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CONTROLLED-RELEASE MECHANISMS THAT ARE DIFFERENT FROM INNOVATOR’s

Executive Summary

CONTROLLED-RELEASE MECHANISMS THAT ARE DIFFERENT FROM INNOVATOR's should be considered by FDA to be a different "dosage form" for the purpose of filing ANDA suitability petitions, Washington, D.C. law firm Wiley, Rein & Fielding said in an Oct. 28 citizen petition to the agency. The petition was filed on behalf of Pfizer. "FDA must recognize the importance of release mechanism in differentiating among controlled-release SODFS (solid oral dosage forms)," the petition says. The Waxman/Hatch Act requires that a sponsor submit an ANDA suitability petition when a drug is different from the innovator's in dosage form, route of administration, strength or active ingredient. Wiley, Rein & Fielding claims that "FDA's 'dosage form' classifications for oral controlled-release products are over broad, arbitrary, and improperly permit non-identical products, including GITS alternatives, to obtain ANDA approval based solely on bioequivalence testing." GITS is the Alza-developed oral osmotic pump controlled-release mechanism in Pfizer's sustained- release nifedipine Procardia XL. The petition says that "to the extent any consistency may be discerned, FDA has traditionally separated solid controlled- release oral dosage forms into only two categories, tablet and capsule, for purposes of the 1984 Amendments [Waxman/Hatch Act]." Providing an example, the law firm notes "in approving a nifedipine dosage form suitability petition from KV Pharmaceutical Company, FDA characterized the change as 'from an extended-release tablet to an extended-release capsule' without reference to the substantial differences in release mechanism." KV's suitability petition for nifedipine 30, 60 and 90 mg extended-release capsules was approved in October 1991. Pfizer's marketing exclusivity for Procardia XL expired in September 1992. Pfizer has said it expects generic companies will not be able to prove bioequivalence to Procardia XL. The petition refers to FDA's Sept. 9, 1993 bioequivalence guidance on oral extended-release dosage forms, which says that the agency does not require "the mechanism by which the release of the active drug substance from the formulation be the same" for generic and reference extended-release products. Pfizer maintains that "by using such gross categories as tablet and capsule and refusing to consider differences in release mechanism for controlled-release SODFS, FDA is failing to comply with the Congressional mandate to establish reasonable, scientifically supported distinctions among different dosage forms." The agency's "failure to implement the ANDA regime with a meaningful recognition of therapeutically significant variations in dosage form, unless promptly remedied, can put patient health and safety at needless risk and lead to legally invalid ANDA reviews and approvals," the petition states. FDA should determine "whether enhancement of tests short of full clinical trials are warranted by recognized differences in dosage form." Procardia XL is facing competition from Miles' extended- release nifedipine product Adalat CC; the NDA was approved in April and launched at a 26.5% discount to Pfizer's drug ("The Pink Sheet" July 5, T&G-1). Elan is awaiting FDA approval of its NDA for Nifelan once-daily nifedipine. However, Pfizer has tried to prevent Nifelan's approval by means of a lawsuit alleging infringement, which was dismissed, and then a citizens petition requesting that FDA deny Elan's application ("The Pink Sheet" April 5, T&G-7). Alza's patent on the GITS delivery system expires in September 2003. The petition urges that "FDA must immediately require that any ANDA for a proposed nifedipine drug product using a controlled- release mechanism other than GITS be considered only following submission and approval of a suitability petition." The agency "should require all suitability petitions arising from, or including, deviations from the controlled-release 'dosage form' of the reference drug to include the 'full statement' of 'all relevant information' required by FDA's regulations and necessary to permit FDA to make a fully informed, articulated decision."
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