FDA Responds to Citizen Petition & Publishes Revised BE Recommendations for Difluprednate

February 21, 2017

On Wednesday, February 15th, the FDA issued a revised draft guidance, entitled “Draft Guidance on Difluprednate.” regarding its bioequivalence recommendations for the product.  In the revised document, FDA “provides specific guidance on the design of bioequivalence (BE) studies to support abbreviated new drug applications (ANDAs) for difluprednate emulsion.”


In 2008, the FDA approved the New Drug Application (NDA) for Durezol (diflprednate emulsion).  Durezol is a “topical corticosteroid that is indicated for the treatment of inflammation and pain associated with ocular surgery and the treatment of endogenous anterior uveitis.”  In January 2016, the Agency issued an initial draft guidance regarding its BE recommendations for the generic version of this product.

Citizen Petition & Revised Draft Guidance

In September 2016, a citizen petition was submitted by Alcon and Novartis.  In this petition, the companies “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,”.  In a recent RAPS article, it was noted that “the companies also requested that FDA require companies taking the in vivo route measure the active metabolite, 6α, 9-difluoropredisolone 17-butyrate (DFB) of difluprednate instead of the parent drug.”

FDA responded to this petition by denying the first part of the companies’ request and accepting the second part.

In its response, FDA wrote the following:

“We disagree with the contention that the in vitro option is insufficient. The in vitro option is a weight-of-evidence approach based on testing that demonstrates comparative physicochemical characteristics and drug release rate to the RLD.”

In addition, the Agency also noted that its draft guidance for difluprednate only recommends in vitro testing if the proposed generic is Q1/Q2 the same as the RLD.  Furthermore, FDA states that “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, the Agency did partially accept Alcon’s argument regarding the in vivo option.  As such, the FDA “will request that generic sponsors submit DFB metabolite data in their BE demonstration in addition to data on the parent drug.”

For additional information, view the Citizen Petition, FDA’s response, and the Agency’s revised draft guidance on the subject.

Are you in the process of developing a nonprescription drug that may be subject to the guidelines provided in the Agency’s recent draft guidance? We can help you achieve successful interactions with the Agency and get your product approved by the FDA.Contact us today to learn more about our services and how we can be of assistance to you.


August 29, 2016

FDA Issues Guidance Regarding the Agency’s Refuse to Receive Policy for Certain Abbreviated New Drug Applications

On Wednesday, August 24th FDA released a final guidance document, entitled “Abbreviated New Drug Application Submissions – Refuse to Receive for Lack of Justification of Impurity Limits,” which...

March 6, 2017

2016 was Record-Setting Year for Generic Drug Approvals, Reports FDA

In a recent post on the FDA Voice blog, the Agency reported that its generic drug program hit record highs in 2016. In the blog post, Kathleen “Cook” Uhl, M.D., Director of FDA’s Office of Generic...

October 6, 2016

FDA Issues 67 New & Revised Bioequivalence Study Recommendations for Generic Drug Makers

In order for a generic drug to be approved by the FDA, the drug maker must prove that the product is pharmaceutically equivalent to its reference listed drug (RLD). There are many different types of...