CANADIAN ALBUTEROL MDI BIOEQUIVALENCE DRAFT GUIDELINE ALREADY REQUIRES BRONCHOPROVOCATION/BRONCHODILATION TESTS; OCT. MEETING SET TO FINALIZE DRAFT

Canada's draft guideline for albuterol metered dose inhalers bioequivalence already requires both bronchoprovocation and bronchodilation studies, Health Protection Branch (HPB) representatives told a joint FDA Generic Drugs and Pulmonary- Allergy Drugs Advisory Committee meeting Sept. 14. Explaining the rationale for requiring both studies, BPB representative Daniel de Jesus, MD, stated: "There is no clear evidence as to which of these responses is more important; therefore, it is [critical] to test both modes of action and it is recommended that generic and secondary bronchodilators show equivalence to both responses." FDA officials came to the advisory committee meeting with the idea that companies may have to conduct only one study, either a bronchoprovocation study or a bronchodilation study. Results of studies conducted by Johns Hopkins University and FDA suggest that a bronchoprovocation study design offers more sensitivity than a bronchodilation design. However, the committee suggested that both studies be done after hearing the presentations by HPB representatives de Jesus and Paul Roufail, PhD. Pulmonary-Allergy Drugs Advisory Committee member Sally Wenzel, PhD, National Jewish Center for Immunology and Respiratory Medicine, said she thinks "it is important that we do evaluate both the bronchodilatory and the bronchoprotective effects." She noted that "to market these generics as only equivalent in bronchoprotection, I think we're somehow or other missing most of the clinical relevance of these drugs." The Canadian bronchodilation equivalence protocol, de Jesus explained, "involves a randomized, double-blind crossover study of 32 patients to compare the magnitude and duration of effects of 1, 2 and 4 puffs of the innovator drug with two puffs of the generic and placebo. Patients to be enrolled must have an acute reversibility as demonstrated by an improving FEV, of greater or equal to 50% 15 minutes after the recommended dose of the innovator bronchodilator and have a natural extraction [of] less than 80% of predicted medication for the recommended time." "FEV[1] data," de Jesus continued, "should be expressed as a percentage increase from baseline recorded at 5, 10, 15, 20, 25 and 30 minutes and then every 30 minutes for six hours. Cardiovascular response should be monitored at the same time as FEV, measurements. Any adverse reactions should be noted." De Jesus explained the bronchoprotection equivalence protocol as a "methacholine challenge comparison of 1, 2 and 4 puffs of the innovator versus two puffs of the generic and placebo." The 16 "subjects to be studied should have asthma indicated by symptoms and airway hyper-responsiveness to methacholine when the baseline FEV[1] is 70% of predicted or is 70% after temporarily withholding relief medication. The PD[20] methacholine should increase at least four-fold, that is doubling concentration after inhaling the usual dose [of] two puffs of the innovator." The bronchodilation and bronchoprotection bioequivalence protocols "require [that] two puffs of the generic should have a significantly greater effect than one puff and less effect than four puffs of the innovator," de Jesus said. In addition, "comparison of two puffs of the generic and two puffs of the innovator should not be significantly different. Cardiovascular response should not be different for the generic and the innovator and the incidence of adverse events should not be significantly greater." De Jesus added that "generic or second entry products should not cause greater side effects than the originator does at equivalent doses. Therefore, additional studies on safety may be required to evaluate the equivalency of the [products]. This study should include monitoring of acute side effects [such as] heart rate and serum potassium [levels]." The committee suggested that monitoring of side effects should be incorporated into FDA's interim guidance. The HPB official cautioned the committee that "the difficulty in establishing such guidelines is the lack of validated methods to compare equivalence of the methods." HPB's Roufail outlined the Canadian experience for the committee, stating that "generic companies approached the HPB regarding MDI applications as early as 1981." HPB issued notices of compliance in December 1988 and January 1989 for generic albuterol MDls "after consulting with experts in Canada and abroad" on the results of clinical studies of in vivo testing collected over the previous eight years, Roufail added. HPB initiated a first draft guideline developed with input from Canadian government officials and professional associations. The draft guideline was presented by HPB at a workshop in Ottawa in February 1990. That draft was distributed for comment from experts in the United Kingdom, United States and Australia. Roufail said "HPB would like to establish guidance for MDIs" and that a "meeting of [Canadian] food and drug officials to finalize the [second] draft guidelines will take place Oct. 18-19 in Toronto." The second draft guideline, which has been released for comment, was the subject of de Jesus" presentation to the committee. FDA Division of Oncology and Pulmonary Drugs Director Gregory Burke, MD, said: "I think that the Canadian approach and what's been proposed here by the FDA come out with essentially the same approach." He noted that the FDA approach makes a "determination ahead of time that you're going to get" a patient population that responds, but with the Canadian method "unless there is some kind of screening there's no guarantee that you actually are going to get that dose response [you want]." Pulmonary-Allergy Drugs Advisory Committee member, Richard Ahrens, MD, University of Iowa, interjected: "I like the Canadian approach to the statistical analysis and it still gets at the issue of relative potency or doses that produce equal effects."