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Executive Summary

Any change made in the composition of a brandname or generic inhaled bronchodilator should be tested for unexpected adverse reactions, FDA's Pulmonary-Allergy Drugs Advisory Committee suggested at its June 12 meeting. Committee Chairman Leonard Bernstein, MD, University of Cincinnati Medical Center, asked the panel: "Are we going to insist that the generic people and the brandname people do entirely new studies when they change the composition of a new product?" In response, the committee unanimously voted "yes." Committee members had expressed concern that a change in composition could lead to unexpected adverse reactions such as was the case when Boehringer Ingelheim changed the suspension agent in its metered dose inhaler Alupent (metaproterenol) ("The Pink Sheet" Nov. 6, 1989, T&G-16). To increase the product's stability, the firm replaced sorbitan trioleate with soya lecithin. After introducing the reformulated product last September, Boehringer noticed an increase in the frequency of complaints among long-term Alupent patients. The most commonly reported complaint was coughing with a choking or gagging sensation. The firm initiated a voluntary market withdrawal of the reformulated product and returned to producing the original formulation. Casting an affirmative vote for adverse effect testing, panel member Joann Blessing-Moore, MD, Stanford Medical Center, asked whether the committee was "setting a new standard compared to what happened [with] Alupent?" Bernstein replied: "I think Alupent is the thing that catalyzed this whole thing." Bernstein emphasized that "the crucial point here is to remember [that] the active ingredient is the same." The panel members, he said, are "worried about side effects and the fact that the excipients might affect efficacy as well because of the different particle sizes." Panel members suggested several types of studies that could be used to check for unexpected adverse events that may result from a composition change. Committee member Leslie Hendeles, PharmD, University of Florida, recommended "either some sort of bronchoprovocation test, which would require a smaller sample size and be more sensitive, or a cumulative dose-response curve, which is a very economical study design." Hendeles asked what sample size would have been needed to pick up the adverse events associated with reformulated Alupent. FDAers replied that the numbers would have to be in the thousands. The idea of requiring a post-marketing surveillance study to test the effects of a change was suggested but rejected. Panel member Gail Shapiro, MD, Seattle, Washington, noted that a surveillance study may not be "the most cost-effective way to go" and instead suggested a pilot study involving "100 patients studied for two or three months" in order "to detect any major problems." The committee also reviewed the issue of comparisons between innovator and generic beta-2 agonist bronchodilators delivered with metered dose inhalers. The committee unanimously agreed that firms should make generic products identical in composition to innovator products. A representative from 3M Pharmaceuticals observed that "the quantitative composition of the innovator product is generally not available...and some of these surfactants especially tend to be difficult to quantitate." He added: "It's very easy to say that all generic products should be exactly the same as the innovators' but when you actually try to do that you [wind up] against the practical considerations that require you to look at the other available surfactants." Another commenter, James Kemp, MD, University of California at San Diego, contended: "I would propose that we do know something about the composition of various metered dose inhalers and I would also propose that these factors are important." Expressing his concern that inhalers are not identical, Hendeles said that "these products are being made for pharmacists to substitute without the physician's knowledge. I think that has to be kept in mind." The committee also concluded that a change in the actuator of a bronchodilator product should require a new bioequivalence study comparing the new actuator versus the old actuator. FDA Office of Drug Evaluation II Assistant Director (Pharmacology) Judith Weissinger, PhD, provided the committee with an update on nonclinical pharmacological/toxicological considerations for replacement of chlorofluorohydrocarbons with new propellants. Weissinger said that FDA supervisory pharmacologists and product sponsors "all agree that a novel propellant will be treated as a new ingredient." The FDAer listed a battery of toxicology tests that will have to be done on new propellants. For a new chemical entity, well under development, in which most of the toxicology studies have been done, she said that a firm will have to do "a single-dose toxicity study...use in the I.V. and inhalation route in at least two species, definitely the teratology component of a reproductive study...and a mutiple-dose toxicity of the duration of which the product is proposed for use." For existing NDAs of marketed products, if clinical studies are going to be needed to also look at the implications of a new propellant, FDA wants "a short-term subacute study to support using the formulation in the clinic," a 90-day study in the most sensitive species, and possibly carcinogenicity and reproductive studies. Weissinger reiterated the committee's opinion on clinical studies: "you'd want to see some clinical information" on the propellant itself "and then some clinical information on the final formulation, yet to be determined." The FDAer suggested that, should NDA holders conduct clinical studies on the safety and efficacy of their inhalers because of a new propellant, they could gain three years of marketing exclusivity for the products.

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