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Executive Summary

GLAXO E-Z-V METERED-DOSE INHALER ACTUATOR APPROVAL CHALLENGED by 3M Pharmaceuticals in an Aug. 2 petition to FDA. 3M contends that Glaxo's 510(k) approval for the product should be voided and the firm required to submit an NDA. Glaxo submitted a 510(k) "substantial equivalence" application for the E-Z-V in August 1992, 3M said, and obtained clearance approximately three months later. "Glaxo clearly used the 510(k) procedures to circumvent the need for an NDA," the petition asserts. "Thus, Glaxo quickly obtained market approval for the E-Z-V under the device standards, even though E-Z-V is actually a combination product which should be regulated as a drug." 3M sells a similar metered-dosed inhaler, the Autohaler for use with the drug product Maxair, which the company says required NDA approval under an intercenter agreement between the Center for Devices & Radiological Health and the Center for Drug Evaluation & Research. 3M also suggested in an accompanying petition that FDA "allocate lead jurisdiction for regulation of all metered-dose inhalers...actuators and spacers to" CDER. 3M challenges the Glaxo 510(k) on several grounds: that the submission failed to establish substantial equivalence to a predicate device; that the 510(k) did not comply with FDA's reviewer guidance for nebulizers, metered-dose inhalers (MDI), spacers and actuators; and that E-Z-V is intended for use with specific drugs rather than "all drugs in the category of aerosol drug products for inhalation." Under the intercenter agreement, which was established to clarify the centers' roles in regulating combination products ("The Pink Sheet" Nov. 25, 1991, p. 14), drug and device components in products such as MDIs and accessories are regulated separately by CDRH and CDER "unless the intended use of the two products, through labeling, creates a combination product." 3M argues that "all MDIs, actuators and spacers and the aerosol drug(s) they deliver are combination products, regardless of the manufacturer's 'label.'" Because the products "have no other function independent of drug delivery," the firm said, their "primary mode of unequivocally that of a drug" and therefore they fall under CDER jurisdiction. Currently, the device center reviews all MDIs labeled for use with a category of marketed drugs, such as aerosol drug products. The device center also has lead regulatory authority over delivery system/drug combinations in which the drug already has been marketed and the "studying of device technology predominates." CDER, on the other hand, is the primary reviewer when the inhaler is marketed and the study focuses on the drug. CDER also regulates drug delivery products when the drug component labeling does not encompass the substitution of a generic delivery device, as well as combination products in which "a device...serves as a container for a drug" or the delivery system is attached to the drug container, or whose "primary purpose" is a drug, 3M said. E-Z-V, according to the device's 510(k) summary, is only "intended for use with certain metered-dose inhalers." Although "the 510(k) suggests broad substitutability of the Glaxo E-Z-V for standard press-and-breathe aerosol drug delivery devices," 3M said that "two points suggest" it was intended as "a device 'dedicated' for use with Glaxo's proprietary drugs" and should therefore be regulated under CDER. First, E-Z-V is not "physically designated" to be compatible with inhalable aerosol drugs other than Glaxo's Beclovent and Ventolin and Schering-Plough's Proventil, according to 3M. In addition, 3M said that Glaxo has promoted the MDI so as to "establish an intended use of the E-Z-V solely with these specific drugs." In addition to arguing that E-Z-V is a combination drug rather than a device, 3M argued that Glaxo's 510(k) clearance should be revoked because studies were not conducted properly. FDA's reviewer guidance for nebulizers, MDIs and MDI accessories stipulates that submissions include particle size distribution data from "at least three different drugs," preferably of different sizes. 3M contended that Glaxo's clearance should be voided because the firm's submission did not meet this requirement. Glaxo, 3M said, submitted data "on essentially only two...drugs" because Ventolin and Proventil are both albuterol sulfate products. 3M also challenged Glaxo's claim of equivalence to a predicate device. Glaxo cited the OptiHaler drug delivery system, distributed by HealthScan Products, as the predicate device for E- Z-V. 3M said, however, that the submission "provides no data that permits a comparison of the safety and efficacy of the E-Z-V to the OptiHaler." Comparative in vitro data are "essential," 3M reasoned, because E-Z-V and the OptiHaler differ significantly in their breath activation characteristics. 3m also faulted Glaxo for conducting non-clinical tests of E- Z-V "in comparison with 'standard actuators'" rather than the OptiHaler. "Standard actuators on the market today," the firm argued, "are dedicated for use with a single drug and are therefore considered drug products, or at a minimum, combination products with the primary mode of action of a drug" (emphasis 3M's), neither of which "constitutes a legally marketed predicate device."

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