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OTC DIET AIDS: FDA PLACING PHENYLPROPANOLAMINE IN CATEGORY III

Executive Summary

OTC DIET AIDS: FDA PLACING PHENYLPROPANOLAMINE IN CATEGORY III (insufficient data to support safety or efficacy) in the agency's upcoming proposed rule for OTC weight control drug products, FDA reported to Rep. Wyden (D-Ore.) in a Jan. 14 letter. Wyden requested information about the status of FDA's examination of the safety and efficacy of phenylpropanolamine in November. The notice of proposed rulemaking is expected in "early 1993," FDA said. Phenylpropanolamine's new categorization also will be announced via a "feedback letter to the industry" that is expected to be disseminated "within the next two months," FDA told Wyden. Until FDA issues a final monograph for OTC weight control products, manufacturers of phenylpropanolamine-containing diet aids may keep their products on the market. Phenylpropanolamine is currently available over the counter as a decongestant and in diet aid products, including Thompson Medical's Dexatrim and Ciba Consumer's Acutrim. FDA underscored that phenylpropanolamine's ultimate fate "will depend on the outcome" of an epidemiologic study being conducted by the Nonprescription Drug Manufacturers Association to determine whether there is an association between phenylpropanolamine (PPA) use and hemorrhagic stroke. The agency maintained that the ingredient's Category III status "will be transient and not prolonged." In 1982, an FDA advisory committee recommended that phenylpropanolamine be placed in Category I (generally recognized as safe and effective). In a Jan. 28 letter to HHS Secretary Shalala following up on his FDA communications, Wyden asked the department to "examine the issues raised" in FDA's evaluation of the safety and efficacy of phenylpropanolamine "as a diet product and how the FDA might improve a bureaucratic process that has left indeterminate the status of this widely used drug for over 20 years." Wyden included a copy of FDA's Jan. 15 response in his letter to Shalala, noting that "you will see in the enclosed letter that additional studies requested by the FDA will again delay a final determination on the status of this drug." Wyden added that he does not consider "FDA's continued inaction in this matter in the best interest of the public health." The agency told Wyden that it will soon ask NDMA to "submit a protocol and proceed promptly with a case-control study of PPA and stroke." The proposed study, which was the subject of a November OTC drug "feedback" meeting between FDA and NDMA officials ("The Pink Sheet" Nov. 16, 1992, p. 7), will "provide a large enough data base to determine whether the incidence of stroke associated with ingestion of PPA is greater than the spontaneous rate of stroke," the agency said. NDMA says that it already has devised a draft case-control study that it will submit to FDA soon. FDA explained to Wyden that while it "continues to have concerns about the possibility that PPA may increase the risk of stroke, we do not believe that available data document this convincingly." Even a small documented risk of stroke, the agency argued, "would be a major liability for a weight control product and would, in all likelihood, lead to a change from OTC to prescription status." FDA said that its evaluation of phenylpropanolamine's safety is "still ongoing" because the "issue is very complex and the data are inadequate." The agency noted that it asked three outside epidemiologists to review its assessment of currently available stroke data; all three consultants "agreed that the agency's analysis was valid and reasonable based on the available data." The outside epidemiologists, FDA said, also agreed that an as yet unavailable estimate of phenylpropanolamine-associated adverse drug reactions in the OTC setting is "crucial" to the agency's final decision. At a Feb. 3 seminar for Center for Drug Evaluation & Research staffers, Raymond Lake, MD/PhD, Kansas University Medical Center, presented results from a double-blind, placebo-controlled study of 16 individuals who took various formulations of phenylpropanolamine. Study results showed a "significant" increase in blood pressure among the phenylpropanolamine cohorts. Rep. Wyden asked Shalala whether a pharmacist-controlled OTC class of drugs "might not be advisable" for phenylpropanolamine and whether "there are not better ways to control OTC drugs that - - like PPA -- may pose a particular hazard to young people, or which are manifestly ineffective for the promoted condition?" Wyden concluded his letter by arguing that a labeling change proposed by NDMA at the November FDA feedback meeting -- that "persons between 12 and 18 are advised to consult their physician before using" diet aid drug products -- is insufficient. "It is difficult to believe that a mere change in labeling will somehow head off the dangerous dieting practices made easy by free and unfettered access to drugs like PPA," he charged. Responding to Wyden, FDA maintained that NDMA's proposed cautionary language "is sensible and represents good advice." The safety of phenylpropanolamine-containing OTCs has been a long-standing concern of Wyden's House Small Business/Regulation Subcommittee. The Oregon legislator devoted a hearing to the issue in September 1990 ("The Pink Sheet" Oct. 8, 1990, T&G-11) and quizzed CDER officials about the status of FDA's phenylpropanolamine review at an April 1992 hearing. FDA also has publicly declared its attention the issue of phenylpropanolamine safety. At the inaugural meeting of the OTC Drugs Advisory Committee, FDA Office of Drug Evaluation I Deputy Director Paula Botstein cited the ongoing evaluation of the ingredient as-an important and complex scientific problem for the OTC drug office.

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