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GENERIC BRONCHODILATOR ANDAs SHOULD INCLUDE EXERCISE STRESS TESTS, FDA ADVISORY COMMITTEE RECOMMENDS; TRIPLE CROSS-OVER STUDY DESIGN SUGGESTED

Executive Summary

FDA approvals for generic bronchodilators should be based on the results of exercise stress tests as well as pulmonary function studies, FDA's Pulmonary-Allergy Drugs Advisory Committee agreed unanimously at its Nov. 18 meeting. Explaining the need for exercise stress tests, Committee member Leslie Hendeles, PharmD, University of Florida, said: "You have got to prove that [the drug] really does block exercise-induced bronchoconstriction [because] it is an indication on the package label." Currently, ANDAs for bronchodilators are only required to include pulmonary function studies. The FDA advisory committee considered and made recommendations on FDA "Guidelines for the Testing of Generic Bronchodilators." FDA would like to include that section in new "Guidelines for the Evaluation of Bronchodilator Drugs." FDA indicated that it is developing the generic guidelines in response to submissions for generic forms of albuterol and metaproterenol. The agency's current "Guidelines for Bronchodilator Drugs" were drafted in 1978. Noting that prevention of exercise-induced bronchoconstriction is "a major use" of inhaled beta agonists (Glaxo's Ventolin, Schering's Proventil, and Boehringer Ingelheim's Alupent), Hendeles commented that although a generic bronchodilator drug may perform equivalently in FEVI (Forced Expiratory Volume per 1 second) pulmonary function tests, it may not prevent bronchospasms resulting from exercise. "Every study looking at exercise has shown a divergence between FEVI and exercise [stress test results]," Hendeles remarked. Recommendations by the advisory committee concerning the protocol for clinical studies of generic bronchodilators include: - - a double-blind study with placebo for both brand and generic bronchodilators - - randomization within study days and between days - - an exercise stress test one-to-two hours after administration of the drug - - allowing continued cromolyn use during study - - discontinuing use of corticosteroids 30 days prior to the study - - double or triple cross-over study design - - and division of patients into mild and moderate asthmatic groupings by pulmonary function tests. The committee defined "moderate" patients as those with FEVI test values between 40-60% of normal, and "mild" patients as those with FEVI values 60-80% of normal. In order to prove bioequivalence to both Proventil and Ventolin, generic submissions for inhaled albuterol must include triple cross-over studies, the advisory committee recommended. FDA reviewer Richard Nicklas, MD, told the committee that although the brands are used interchangeabely by pharmacists, "the two innovator products have not been conclusively demonstrated to be bioequivalent." Ventolin and Proventil are rated not therapeutically equivalent (a BN rating) in FDA's Approved Drug Products with Therapeutic Equivalence Evaluations. The committee noted that one problem in conducting a three-way cross-over study is the absence of a placebo for Proventil. "Sponsors are not eager to assist their competititors in obtaining marketed drugs," Nicklas remarked. The committee members agreed that FDA and the generic companies will need to work out the placebo problems, including differences in taste, actuator function, and formulation, before blinded studies are possible. Explaining why clinical studies are necessary for bronchodilators, Nicklas told the committee that "certain levels of inhaled beta agonists by metered dose inhalers are so low that it is not feasible to attempt to quantitate equivalence" by conventional measures of bioequivalence. FDA is also requesting in vitro evaluations of generic inhaled beta agonists including: particle size delivered through the actuator; spray pattern; delivery rate; unit spray content; and valve delivery.
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