3/6 as. FOOD DRUG ADMINISTRATION Thomas F. Poch?, V.P. Assistant General Counsel Allergan, Inc. Morris Corporate Center 111 400 Interpace Parkway Parsippany, NJ 07054 JAN 0 2 2018 Re: Docket No. Dear Dr. Poch?: This letter responds to the citizen petition Allergan, Inc. (Allergan), submitted to the Food and Drug Administration (FDA or the Agency) on August 5, 2017 (Petition), concerning the Agency?s bioequivalence (BE) recommendations for cyclosporine ophthalmic emulsion, 0.05%. Allergan challenges the scienti?c validity of the in Vitro testing option included in the Agency October 2016 draft guidance on bioequivalence testing for cyclosporine (Draft Cyclosporine BE Guidance). The Petition reiterates many of the arguments and requests from Allergan? 5 previous citizen petitions regarding BE recommendations for abbreviated new drug applications (ANDAs) for cyclosporine ophthalmic emulsion, 0 05% products. You also provided additional information relating to your arguments in a supplement to the Petition dated October 13, 2017 (Supplement). 3 We have carefully considered your Petition, the Supplement to your Petition, and Mylan Pharmaceuticals, Inc.?s comment on the Petition dated December 22, 2017. For the reasons explained below, we deny your Petition. I. BACKGROUND A. Restasis Allergan holds the new drug application (N DA) for Restasis (N DA 50?790), which was approved on December 23, 2002. Restasis is an ophthalmic emulsion containing cyclosporine 0.5 milligram (mg)/milliliter (mL) that is indicated to increase tear production in patients whose tear production is presumed to be suppressed due to ocular in?ammation associated with FDA has issued three versions of the Dra? Cyclosporine BE Guidance to date. The ?rst version was issued in June 2013; the revised versions were issued in February 2016 and October 2016. 2 Allergan?s previous citizen petitions on this topic were submitted in February 2014 (Docket No. FDA-2014-P- 0304) and December 2014 (Docket No. FDA-2015-P-0065). FDA responded to these petitions in November 2014 and February 2016. 3 The Supplement to the Petition contains declarations and scienti?c articles in support of the Petition. It does not contain new arguments or request additional actions by FDA. US. Food 8- Drug Administration 10903 New Han?pshire Avenue Silver Spring, IVD 20993 Docket No. keratoconjunctivitis sicca dry disease). Cyclosporine, the active ingredient in Restasis, is a t0pical immunomodulator with anti?in?ammatory effects.4 B. August 2017 Petition Allergan?s petition received on August 5, 2017, relates to Draft Cyclosporine BE Guidance. The October 2016 version of the Draft Cyclosporine BE Guidance states that ANDA sponsors may demonstrate BE through in vitro testing alone or through an in vivo study with clinical endpoints. To qualify for the in vitro option, the Draft Cyclosporine BE Guidance provides that three criteria should be met: (1) the test and RLD formulations are qualitatively (Q1) and quantitatively (Q2) the same; (2) acceptable comparative physicochemical characterization of the test and RLD formulations, with comparative studies performed on at least three exhibit batches of both test and RLD products; and (3) acceptable comparative in vitro drug release rate tests of cyclosporine from the test and RLD formulations. The Draft Cyclosporine BE Guidance advises ANDA sponsors to measure the following parameters of both the test and RLD products as part of the comparative physicochemical characterization: globule size distribution, viscosity pro?le as a function of applied shear, pH, zeta potential, osmolality, and surface tension. The Draft Cyclosporine BE Guidance also states that equivalence between the test and RLD formulations in the shape of the globule size distribution (such as the presence of multiple peaks) should be demonstrated by a method proposed by the sponsor. This is Allergan?s third petition concerning the methods an ANDA applicant might use to demonstrate that a proposed generic drug is bioequivalent to Restasis. As in its previous petitions and comments to the Draft Cyclosporine BE Guidance,5 Allergan explains that it is opposed to the in vitro testing approach included in the Draft Cyclosporine BE Guidance. Allergan has three major objections to the in vitro testing approach. Allergan asserts that: (1) Current scientific methods and current lack of knowledge about in vivo?in vitro relationships do not presently allow an in vitro-only approach to demonstrate BE for cyclosporine ophthalmic emulsion (Petition at 5?21) 4 The Restasis labeling states that patients whose tear production is presumed to be suppressed due to ocular inflammation associated with keratoconjunctivitis sicca, cyclosporine emulsion is thought to act as a partial immunomodulator. The exact mechanism of action is not known? (Restasis labeling approved on May 31, 2013, available online at 05079050211b1.pdf, at 6). 5 A notice announcing the availability of our initial Draft Cyclosporine BE Guidance was published in the ederal Register in June 2013 (?Draft and Revised Draft Guidances for Industry Describing Product-Speci?c Bioequivalence Recommendations; Availability,? 78 FR 37230 (June 20, 2013)). Allergan provided comments on the Draft Cyclosporine BE Guidance in a 43?page submission to Docket No. on August 17, 2013. A notice announcing the availability of our revised Draft Cyclosporine BE Guidance was published in the Federal Register in February 2016 (?Draft and Revised Draft Guidances for Industry Describing Product-Speci?c Bioequivalence Recommendations; Availability,? 81 FR 7810 (February 16, 2016)). Allergan provided comments on the revised Draft Cyclosporine BE Guidance in a 6-page submission to Docket No. on April 18, 2016. In October 2016, a notice announcing the availability of our current revised Draft Cyclosporine BE Guidance was published in the Federal Register (?Draft and Revised Draft Guidances for Industry Describing Product-Speci?c Bioequivalence Recommendations; Availability,? 81 FR 69064 (October 5, 2016)). Allergan provided comments on the October 2016 version of the Draft CyCIOSporine BE Guidance in a 44?page submission to Docket No. on December 5, 2016. Docket No. (2) The Draft Cyclosporine BE Guidance has serious analytical gaps that hinder a robust assessment of BB for cyclOSporine ophthalmic emulsion (Petition at 21-22) (3) The BE standards for cyclosporine ophthalmic emulsion were determined using a ?awed process; FDA must revise its process to increase transparency and better ensure scienti?c rigor in the BE standards? establishment and application (Petition at 22?28). The Petition includes examples of prior Agency actions and statements, among other things, that purportedly support the above objections to the Draft Cyc103porine BE Guidance?s in vitro option (see, e. Petition at 12 and 19). C. Section 505(q) of the Federal Food, Drug, and Cosmetic Act Section 505(q) of Act was added by section 914 of the Food and Drug Administration Amendments Act of 2007 (F (Public Law 110-85, 121 Stat. 823) and was amended by the Food and Drug Administration Safety and Innovation Act (Public Law 1 12?144, 126 Stat. 993). Section 505(q), as originally added by the applies to certain citizen petitions and petitions for stay of Agency action that request that FDA take any form of action relating to a pending application submitted under section 505(b)(2) or of the Act (21 U.S.C. 355(b)(2) or and governs the manner in which these petitions are treated. Among other things, section 505(q)(1)(F) of the Act governs the time frame for ?nal Agency action on a petition subject to section 505(q). Under this provision, FDA must take ?nal Agency action on such a petition no later than 150 days after the date on which the petition is submitted. II. DISCUSSION In your Petition, you request that FDA take the following actions: (1) Not approve any pending ANDA referencing Restasis that relies on in vitro or other nonclinical analyses, and does not rely on one or more appropriately designed clinical endpoint BE studies, as Allergan claims FDA has previously suggested, to purportedly demonstrate BE to Restasis; (2) Alternatively, to the extent FDA believes a scienti?cally valid in vitro-only approval pathway exists, not approve any ANDA until at least sixty (60) days after publication of a ?nal BE guidance on cyclosporine ophthalmic emulsion that provides an explicit, validated, and detailed description of the testing requirements, the scienti?c basis supporting those requirements, and associated regulatory criteria comparisons required for regulatory approval; approval criteria, including con?dence intervals); (3) Not approve any ANDA until at least sixty (60) days after FDA has developed and publicly announced scienti?cally valid ?nal guidelines for the evaluation and approval of generic versions of nonbiological complex drugs and after allowing the public at least thirty (30) days to comment following the presentation of such ?nal NBCD guidelines; (4) Prior to the approval of any ANDA, publicly identify in detail all tests, standards, and criteria (including con?dence intervals) that the Agency has used, is using, or intends to use in evaluating such any ANDA. This includes, but is not limited to, tests, standards, and criteria described in statements made by FDA employees on this matter; Docket No. FDA-2017-P-4745 (5) (6) (7) (8) (9) At least sixty (60) days before approving any ANDA, publish in a public docket all- protocols, analytical results, and analytical reports related to the following research, and provide at least thirty (30) days for related public comments to be submitted to FDA: a. FDA?funded research pursuant to grant or contract and any extensions or modifications thereof (awarded to Physical Phannaceutica LLC) for the evaluation of pulsatile microdialysis and in vitro release testing of ophthalmic emulsions; b. Physicochemical analyses that FDA believes are pertinent to the Draft Cyclosporine BE Guidance and/or cyclosporine ophthalmic emulsion, including (but not limited to) studies described in four sources listed by Allergan; If FDA continues to adhere to its October 2016 version of the Draft Cyclosporine BE Guidance or otherwise takes the position that it may be permissible to approve an ANDA using an in vitro-only approval pathway, prior to the approval of any ANDA identify and disclose with speci?city the complete scientific and clinical evidentiary basis that supports or otherwise relates to the October 2016 version of the Draft Cyclosporine BE Guidance or in vitro-only position (and if FDA no longer adheres to the in vitro-only option in the October 2016 version of the Draft Cyclosporine BE Guidance, or otherwise no longer takes the position that it may be permissible to approve such an ANDA based on in vitro data only, withdraw the Draft Cyclosporine BE Guidance and state the Agency?s revised position publicly); Identify and disclose with speci?city the extent to which, and how, FDA considers research involving products other than cyCIOSporine Ophthalmic emulsion to be relevant to the potential use of in vitro analyses in lieu of appropriately designed clinical endpoint BE studies for the review or approval of an ANDA for cyclosporine ophthalmic emulsion; Publicly explain the inconsistent statements that FDA has made about potential reliance on research involving products other than cyclosporine ophthalmic emulsion in establishing or supporting an in vitro-only approach to demonstrating BE of cyclosporine ophthalmic emulsion; and Publicly explain the manner in which all interested stakeholders (including, but not limited to, innovator and generic product manufacturers) will receive both information and reasonable opportunity for input on contemplated new program, with a special focus on complex generics. Applicants would obtain regulatory clarity earlier in product development, so they can submit ANDAs that are ?right the ?rst time.?6 (Petition at This is Allergan?s third citizen petition concerning the methods an ANDA applicant might use to demonstrate that a proposed generic drug is bioequivalent to Restasis. This Petition repeats many of the assertions that were central to Allergan?s February 2014 citizen petition (First Allergan ?5 Opening Remarks by Dr. Scott Gottlieb for Part 15 Public Meeting on Generic Drug Competition (July 18, 2017), available at Allergan cites to Dr. Gottlieb?s remarks in the petition. Docket No. FDA-2017-P-4745 Petition) and Allergan?s December 2014 citizen petition (Second Allergan Petition)? Because FDA has addressed those assertions in its responses to the previous citizen petitions, it does not address them again here.8 To the extent this Petition raises issues different from Allergan?s previous citizen petitions challenging our BE recommendations that are generally applicable to all ANDAs for cyclosporine ophthalmic emulsion, we will consider any such issues in our development of the guidance on bioequivalence testing for cyclosporine. As with any Agency guidance development process, we intend to consider relevant scienti?c information and revise, re-issue, or ?nalize the BE guidance for cyclosporine ophthalmic emulsion, as appropriate. As explained in our reSponse to the First Allergan Petition9 and the Second Allergan Petition,10 the Draft Cyclosporine BE Guidance?s bioequivalence recommendations are being developed in accordance with the process outlined in the guidance for industry Bioequivalence Recommendationsfor Speci?c Products (Product-Speci?c BE Guidance). 1? We solicit comments on our draft bioequivalence recommendations because we want the public?s input on the contents of the ?nal bioequivalence recommendations. ?2 Interested stakeholders were invited to submit comments on the guidance?s bioequivalence recommendations for cyclosporine ophthalmic emulsion to the docket established for the draft guidance in accordance with the procedures set forth in the Federal Register Notice of Availability for the draft guidance. Allergan has actively participated in this process for all three versions of the draft guidance. To the extent this Petition requests actions different from those requested in Allergan?s previous citizen petitions that might have implications regarding the nature of the data and information necessary to support approval of an ANDA for cyclosporine ophthalmic emulsion, we deny those requests without comment. We will consider any issues related to such requests in the context of our review of speci?c applications and the record for the Draft Cyclosporine BE Guidance. 7 response to the First Allergan Petition is available on the Regulationsgov Web site under Docket No. FDA- 2014-P-034 (Document ID (FDA Response to the First Allergan Petition). response to the Second Allergan Petition is available on the Regualtionsgov Web site under Docket Nos. FDA- 2015-P-0065 and (Document ID FDA-2015- P-l404-0007) (FDA Response to the Second Allergan Petition). 8 We note that the Agency has explained in detail its process for developing and issuing BE recommendations in the reSponse to the First Allergan Petition. (FDA Response to the First Allergan Petition at 27?32). Therefore, we consider the Petition?s requests related to aspects of the Agency?s process for developing and issuing BE recommendations as addressed. 9 FDA Response to First Allergan Petition at 9-1 1, 29?30. '0 FDA Response to Second Allergan Petition at 13-15. The Product?Speci?c BE Guidance is available on the FDA Drugs guidance Web page at '2 See 65 FR 56468, 56470 (Sept. 19, 2000). We note that FDA is not required to publish draft or final product- speci?c BE recommendations before it approves an ANDA for the drug product. If the Agency determines that, as required by the statute and regulations (21 U.S.C. 3550)(2); 21 CFR 314.94), an ANDA contains sufficient evidence that the proposed generic drug product is bioequivalent to its reference listed drug and the application meets the other requirements for approval, FDA will approve the ANDA. See Product-Speci?c BE Guidance. Docket No. FDA approves only those applications that meet the applicable statutory and regulatory requirements for approval (see generally sections 505(c) and 5050) of the Act (21 U.S.C. 355(c) and and 21 CFR 314.50, 314.94, 314.105, 314.125 314.127). Approval decisions are based on the adequacy of the data and information supporting the particular application. As described above, section 505(q)(1)(F) of the Act requires FDA to take ?nal Agency action on your Petition within 150 days of submission. Therefore, we are denying your request to take the speci?ed actions that might have implications regarding the nature of the data and information necessary to support approval of an ANDA for cyclosporine ophthalmic emulsion 0.05% at this time insofar as we are continuing to consider, in the context of application-speci?c reviews, the issues you raised that have not been addressed in previous responses. We will consider any such issues in the context of our review of speci?c applications and the record for the Draft Cyclosporine BE Guidance. CONCLUSION For the reasons explained above, your Petition is denied. Sincerely, Janet Woodcock, MD. Director Center for Drug Evaluation and Research