By Jeffrey H. Brochin, J.D.
The FDA’s ‘same-moiety’ (active ingredient) limitation on the scope of a drug manufacturer’s marketing exclusivity period does not conflict with the drug approval provisions of the federal Food, Drug and Cosmetics Act (FDC Act), a federal appeals court in the District of Columbia has ruled. The FDA’s method for determining whether a new drug bears a sufficiently close relationship to a pioneering drug so as to fall within the latter’s zone of exclusivity was a reasonable one (Otsuka Pharmaceutical Co., Ltd. v. Price, August 29, 2017, Srinivasan, S.).
Background. In 2002, Otsuka Pharmaceutical Co., Ltd (Otsuka) obtained FDA approval for Abilify® Tablets, an antipsychotic drug. In the ensuing fifteen years, Otsuka received FDA approval for several additional drug products sharing Abilify Tablets’ active moiety: aripiprazole. In August 2014, a competing pharmaceutical company, Alkermes, submitted an abbreviated application for Aristada®, another injectable antipsychotic. The application for Aristada included a clinical trial conducted by Alkermes to demonstrate the drug’s safety and efficacy at intervals up to six weeks. However, the company also sought to rely on prior studies conducted by Otsuka which had demonstrated the safety and efficacy of Abilify Tablets. The FDA granted approval of the new drug to Alkermes, at which point Otsuka objected that such approval infringed upon its period of marketing exclusivity for its earlier pioneering drug. The FDA rejected Otsuka’s arguments, claiming that the two drugs possessed different active moieties. Otsuka sought judicial review of the FDA action, and a federal court upheld the FDA’s approval. Otsuka appealed to the appellate court which has now upheld the lower court’s ruling.
Two routes to FDA approval. In order to reduce the need to conduct duplicative studies, the Drug Price Competition and Patent Term Restoration Act of 1984—better known as the Hatch-Waxman Amendments—amended the FDC Act to establish two streamlined pathways to FDA approval. The first abbreviated route, known as an Abbreviated New Drug Application (ANDA), permits approval of "bioequivalent" (generic) versions of previously approved drugs without an independent showing of their safety and efficacy. The second abbreviated route—which is at issue here---enables new drug applications for non-generic drug products to rely, in part or in whole, on studies that were not conducted by or for the applicant to show the applied-for drug’s safety and efficacy. Known as "(b)(2) application," the process requires an applicant to show the propriety of relying on the preexisting studies to demonstrate the applied-for drug’s safety and efficacy. A (b)(2) application must also certify that sales of the applied-for drug would not infringe upon active, valid patents for any previously approved drugs.
No ‘free ride’ under (b)(2). The Hatch-Waxman Amendments’ abbreviated pathways in theory could enable competitors to "free ride" off of the work of innovators without having to foot the substantial expenses associated with safety-and-efficacy testing. Hatch-Waxman also introduced a regime of marketing exclusivity into the FDC Act under which the statute grants a first-in-time innovator a period of exclusivity during which the FDA must deny approval of second-in-time abbreviated applications (both ANDAs and (b)(2) applications) for drug products meeting certain conditions. If an applicant seeking to use an abbreviated pathway is blocked by a previously approved drug’s exclusivity, the applicant can either wait for the exclusivity period to expire, or submit a standalone, non-abbreviated application that does not rely on any previously approved drugs.
The FDC Act confers marketing exclusivity under three distinct provisions which the court referenced as "romanette ii," "romanette iii," and "romanette iv." Otsuka was granted a five-year exclusivity period under romanette ii for introducing aripiprazole as a New Chemical Entity, and although the five-year period for Abilify Tablets lapsed nearly a decade ago, the company’s successor drug, Abilify Maintena® subsequently received two successive marketing-exclusivity periods of three years each.
FDA focus on the active moiety. Although the issue would appear to be rather simply framed as: "when should a second-in-time drug be considered the same as the drug in the first-in-time application?" the FDA rejected such a narrow understanding under which exclusivity would only cover specific drug products, and instead concluded that a first-in-time drug’s marketing exclusivity attaches not to the specific drug product receiving approval, but to a particular feature of the drug: its active moiety. The FDA derived that understanding from the fact that all three romanettes condition a drug’s eligibility for exclusivity on whether its active ingredient-- its active moiety—has been approved in a previous application. Although Otsuka argued that such an interpretation conflicted with the statute, the court disagreed and upheld the FDA’s active moiety test for determining limitation on marketing exclusivity.
The case is No. 16-5229.
Attorneys: Seth Paul Waxman (Wilmer Cutler Pickering Hale and Dorr LLP) for Otsuka Pharmaceutical Co., Ltd. Scott R. McIntosh, U.S. Department of Justice, for Thomas E. Price.
Companies: Otsuka Pharmaceutical Co., Ltd.
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