CFC-FREE ALBUTEROL MDI STUDIES SHOULD TRY TO ACHIEVE DOSE RESPONSE FOR COMPARABILITY -- FDA's JENKINS; ACUTE ASTHMA AND PEDIATRIC STUDIES SUGGESTED

Chlorofluorocarbon-free albuterol metered-dose inhaler future studies should strive for an adequate dose response to show comparability to existing products, FDA Division of Pulmonary Drug Products Director John Jenkins, MD, said at the Pulmonary-Allergy Drugs Advisory Committee meeting March 29.

"We have encouraged sponsors to push the study design to try to achieve [a dose response], because that really is the goal of the study," Jenkins said.

3M Pharmaceuticals' Epaq albuterol metered-dose inhaler, which uses hydrofluoroalkane-134a as a propellant, set the precedent March 29 as the first CFC-free albuterol MDI to be judged clinically comparable to Glaxo Wellcome's CFC-propelled Ventolin by the committee. The committee unanimously recommended Epaq for approval ("The Pink Sheet" April 1, p. 18).

Epaq will not be substitutable for Ventolin and subsequent CFC-free MDIs "do not have to be bioequivalent," Jenkins reminded the advisory committee. "They will not be directly substitutable. The physician will have to make a conscious decision that he wants to order Epaq instead of Ventolin or [Schering-Plough's] Proventil or one of the generic versions of CFC albuterol," such as those sold by Ivax, Dey Labs and Warrick.

Under the 1992 Montreal Protocol, 130 countries agreed to eliminate CFCs by Jan. 1, 1996. MDIs currently are exempted from the treaty; however, the Epaq NDA process will help set the stage for forthcoming CFC-free MDI submissions. 3M has been lobbying Congress to keep the transition to CFC-free propellants moving forward ("The Pink Sheet" March 18, p. 13).

3M was allowed to conduct an abbreviated development program using a cumulative dose study for the CFC-free albuterol MDI to show clinical comparability to Ventolin. However, future CFC-free products will have to conduct more definitive dose-response studies. The committee recommended that 3M conduct a Phase IV relative potency study to address this issue. Ivax had similar difficulties in demonstrating dose response for its generic albuterol MDI in bioequivalence study comparisons to Ventolin ("The Pink Sheet" Feb. 19, p. 12).

"The comparability issue, for us, is kind of the fundamental basis behind this whole program," Jenkins said. A goal in evaluating Epaq as the first CFC-free albuterol delivery system, he continued, was "to feel comfortable enough linking the new product and the old product together, that we could rely on much of the old product's safety and efficacy and marketing data to help us write the label for the new product, and get permission and a good estimate of what's a clinically comparable dose."

"I don't want the committee to go away from" the idea of comparability in dose response, Jenkins said, adding "but I wanted to make it clear that we have never put [forth] a...definition of what clinical comparability means. And we've done that probably for a good reason, because it's very hard to find."

Although dose response for MDIs is "very difficult and some would say impossible," Jenkins said "the committee saw some data in November for fluticasone" that was encouraging. Glaxo Wellcome's Flovent (fluticasone MDI) was approved March 27 in three different dosage strengths ("The Pink Sheet" April 1, p. 17).

Committee Chairman Richard Ahrens, MD, University of Iowa, maintained that dose response or relative potency studies are "do-able" for CFC-free albuterol MDIs. Ahrens proposed other models such as histamine or methalcholine bronchoprovocation studies. "There are methods that provide us with much more precise information," Ahrens said.

3M submitted seven trials to FDA, including the 78-patient 1031 trial, a six-way crossover, dose-ranging study. Subjects were administered 100 mcg, 200 mcg and 300 mcg doses of Epaq, compared to 100 and 200 mcg doses each of Ventolin and placebo.

3M Associate Director of Clinical Research Gene Colice, MD, said trial 1031 showed that all active treatments were better than placebo, that active treatments did not differ significantly from the other, and that results were closely matched after two puffs of Epaq and Ventolin. However, Ahrens, called the dose-ranging study "uninformative" because "there is no significant dose-response relationship."

The committee voted to recommend that Epaq be approved for the treatment and prevention of bronchospasm in patients 12 years of age and older with reversible obstructive airway disease.

Jenkins reminded the committee that recommendation for approval was only "in the population studied." No data on acutely ill patients or pediatric patients has been reviewed by FDA, although 3M has completed studies for indications in pediatric patients and those with exercise-induced asthma.

The Epaq safety and efficacy trials were "excellent," said committee member Molly Osborne, MD/PhD, Oregon Health Sciences University, but the generalizability of the data to pediatric and acutely ill patients was of concern, she said. Osborne also raised the question of whether the potency of Epaq was comparable to that of the CFC-propelled albuterol MDIs in those patient populations

"Clearly, we are in precedent-setting area here, which is exciting," Osborne said. "But we need to keep in mind, whatever standards we talk about today will come back to haunt us at the committee, when we're talking about other propellants and other drugs, and so I think that's one reason I'm so concerned about the potency," she said. "I can't figure out, in my own mind, how to know enough about potency to generalize to the pediatric patient or the acutely ill patient."

3M presented one pediatric study, not yet reviewed by FDA, to the committee. The four-week, open-label study compared the effects of HFA albuterol to CFC albuterol in 63 patients, mostly male and Caucasian, ranging in age from four to 11, with a mean age of nine. The three test parameters were peak percent change, duration of effect and area under the curve.

After four weeks of dosing, the peak percent change was comparable in Epaq pediatric patients to that of the CFC albuterol patients, 3M said. Duration of effect in the two treatments was comparable as well. The results of the AUC were not significantly different.

In the double-blind, double-dummy, 12-week efficacy trial 1012, 565 patients were given two puffs of Epaq, Ventolin or placebo, four times a day. The largest of 3M's clinical trials, study 1012 showed that both active treatments were superior to placebo, and the active treatments were comparable in effect at four, eight and 12 weeks.

Safety trial 1106 was a one-year, open-label, 160-patient follow-up trial of 1012 that included a 51-patient subgroup, 24 of whom were switched from Ventolin to Epaq. Patients received two puffs of treatment twice a day. Asthma exacerbations in those treated with Epaq was 32%, in those on Ventolin, 60%. After three months of treatment, results were comparable from peak percent change, duration of effect and AUC.