientific research clearly indicates that antihistamines and expectorants provide no more relief of [cough/cold] symptoms than a placebo," contended Hendeles, a member of FDA's Pulmonary- Allergy Drugs Advisory Committee. Prescription and OTC antihistamines are effective against allergies, he explained, because pollen makes cells lining the nose and eyes release histamine, which "causes itching of the nose, sneezing, runny nose and red, watery, itchy eyes." Antihistamines "specifically block the tissue effects of histamine" and "thereby reduce or prevent" the symptoms, Hendeles maintained. Although similar symptoms are associated with colds, "there is no rationale for the use of antihistamines" to treat them, Hendeles said. "Scientific studies have conclusively demonstrated that these symptoms are not caused by histamine," he said. A viral infection "results in the release of chemicals caused kinins," which inflame the lining of the nose, and "results in sneezing, runny nose and stuffiness." Peck pointed out that "the agency has agreed" that there is no effect on cold symptoms from histamine blockade. However, "the older antihistamines do have an anticholinergic effect," he said. "It was on the basis of the anticholinergic effect -- the drying effect on mucous membranes" -- that anticholinergic antihistamines were judged effective in relieving cold symptoms. FDA's OTC antihistamine tentative final monograph, published in 1985, proposed that chlorpheniramine is effective in treating both cold and allergy symptoms. The proposal was based on studies submitted by Schering-Plough (manufacturer of Chlor-Trimeton) and Contac- maker SmithKline Beecham. Both products contain chlorpheniramine. FDA classified OTC antihistamines effective and safe for treating cold symptoms, based on "human experience" as well as clinical data, the Nonprescription Drug Manufacturers Association contended in a same-day press statement. "More than a dozen clinical trials" prove "what millions of Americans already know first hand -- that OTC antihistamines help relieve the runny nose and sneezing that come with the all-too-common cold," NDMA said. "People wouldn't continue using these products" after 40 years "if they didn't work." Subcommittee Chairman Weiss (D-N.Y.) contended in his opening statement that antihistamines "do not relieve cold symptoms." The "latest medical research concludes that, no matter what the commercials may tell you, antihistamines do not provide relief from the sneezing and runny nose caused by colds," Weiss said. Further, he added, "medical researchers are increasingly skeptical about the usefulness of expectorants and some decongestants." The issue is both a financial and health safety issue, the congressman said. "If many commonly used cold medications don't work, then American consumers are wasting more than $1 bil. every year." Furthermore, "some of these medications are not only useless, they may be terribly dangerous, especially for children." Weiss commented that newer prescription antihistamine products Seldane (Marion Merrell Dow's terfenadine) and Tavist-D (Sandoz' clemastine fumerate with phenylpropanolamine) should not be labeled for cold symptoms, if approved for OTC use, because they "have no measurable anticholinergic effects." FDA also explained why it proposed that 10 OTC antihistamine ingredients be classified as Category I for colds based only on chlorpheniramine data. "FDA determined at the time that the pharmacological action of the various antihistamines included in the proposed rule are similar," Peck said. "Therefore, the agency considered the data submitted for chlorpheniramine maleate to be applicable to the other antihistamines." FDA attorney Kenneth Baumgartner noted that the OTC Review commonly deals with classes of drugs. Due to its immense scope, "the essence of the OTC review is to approach regulation by class, rather than by individual product or individual ingredient," Baumgartner said. Hendeles criticized Schering's chlorpheniramine study. Published in 1979 in the Journal of the American Medical Association, the study showed that "moderate improvement did not occur until the sixth day after onset of symptoms in both the chlorpheniramine and placebo treated groups," Hendeles said. "That is, the antihistamine provided no greater relief than taking placebo." Nonetheless, he contended, "the authors of this study, two of whom were employees of the drug company sponsoring the study, concluded that 'chlorpheniramine maleate, as a model for antihistamines, is clearly superior to a placebo in providing symptomatic improvement of the common cold.'" FDA medical officer Eugenie Triantas, who reviewed the chlorpheniramine studies, testified that she did not feel the data supported use of antihistamines to relieve cold symptoms, but said she "was overruled." Weiss commented that a detailed Government Accounting Office study of the OTC Review process is needed "so that we can see how frequently FDA scientists' recommendations have been overruled." Triantas explained that the studies were flawed in that symptom evaluation reports that were intended to be completed by the various patients "seemed to be filled out by the same handwriting." That observation suggested a single person, perhaps an investigator, completed the patients' evaluation forms, she said. Furthermore, one investigator had no records of the study in 1980, when the physician was contacted by an FDA auditor. Consequently, Triantas said, the agency could not confirm the validity of the study. Finally, she said, the p value of the study (the probability that benefits perceived did not occur by chance) was 80%-90%, rather than the customarily required 95%. Johns Hopkins University Assistant Professor of Pediatrics Nancy Hutton, MD, described a randomized controlled study she conducted. The trial, which included 96 children aged between six months and five years, "found that there was no difference in symptom relief regardless of whether the child received [Robins' Dimetapp], a placebo or no medicine at all."

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