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Executive Summary

FDA INHALED ALBUTEROL BIOEQUIVALENCE DRAFT GUIDANCE could be ready by mid-1992 following the completion of pilot studies to be conducted for the agency by Johns Hopkins University, Office of Generic Drugs Director Roger Williams, MD, told industry representatives at an Oct. 11 agency-sponsored conference on generic albuterol metered-dose inhalers. Stopping short of committing FDA to that target date, Williams remarked: "If we could get a draft guidance by mid-1992, I would be delighted." The meeting was convened by FDA to discuss a draft protocol for pilot studies that would assess the value of different study designs for the determination of bioequivalence of inhaled albuterol products. The agency is seeking comments from industry on the protocol. The pilot studies are scheduled to begin this fall under the direction of Johns Hopkins University clinical pharmacologist Paul Leitman, MD. Williams said that he hopes to have data ready for presentation to a joint advisory committee by the first quarter of 1992. The joint committee would be composed of members from FDA's Pulmonary-Allergy Drugs Advisory Committee and its Generic Drugs Advisory Committee. While Williams has taken the initiative with regard to metered-dose inhalers, asserting that "it is time for generic substitution" for inhaled albuterol, the decision to proceed with investigative studies of new bioequivalence testing methods could delay marketing of a generic inhaler product for at least another year. Such a delay would add another couple years to the already- extended marketing exclusivity for Schering and Glaxo, makers of Proventil and Ventolin. Glaxo's albuterol patent, which is licensed to Schering, expired in December 1989. Following the issuance of a revised MDI guidance in June 1989, FDA received data from several companies. The revised guidance recommended comparisons of one puff and two puffs of generic albuterol to innovator product. When the data came in, Division of Bioequivalence staffer Marilyn Martinez, PhD, commented: "We couldn't even differentiate between a 100% difference in dose of the pioneer product." The finding that such studies would not be able to detect a 20% difference between generic and innovator product led the agency to abandon the revised guidance and develop the new protocol to evaluate other studies. The draft describes two studies: a bronchodilator dose- response study and a methacholine challenge. The objective of the studies is "to measure intra- and interpatient reproducibility and sensitivity of three methods of determing dose-response effects to the beta-2-agonist albuterol when administered by metered dose inhaler (MDI) to mild, stable asthmatics," it states. The first study is comprised of two parts: a double-blind, randomized albuterol single-dose study and two cumulative FEV[1] (forced expiratory volume) response trials. In the single-dose study, 10 patients will receive seven dosages of albuterol or placebo. The active dosages will be 36, 72, two times 36, 90, 180, 288 and 576 micrograms. FEV[1] will be measured 15, 30, 45 and 60 minutes after exposure to drug or placebo. Then patients will be crossed over to the opposite therapy and similar measurements will be taken after the second exposure. In the second part of the bronchodilator response study, 15 patients will receive cumulative doses of zero, 36, 72, 108, 288 and 576 micrograms of albuterol. FEV[1] will be measured 15 minutes following each dosing. The tests require patients to appear at the laboratory nine times (two times for the cumulative dose studies and seven for the single dose studies). Data from the first studies will be analyzed as the absolute change in FEV[1] from placebo baseline and the absolute change in FEV[1] from placebo baseline over the predicted normal FEV[1] times 100. The methacholine challenge study will measure the bronchoprotection of different doses of albuterol. Fifteen patients will visit a laboratory on 10 separate occasions. On each day, patients will receive placebo or 36, 72, 90, 180, 288, and 576 micrograms of albuterol. After FEV[1] has been measured, the patients will be given five breaths of increasing doses of aerosolized methacholine until the patient experiences a 20% or greater reduction in FEV[1]. At the meeting, the proposed protocol was critiqued by some industry members. Several industry representatives maintained that patient compliance would be difficult because the proposed studies require multiple visits to testing labs. Other industry members contended that the studies would take too long to complete and that the small number of patients would not yield a definitive answer as to whether the studies would be of value in determining bioequivalence. One generic company representative said that FDA should continue to use the one puff versus two puffs criteria, asserting that his company had conducted tests using the one puff versus two puff method and had been able to detect differences of 20% between the generic and the innovator.

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