The US Food and Drug Administration (FDA) on Tuesday revised its draft bioequivalence (BE) guidance detailing the agency's expectations for generic versions of Durezol (difluprednate ophthalmic emulsion) in response to a citizen petition from Alcon and its parent company Novartis.
In 2008, FDA approved Sirion Therapeutics' Durezol, a corticosteroid, to treat inflammation and pain associated with ocular surgery. Two years later, Alcon acquired the rights to Durezol from Sirion, shortly before Novartis completed its acquisition of Alcon.
Notably, at least one company, Akorn, has already filed an abbreviated new drug application (ANDA) for Durezol. In November, Akorn announced it had prevailed in an inter partes review (IPR) proceeding for a patent for Durezol that Alcon licensed from Senju Pharmaceutical and Mitsubishi Chemical Corporation.
Background: Initial Draft Guidance
FDA first issued its draft BE guidance for difluprednate in January 2016, recommending that companies seeking generic approval either complete a series of in vitro studies, or a single in vivo study to demonstrate bioequivalence to the reference product.
Specifically, FDA recommended sponsors complete in vitro studies to demonstrate that their version of the drug is qualitatively and quantitatively the same (Q1/Q2) as Durezol, and show acceptable comparative physiochemical characterization and comparable in vitro drug release rate between the two formulations.
Alternatively, FDA said that sponsors could complete an in vivo study measuring difluprednate in aqueous humor in patients undergoing cataract surgery to demonstrate bioequivalence.
Citizen Petition & FDA Response
However, in a citizen petition filed in September 2016, Alcon and Novartis argued that the in vitro-only option proposed by FDA is insufficient to measure bioequivalence for difluprednate ophthalmic emulsions, and called for the agency to remove the option.
The companies also requested that FDA require companies taking the in vivo route measuring the active metabolite, 6α, 9-difluoropredisolone 17-butyrate (DFB) of difluprednate instead of the parent drug.
Last Friday, FDA responded to Alcon and Novartis, denying their first request and partially accepting their second request.
"We disagree with the contention that the in vitro option is insufficient," FDA wrote. "The in vitro option is a weight-of-evidence approach based on testing that demonstrates comparative physiochemical characteristics and drug release rate to the RLD [reference listed drug]. Further … the Draft Guidance on Difluprednate recommends an in vitro testing option only if the proposed generic is Q1/Q2 the same as the RLD."
According to FDA, "For a Q1/Q2 generic difluprednate ophthalmic emulsion product, the only clinically meaningful difference from the RLD would be in its physiochemical properties and drug release rate, which would arise from differences in the product's manufacturing process or formulation steps. When a Q1/Q2 generic difluprednate ophthalmic emulsion product has comparative physiochemical properties and a comparative drug release profile to the RLD, the two products are expected to be bioequivalent."
However, for the in vivo option, FDA partially accepted Alcon's argument, saying it will request that generic sponsors submit DFB metabolite data in their BE demonstration in addition to data on the parent drug. If the generic sponsor finds the parent drug levels are low to provide reliable measurements, FDA said that "the DFB metabolite data will be subject to the [90% confidence interval] approach for BE demonstration."
Revised Draft Guidance on Difluprednate