GENERIC ALBUTEROL MDIs SHOULD UNDERGO BRONCHOPROVOCATION AND BRONCHODILATION BIOEQUIVALENCE STUDIES, AGENCY ADVISORY COMMITTEE SUGGESTS

Generic albuterol metered dose inhalers should be tested in both bronchoprovocation and bronchodilation studies to determine their bioequivalence to the reference product (Glaxo's Ventolin), a joint FDA Generic Drugs and Pulmonary-Allergy Drugs Advisory Committee suggested at a Sept. 14 meeting.

FDA said it may consider making bronchoprovocation the pivotal study and bronchodilation the supportive study. The provocation study may require more rigorous standards than the bronchodilation study, such as screening for patients who are good responders or detectors of dose-response relationships.

The design of acceptable bronchoprovocation and bronchodilation studies will be outlined in an interim FDA guidance. Center for Drug Evaluation and Research Associate Director for Science and Medical Affairs Roger Williams said: "My hope is that some time in the fourth quarter of this year...we will be able to issue an interim guidance to pharmaceutical manufacturers."

The committee arrived at its suggestion after hearing the results of three studies of pharmacodynamic (pharmacologic effect) models for use in bioequivalence studies of albuterol MDIs. The pilot studies were performed at Johns Hopkins University under the leadership of Paul Leitman, MD, and with the assistance of FDA. The committee also heard from Canadian officials about the requirements for MDI bioequivalence currently laid out in an interim guidance (see following story).

The studies, conducted between September 1992 and May 1993, measured the interpatient reproducibility and sensitivity of three methods of determining dose-response effects of albuterol delivered by MDIs to mild-moderate stable asthmatics. Their goal is to provide alternatives to requiring comparative clinical trials of innovator and generic products.

In February 1989, FDA issued an in vivo bioequivalence study guidance that suggested measuring patient's forced expiratory volume in one second (FE[1],) for one puff versus FEV[1] after two puffs. However, data using that method showed relatively small differences in FEV[1] measurements between the two doses. Alluding to the void in generic albuterol MDIS, Williams said: "We're coming on now to four years post- patent expiration, which is a significant period of time not to allow generic substitution of these products."

Although the patent on Ventolin expired in December 1989, no generic products have been approved. Schering licenses rights to the patent and markets albuterol under the name Proventil.

The three methods examined in the JHU studies are dose- response in FEV[1] measured after separate daily single doses of albuterol; cumulative dose-response in FEV[1]; and dose-dependent inhibition of methacholine-induced bronchospasm by single doses of albuterol. Special canisters of albuterol were manufactured so that doses lower and higher than the standard 90 mcg could be tested in the pilot studies.

The single dose/separate days study (Study 1) involved 10 asthma patients who took 1, 2 or 4 actuations of placebo or albuterol ranging in doses from 9 to 576 mcg. Each dose was taken on a separate day. FEV, was measured at 0, 15, 30, 45 and 60 minutes with the option of more sampling at 30-minute intervals up to five hours total. The cumulative dose/single day study (Study 2) involved 10 patients, 9 of whom were from Study 1, who received cumulative doses of placebo and 9 to 576 mcg of albuterol. FEV[1] was determined at baseline, then 15 minutes post- dose, and was immediately followed by the next dose.

The methacholine challenge (Study 3) evaluated the protective (inhibition of the fall in FEV1) dose-response of single doses of albuterol on bronchospasm induced by methacholine. Fifteen mild asthmatic patients received placebo (1, 2 and 4 puffs) or doses of albuterol ranging from 9 to 576 mcg on separate days. Each methacholine challenge was initiated 15 minutes post-dose. The investigators determined the provocative dose of methacholine that produced a 20% fall below saline control FEV[1] (PD[20]).

The dose-response curves were intended to be used as a screening tool. Patients would have to have acceptable dose- response curves to be eligible for admission into the bioequivalence studies. The proposed design of the bioequivalence studies for Study I and Study 3 models would involve comparing one actuation of the test product and reference product in duplicate. The pharmacodynamic methods have not been used in in vivo bioequivalence studies.

FDA concluded from the results of the studies that Study 1 and Study 3 would be the best pharmacodynamic models to use. Discussing the problems with Study 2, Williams noted that "in terms of a dose-response relationship, this particular model isn't very sensitive particularly compared to...the methacholine challenge." The model provided dose-response curves that failed to meet the proposed ED[50] (the dose that produces a half maximal response) and precision criteria.

Attempting to summarize comments made by committee members, committee chairman Terrence Blaschke, NM, Stanford University Medical Center, said: "What we have when we look at the real data for individual patients [is that]...we see a tremendous amount of scatter." He added that "there's no way that we can standardize all these things that we would have to be standardizing in order to make people act as HPLC detectors." There are "too many external variables that are influencing that responsiveness within an individual patient."

Advisory committee members concluded that use of the special canisters is unnecessary and that screening of patients could be based upon multiple puffs of the standard strength product. Blaschke noted that the "consensus among the committee is that the doses that are studied in a bioequivalence study should be clinically relevant doses."

Williams stated: "I can imagine that we could fall back and try to [come up with] an interim guidance that would address some of the suggestions of the committee. [FDA could] mainly use standard marketed [doses] in one, two and three puffs and suggest certain patient populations and certain challenge studies," he continued.

The committee also suggested that the Finney 3 by 3 bioassay be used to validate the bronchoprovocation model. That bioassay involves patients taking 1, 2 or 4 puffs of low and high doses of the generic and innovator product and the measurement of the distance between dose-response curves that provides the estimate of the doses that produce equal effects. The 3 by 3 bioassay could serve as a screening tool for subject admission to the study.

Leslie Hendeles, University of Florida at Gainesville, said it may be possible to combine both the bronchoprovocation and bronchodilation studies to lessen the burden on generic drug firms.

Hendeles discussed a nocturnal asthma study that he said "actually combines both [the bronchoprovocation and bronchodilation studies] and would save the drug company from having to do two studies." Hendeles' patients, who were relatively symptom-free during the daytime and woke up three or more nights a week with acute asthma attacks, were monitored overnight in a clinic. "We can provide the natural bronchoprovocation in a clinically relevant situation," Hendeles said.

In his role as acting chairman, Christopher Rhodes, PhD, University of Rhode Island, noted: "One of the issues that a number of the members of the committee have discussed is whether the subjects used in the studies that we have discussed today... were an appropriate choice or whether for various reasons it would have been better to have gone to more seriously affected patients." Meeting participants pointed out that sicker asthma patients would provide greater ability to detect differences in dose-response curves.

The committee also suggested that safety tests, such as measurements of heart rate and serum potassium, be incorporated in the studies. This recommendation came after representatives for Schering-Plough reported that the firm had developed a low-dose albuterol MDI product with a novel actuator that produced greater extrapulmonary effects than the standard product, such as increases in heart rate and changes in the QTc interval.