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This article was originally published in The Tan Sheet

Executive Summary

NDMA's PPA CASE-CONTROL STUDY WOULD GENERATE PRELIMINARY DATA BY SPRING 1996 if the study gets under way in January, the Nonprescription Drug Manufacturers Association told FDA in an Oct. 14 response to a recent OTC "feedback" meeting. NDMA said that an interim analysis of the phenylpropanolamine-stroke study, called the Yale Hemorrhagic Stroke Study, "would be anticipated in April 1996, assuming a January 1993 start-up date and uniform monthly enrollment of cases and controls over the course of the study." NDMA's response to the Aug. 25 "feedback" meeting outlines changes made in the study protocol based on recommendations from FDA and seeks a "green light" from the agency to begin the study. NDMA's comments on the meeting "represent the collective response" of the Yale investigators to the meeting discussion and have the endorsement of the association's Phenylpropanolamine Working Party, NDMA said. Following the feedback meeting, NDMA is defining the objectives of the study as three-fold: to determine whether phenylpropanolamine users aged 18-49 have an increased risk of hemorrhagic stroke compared to non-users; to estimate the association between phenylpropanolamine and hemorrhagic stroke by both cough/cold indication and by the use of appetite suppressants in women aged 18-49; and to estimate the association between "first dose" use of phenylpropanolamine as either a cough/cold remedy or a diet aid and hemorrhagic stroke in women aged 18-49. NDMA and the Yale University investigators had initially proposed designing the study to look at all phenylpropanolamine users between the ages of 18 and 54, including users of cough/cold products. However, several FDAers questioned the design, indicating that the agency was more concerned with the relationship of hemorrhagic stroke and the use of phenylpropanolamine in diet aids by women aged 18-49 ("The Tan Sheet Aug. 30, p. 8). The agency officials at the meeting also indicated that the agency was primarily concerned with the potential for hemorrhagic stroke during the 24 hours after the first use of a phenylpropanolamine-containing OTC product. Consequently, NDMA and the investigators agreed to add a third analysis to the study to examine the risk of stroke on "first dose/first day exposure" in women aged 18-49. Under this specification, NDMA explained, "a patient would be counted as 'exposed' only if the index event (stroke in cases or corresponding date in the controls) occurred within 24 hours of the first dose of phenylpropanolamine used by the patient." However, the study will consider a three-day exposure in determining the risk of stroke in all phenylpropanolamine users and in estimating the association of stroke to phenylpropanolamine use by indication. In addition, a third analysis has been added to examine the risk of stroke following first dose in women. The investigators also said they "intend to conduct a series of additional analyses to explore the impact of dose and timing of use on the association between phenylpropanolamine and hemorrhagic stroke" by looking at "differences in recency (time of last use), latency (time of first use), and pattern of use." NDMA also agreed to further expand the size of the study in order to increase its statistical power. For the first dose/first effect arm of the study, NDMA is proposing to collect data from 350 cases and 700 controls among women aged 18-49. For any phenylpropanolamine use, the study would add 350 men and 700 male controls, which will provide an equal number of men and women with hemorrhagic stroke in the study. The interim analysis, aimed for April 1996, "will focus on the first (any phenylpropanolamine use, three-day window, men and women) and third (appetite suppressant phenylpropanolamine use, first day/dose window, women only) objectives," NDMA noted. In a separate Oct. 4 submission to FDA, Caprice-Greystoke, which markets Spray-U-Thin phenylpropanolamine spray ("The Tan Sheet" Sept. 13, In Brief), provided the agency with a literature review in support of the safety and efficacy of a 12.5 mg PPA dosage every two hours. Caprice-Greystoke maintained that the 12.5 mg dosage schedule is as effective as phenylpropanolamine 25 mg every four hours "with less of the adverse effects." The Vista, Calif.-based company said it is "currently working with the University of California School of Medicine to test approximately 400 subjects in two separate geographic locations."

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