AQUEOUS SOLUTION METERED DOSE INHALERS: IN VITRO BIOEQUIVALENCE DATA ARE SUFFICIENT IF "SAME" DEVICE USED, FDA GENERIC DRUGS ADVISORY CMTE. CONCLUDES

FDA should waive in vivo data requirements to establish device bioequivalence for metered dose inhalers delivering aqueous solutions if the inhaler is the "same" as that used by the innovator, FDA's Generic Drugs Advisory Committee concluded Sept. 15. Four members of the agency's Pulmonary-Allergy Drugs Advisory Committee also participated in discussions and voted at the meeting. With the assumption "that the solutions...themselves can be established as equivalent by in vitro" data alone, then given "the same valve, the same manufacturer" as the innovator MDI product, "then, yes, we could accept this class just on in vitro" data, committee member Kathleen Lamborn, PhD, Quintiles Pacific, summarized. Whether and under what circumstances in vivo data would be required by FDA to demonstrate the bioequivalence of the solution formulation itself is an issue still being hammered out by FDA. On Sept. 14, the committee said it supported the idea of using in vivo studies to determine bioequivalence of albuterol metered dose inhalers (see story, p. 3). Because of the potential for variability within MDI devices, evaluation of inhaler bioequivalence for MDls delivering solutions should include "physical dimensional characterization as fully as possible because of the number of different metered valves" available, Garnet Peck, PhD, Purdue University, added. Pulmonary-Allergy Drugs Advisory Committee member Richard Ahrens, MD, University of Iowa, said inhaler in vitro bioequivalence data should be evaluated recognizing that even with the innovator product, "suppliers of various components that go into the making of that valve can change from one time to the other." Peyton Eggleston, MD, Johns Hopkins, suggested that the approach to this product category would be "similar to [that of the] nebulizer solution in that the whole testing should be directed towards the content of the canister rather than the canister and its valve." Ahrens expressed his caution toward the evolving in vitro tests for inhaler equivalence. Ahrens said he was "particularly glad to see the attention being now paid to velocity-sensitive methods for characterizing these aerosols." However, "it is still very much...an evolving field where there's anything but consensus on what exactly should be done and what it means in terms of being able to predict what happens," Ahrens said. FDA proposed for discussion a group of in vitro tests that would be required for a manufacturer to obtain a waiver for in vivo bioequivalence testing of MDIs. Those tests would provide characterization of particle size distribution by cascade impactor and one other method; spray pattern and/or plume geometry; and unit spray content. The committee voted seven to two with one abstention to recommend that "limited" in vivo bioequivalence data should be required in cases in which the innovator's valve or actuator is patented and thus not available to the prospective manufacturer of an aqueous solution MDI. The "limited" in vivo bioequivalence data required for these MDIs would be a "bioassay of the quantity delivered to the relevant biophase in the lung," Pulmonary-Allergy Committee member Ahrens suggested. Some committee members suggested that the in vivo requirements could be waived for this particular category of MDIs at a later date, after validation of the in vitro tests had been performed through clinical testing. However, the committee left the question of what constitutes adequate validation in this case for future resolution. FDA noted at the meeting the agency has not yet approved changing the valve used in the delivery system of an NDAed drug. The agency currently has one or two requests pending to modify an MDI actuator. FDA is "still negotiating because some of the differences [the agency has] observed haven't assured us that the [in vitro] plume geometry and spray pattern approach are the same" with the new actuator, FDA Oncology and Pulmonary Drug Products Supervisory Chemist Guiragos Poochikian, PhD, told the committee. FDA has approved different actuators for NDAed products based on clinical data. For nasal sprays that deliver aqueous drug solutions, the group agreed that in vitro data should be sufficient to determine bioequivalence. Ahrens explained: "it's a very difficult proposition to get drugs into the lungs particularly if you want to target [a specific lung area]. On the other hand, in the nose it's not a difficult proposition to get the majority of the drug deposited in the upper airway, in this case, the nasal passages." Although not asked specifically to comment on excipients at this meeting, the committee expressed concern with a threshold of difference for generics. The Office of Generic Drugs "has discussed differences greater than [plus or minus] 20% as raising safety issues," presentation materials from OGD's Division of Biostatistics note. The committee felt they had insufficient information to choose another threshold and suggested discussing generic excipient requirements at its next meeting. Williams told the group that FDA "can try to set...levels in such a way that it's not what [one] would call a lockout, but yet it addresses your concerns in a scientific and reasonable way. It will be much less than the 20%" level that had been considered, he assured the group.