Alcon Pharmaceuticals, Ltd. 6201 South Freeway

Fort Worth, TX 76134-2099 Telephone: 1 800 862 5266

September 14, 2016

Division of Dockets Management (HFA-305) Food and Drug Administration Department of Health and Human Services 5630 Fishers Lane, Room 1061 Rockville, Maryland 20852

CITIZEN PETITION

Alcon Pharmaceuticals, Ltd. (Alcon), on behalf of itself and its affiliated company, Novartis Pharmaceuticals Corporation (collectively, the “Petitioners”1), respectfully submits this petition under section 505(q) of the Federal Food, Drug, and Cosmetic Act (FDCA) to request the Commissioner of Food and Drugs to take the actions set forth below in Section A with respect to: (1) the bioequivalence testing requirements for any abbreviated new drug application (ANDA) that cites Durezol® (difluprednate ophthalmic emulsion, 0.05%) (new drug application (NDA) 022212) as the reference listed drug (RLD); and (2) revisions to the Food and Drug Administration (FDA or the agency) product-specific bioequivalence draft guidance for difluprednate ophthalmic emulsion, “Draft Guidance on Difluprednate.”

A. ACTIONS REQUESTED

Petitioners believe that only in vivo pharmacokinetic testing or comparative clinical endpoint testing, and not in vitro testing, is sufficient to accurately, sensitively, and reproducibly measure bioequivalence of difluprednate ophthalmic emulsions. Thus, to promote the public health interest in ensuring safe and effective generic difluprednate ophthalmic emulsions, Petitioners request that FDA take the following actions:

1. Require any ANDA applicant that cites Durezol as the RLD to establish bioequivalence by performing an in vivo pharmacokinetic study in aqueous humor that measures 6α, 9-difluoroprednisolone (DFB), an active metabolite of difluprednate, or alternatively, if FDA retains the in vitro option for establishing bioequivalence in the Draft Guidance on Difluprednate, require the in vitro testing described in Section B.V of this petition.

2. Expressly acknowledge that a difference in the inactive ingredients of a proposed generic difluprednate ophthalmic emulsion and Durezol also may necessitate a clinical endpoint study to establish bioequivalence.

1 Alcon Pharmaceuticals, Ltd. and Novartis Pharmaceuticals Corporation are each part of the Novartis group of companies, and are under common ownership and control. As announced previously, management of Alcon’s prescription drug portfolio is transitioning to Novartis’s global pharmaceuticals business unit. In the United States, responsibility for distributing these drugs and maintaining the corresponding regulatory filings will transfer to Novartis Pharmaceuticals Corporation. This petition is submitted by Alcon Pharmaceuticals, Ltd., on behalf of both itself and its affiliate, Novartis Pharmaceuticals Corporation.

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3. Promptly issue a final guidance document on demonstrating bioequivalence for 0.05% difluprednate ophthalmic emulsions that reflects the above principles.2

B. STATEMENT OF GROUNDS

I. Executive Summary of Grounds

In January 2016, FDA announced the availability of the Draft Guidance on Difluprednate, which proposes product-specific bioequivalence recommendations for 0.05% difluprednate ophthalmic emulsions.3 The Draft Guidance on Difluprednate states that an ANDA applicant for a generic difluprednate ophthalmic emulsion could establish bioequivalence to Durezol either through in vitro testing or an in vivo pharmacokinetic study in aqueous humor. Under the Draft Guidance, the in vitro option would be available to proposed generic products that are qualitatively and quantitatively (Q1/Q2) the same as Durezol.

As a general matter, Petitioners agree that in vivo pharmacokinetic studies are an appropriate approach to establishing bioequivalence for difluprednate ophthalmic emulsions. Because Durezol is a topical oil-in-water emulsion with a complex release profile affecting absorption characteristics, parameters, and rates, it presents bioequivalence challenges warranting an in vivo study. This request accords with FDA’s near-uniform approach of calling for in vivo pharmacokinetic studies to establish bioequivalence for ophthalmic corticosteroid products.4 It also accords with the agency’s general approach of recommending in vivo bioequivalence studies for other complex ophthalmic dosage forms. Petitioners therefore request that FDA require an in vivo pharmacokinetic study in aqueous humor to establish bioequivalence for any ANDA that lists Durezol as the RLD. The measured analyte for this study should be DFB rather than difluprednate, given that difluprednate is rapidly hydrolyzed to the active metabolite DFB.

Further, FDA should eliminate the proposed in vitro testing option, which to our knowledge has not been correlated with in vivo bioavailability of difluprednate. For this reason and given Durezol’s complex release profile, the proposed in vitro method is insufficient to ensure that there are no significant differences between Durezol and generic ophthalmic difluprednate emulsions in the rate and extent to which DFB becomes available at the site of action, i.e., in the target ocular tissues. Eliminating the in vitro option would bring the Draft Guidance into line with the vast majority of FDA’s draft bioequivalence guidances for ophthalmic suspensions and other complex ophthalmic dosage forms, as noted above. FDA’s departure from its established in vivo testing approach to recommend in vitro testing for another ophthalmic emulsion—in its Draft Guidance on Cyclosporine5—is distinguishable from this case for numerous reasons. For example, cyclosporine is not a corticosteroid. Also, FDA’s 2 We will also submit this petition to the docket for the Draft Guidance on Difluprednate, Docket No. FDA-2007-D-0369-0372. See 21 C.F.R. § 10.115(g)(5).

3 FDA, Draft Guidance on Difluprednate (Jan. 2016), http://www.fda.gov/downloads/Drugs/ GuidanceComplianceRegulatoryInformation/Guidances/UCM481813.pdf [hereinafter Draft Guidance on Difluprednate].

4 See infra note 44.

5 FDA, Draft Guidance on Cyclosporine (rev. Feb. 2016), http://www.fda.gov/downloads/drugs/ guidancecomplianceregulatoryinformation/guidances/ucm358114.pdf [hereinafter Draft Guidance on Cyclosporine].

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rationale for recommending the in vitro option for cyclosporine—that an in vivo bioequivalence study would be insensitive and infeasible due to the product’s “modest showing of clinical effect”6—is inapplicable to difluprednate, which has robust efficacy.

If FDA denies the above requests and retains the option to establish bioequivalence to Durezol through in vitro testing alone, Petitioners alternatively request that FDA require additional in vitro testing as set forth in Section V. These requirements would increase the likelihood that any meaningful differences between the in vivo bioavailability of generic difluprednate ophthalmic emulsion products and Durezol are detected, reducing patient risk.

Finally, we ask that the agency promptly issue a final guidance document with content that is consistent with this petition.

II. Background

A. Durezol

Alcon currently holds NDA 022212 for Durezol, which was approved for the treatment of inflammation and pain associated with ocular surgery in 2008 and for the treatment of endogenous anterior uveitis in 2012. Durezol is a topical formulation of difluprednate that is an ophthalmic emulsion for ocular instillation. Difluprednate is a potent glucocorticoid in the “strong steroid” class7 and is a synthetic derivative of prednisolone.8

Prior to the development of Durezol, topical ophthalmic corticosteroids (such as prednisolone) in solution or suspension formulations were the mainstay therapy for ocular inflammation, and several other drugs were approved for treatment of post-operative inflammation and pain.9 There was an unmet medical need, however, for a faster-acting and more bioavailable agent that could address pain and discomfort in addition to inflammation.10 Durezol was developed as a strong steroid to address these needs. Difluprednate emulsion has greater potency at the glucocorticoid receptor site than prednisolone.11 The emulsion

6 Letter from Janet Woodcock, M.D., Director, Center for Drug Evaluation and Research, FDA, to Damon Burrows, Vice President, Associate General Counsel, Allergan, Inc. (Nov. 20, 2014), Docket No. FDA-2014-P-0304-0042, at 34 [hereinafter First Restasis Citizen Petition Response].

7 E.g., FDA, Briefing Package, Division of Anti-Infective and Ophthalmology Products Advisory Committee Meeting, at 6 (May 29, 2008), http://www.fda.gov/ohrms/dockets/ac/08/briefing/2008-4358b1-01-FDA.pdf [hereinafter FDA Briefing Package].

8 E.g., id. at 4.

9 E.g. id. at 5; Jamal K.N. & Callanan D.C., The role of difluprednate ophthalmic emulsion in clinical practice, 3 Clinical Ophthalmology 381, 381 (2009), http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2709030/pdf/opth-3-381.pdf.

10 See Jamal & Callanan, supra note 9, at 381 (“Currently, the most widely prescribed strong topical corticosteroid in the US is prednisolone acetate 1%. While it controls inflammation effectively, it has not been shown to consistently address postoperative pain and discomfort in a large clinical trial.”).

11 FDA, Pharmacology Review NDA 22-212, at 8 (May 8, 2008), http://www.accessdata.fda.gov/ drugsatfda_docs/nda/2008/022212s000_PharmR.pdf (“In its dermatological formulation, difluprednate 0.05% is over 4 times more potent than prednisolone valerate acetate 0.3% and 3200 times stronger than prednisolone 0.5%, as measured by peripheral vasoconstriction. The potency of difluprednate is approximately the same as that of betamethasone.”) [hereinafter FDA Pharmacology Review].

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formulation of difluprednate also enables consistent dosing without the need for shaking (which is necessary for prednisolone acetate ophthalmic suspension),12 while providing greater bioavailability than a suspension.13

Durezol is designed to act at the site of initial application and to be metabolized and inactivated in the eye before reaching systemic circulation or other tissues. Difluprednate penetrates the epithelium, where it is quickly deacetylated to an active metabolite, DFB.14 DFB saturates the corticosteroid receptors in the ocular target tissues, quickly and effectively activating them.15 Any unbound drug is converted to DF, the inactive breakdown product of DFB.16 Thus, difluprednate, once instilled, is rapidly converted to the active metabolite and distributed to the main ocular target tissues that are affected by inflammation (cornea, iris/ciliary body, and aqueous humor in the anterior chamber), rather than accumulating in the blood.17 After repeat ocular instillation of two drops of difluprednate (0.01% or 0.05%) four times daily for seven days in clinical pharmacokinetic studies, DFB levels in blood were below the quantification limit (50 ng/mL) at all time points for all subjects, indicating the systemic absorption of difluprednate and DFB after ocular instillation is limited.18

B. Legal and Regulatory Framework

Any ANDA must contain, among other things, information demonstrating that the proposed generic drug is bioequivalent to the RLD.19 Bioequivalence of a generic drug is established if “the rate and extent of absorption of the drug do not show a significant difference from the rate and extent of absorption of the listed drug when administered at the same molar dose of the therapeutic ingredient under similar experimental conditions in either a single dose or multiple doses.”20 FDA’s regulations define bioequivalence, in pertinent part, as “the absence of a significant difference in the rate and extent to which the active ingredient or active moiety . . . becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study.”21

As FDA has noted, “[f]or systemically acting drug products, the rate and extent of systemic absorption of the drug is usually the most sensitive, accurate and reliable indicator of

12 See FDA, Cross-Discipline Team Leader Review NDA 22-212, at 1 (June 18, 2008), http://www.accessdata.fda.gov/drugsatfda_docs/nda/2008/022212s000_CrossR.pdf [hereinafter FDA Cross-Discipline Team Leader Review].

13 See, e.g., FDA Pharmacology Review, at 12 (noting that difluprednate as an emulsion has a 40% higher bioavailability than difluprednate administered as a suspension).

14 Id. at 9.

15 Id. at 10.

16 Id. at 9.

17 Id. at 10-12.

18 FDA Briefing Package, at 6; FDA Cross-Discipline Team Leader Review, at 7.

19 FDCA § 505(j)(2)(A)(iv), 21 U.S.C. § 355(j)(2)(A)(iv); 21 C.F.R. §§ 314.94(a)(7), 314.127(a)(6)(i).

20 FDCA § 505(j)(8)(B)(i), 21 U.S.C. § 355(j)(8)(B)(i).

21 21 C.F.R. § 320.1(e).

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the rate and extent to which the active ingredient becomes available at the site of drug action.”22 For such drugs, the determination of bioequivalence generally rests on a comparison of drug and/or metabolite concentrations in an accessible biological fluid, such as blood. The FDCA also recognizes that some drugs do not reach their site of action through absorption into the bloodstream: “For a drug that is not intended to be absorbed into the bloodstream, the Secretary may establish alternative, scientifically valid methods to show bioequivalence if the alternative methods are expected to detect a significant difference between the drug and the listed drug in safety and therapeutic effect.”23 The statute also provides that FDA may “assess bioavailability by scientifically valid measurements intended to reflect the rate and extent to which the active ingredient or therapeutic ingredient becomes available at the site of drug action.”24

FDA regulations identify six categories of tests for measuring bioavailability and establishing bioequivalence, listed in “descending order of accuracy, sensitivity and reproducibility”: (i) in vivo studies in humans comparing drug/metabolite concentrations in an accessible biological fluid or an in vitro test that has been correlated with and is predictive of human in vivo bioavailability data, (ii) in vivo measurements of drug/metabolite in urine, (iii) in vivo testing in humans of an appropriate acute pharmacological effect, (iv) controlled clinical trials in humans to establish safety and efficacy, (v) in vitro testing that ensures human in vivo bioavailability, and (vi) any other approach deemed adequate by FDA.25

In addition, generic ophthalmic drugs generally must also “contain the same inactive ingredients and in the same concentration” as the listed drug.26 FDA will consider an inactive ingredient in, or the composition of, a proposed generic ophthalmic drug “unsafe” and refuse to approve the ANDA if the drug does not contain the same inactive ingredients in the same concentration as the RLD and if the applicant fails to demonstrate that any allowable difference does not affect the safety or efficacy of the proposed product.27

C. Draft Guidance on Difluprednate

In January 2016, FDA announced the availability of the Draft Guidance on Difluprednate.28 The Draft Guidance proposes product-specific bioequivalence recommendations for 0.05% difluprednate ophthalmic emulsions and includes two options for

22 Letter from Janet Woodcock, Director, Center for Drug Evaluation and Research, FDA, to Dwight O. Moxie, Senior Attorney, Allergan, Inc. and Robert A. Bellantone, President and Chief Scientific Officer, Physical Phamaceutica, LLC (Feb. 10, 2016), Docket Nos. FDA-2015-P-0065-0027 and FDA-2015-P-1404-0007, at 10 [hereinafter Second Restasis Citizen Petition Response].

23 FDCA § 505(j)(8)(C), 21 U.S.C. § 355(j)(8)(C).

24 FDCA § 505(j)(8)(A)(ii), 21 U.S.C. § 355(j)(8)(A)(ii).

25 21 C.F.R. § 320.24(b).

26 21 C.F.R. § 314.94(a)(9)(iv). The proposed generic product may differ from the RLD in its “preservative, buffer, substance to adjust tonicity, or thickening agent provided that the applicant identifies and characterizes the differences and provides information demonstrating that the differences do not affect the safety or efficacy of the proposed drug product.” Id.

27 21 C.F.R. § 314.127(a)(8)(ii)(C).

28 Product-Specific Bioequivalence Recommendations; Draft and Revised Draft Guidances for Industry; Availability, 81 Fed. Reg. 4913 (Jan. 28, 2016).

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demonstrating bioequivalence of such proposed generic products to Durezol: in vitro testing or an in vivo pharmacokinetic study. To qualify for the in vitro option:

• The test product should be Q1/Q2 the same as Durezol.29

• A comparative study on at least three exhibit lots of the test and RLD products should demonstrate “acceptable comparative physicochemical characterization of the test and RLD formulations.”30 Parameters that should be measured are globule size distribution, viscosity profile as a function of applied shear, pH, zeta potential, osmolality, surface tension, and drug distribution in different phases of the formulation.31

• “Acceptable comparative in vitro drug release rate tests of difluprednate from the test and [RLD] formulations” should also be demonstrated.32 “The methodology used for in vitro drug release testing should be able to discriminate the effect of process variability in the production of the test formulation.”33

Alternatively, the Draft Guidance on Difluprednate proposes to recommend one single-dose, parallel design in vivo bioequivalence study, using a pharmacokinetic endpoint, in the aqueous humor of patients undergoing indicated cataract surgery.34 This section of the Draft Guidance on Difluprednate refers to the agency’s draft product-specific bioequivalence guidance for loteprednol etabonate ophthalmic suspension35 for additional recommendations on the design of the in vivo pharmacokinetic study.36

III. FDA Should Require a Clinical Pharmacokinetic Study to Establish Bioequivalence to Durezol and Revise the Draft Guidance on Difluprednate Accordingly.

An accurate, sensitive, and reproducible measure of bioavailability is critical to ensuring that generic difluprednate ophthalmic emulsion products are bioequivalent to Durezol and therefore, can be expected to have the same safety and effectiveness. A clinical pharmacokinetic study in aqueous humor is the most accurate, sensitive, and reproducible method to demonstrate bioequivalence of a generic difluprednate ophthalmic emulsions to Durezol. Requiring this study is consistent with FDA’s near-uniform practice of calling for such a study to

29 Draft Guidance on Difluprednate, at 1. “Q1 (qualitative sameness) means that the test product uses the same inactive ingredient(s) as the reference product,” and “Q2 (quantitative sameness) means that the concentrations of the inactive ingredient(s) used in the test product are within ± 5% of those used in the reference product.” Id. at 1 nn.1-2.

30 Id. at 1.

31 Id.

32 Id.

33 Id. at 1-2.

34 Id. at 2.

35 FDA, Draft Guidance on Loteprednol Etabonate (rev. June 2016), http://www.fda.gov/downloads/ Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM249244.pdf [hereinafter Draft Guidance on Loteprednol Etabonate].

36 Draft Guidance on Difluprednate, at 2.

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demonstrate bioequivalence for ophthalmic corticosteroids and most other complex ophthalmic dosage forms. Because Durezol is an emulsion with a complex release profile and a highly effective steroid, FDA’s proposed in vitro testing alternative is not appropriate to ensure that a proposed generic difluprednate ophthalmic emulsion is bioequivalent to Durezol.

A. Ophthalmic Emulsions Present Unique Bioequivalence Challenges.

Durezol is a complex ophthalmic oil-in-water emulsion that delivers its active ingredient to the eye surface for absorption and therapeutic effect. The drug substance is a micronized form of difluprednate that is solubilized in castor oil to form the oil phase of the emulsion.

A number of factors affect the bioavailability of any topical drug product, including drug attributes (solubility and dissolution rate in the vehicle, size, membrane permeability, charge, and metabolism), vehicle attributes, membrane attributes, and method of application.37 Even where two ophthalmic emulsion drug products are Q1/Q2 the same, differences in their manufacturing processes and formulation steps may result in differences in their physicochemical properties.38 Such physiochemical differences may affect a proposed generic product’s drug release, absorption, and dose uniformity.39 Differences in the physicochemical properties and release rates of two ophthalmic emulsions may result in differences in the bioavailability of the products, even though the two products are otherwise Q1/Q2 the same.

FDA has recognized that ophthalmic emulsions and other nonsoluble dosage forms present unique bioequivalence challenges as compared to ophthalmic solutions. For example, in a notice of available grant funding to study the effect of physiochemical properties of ophthalmic formulations on ocular bioavailability, FDA noted:

For generic ophthalmic solutions that are [Q1/Q2] the same as the RLD, bioequivalence is considered to be self-evident and a waiver of in vivo study requirements may be requested. For other ophthalmic dosage forms that are Q1 and Q2 the same as the RLD, bioequivalence must be demonstrated as manufacturing differences have the potential to affect ocular bioavailability. Manufacturing differences may result in physicochemical differences which in turn may affect clearance, distribution, and release of the drug. Suitable bioequivalence methods are lacking for many generic ophthalmic formulations, including suspensions and emulsions.40

37 See Ajaz Hussain, Office of Testing and Research, Center for Drug Evaluation and Research, FDA, “Methods for Assessing Bioequivalence of Topical Products: How Should FDA Redirect its Research Program” (Nov. 17, 2000), http://www.fda.gov/ohrms/dockets/ac/00/slides/slides/3661s1_01.PPT.

38 First Restasis Citizen Petition Response, at 12.

39 Id.; Second Restasis Citizen Petition Response, at 20-21.

40 Department of Health and Human Services, Grant Announcement, RFA-FD-12-020, Effect of Physiochemical Properties of Ophthalmic Formulations on Ocular Bioavailability (Apr. 27, 2012), http://grants.nih.gov/grants/guide/rfa-files/RFA-FD-12-020.html.

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B. FDA Has Called for In Vivo Bioequivalence Testing for Nearly All Ophthalmic Corticosteroid Products and Many Topical Complex Ophthalmic Dosage Forms.

The agency has nearly uniformly recommended an in vivo pharmacokinetic study in aqueous humor to demonstrate bioequivalence to ophthalmic corticosteroid products, reflecting FDA’s recognition that an in vivo pharmacokinetic study in an accessible bodily fluid is generally the most accurate, sensitive, and reproducible method of measuring bioavailability and establishing bioequivalence to ensure patients receive therapeutically beneficial doses. Likewise, in recognition of the unique bioequivalence challenges presented by complex ophthalmic dosage forms, FDA has generally recommended in vivo testing to demonstrate their bioequivalence in its product-specific bioequivalence draft guidances.

First, the vast majority of FDA’s product-specific bioequivalence draft guidances for ophthalmic corticosteroids recommend in vivo pharmacokinetic studies. In the product-specific bioequivalence draft guidances for prednisolone acetate,41 loteprednol etabonate,42 and rimexolone43 ophthalmic suspension products—all corticosteroids—FDA has recommended an in vivo pharmacokinetic study in aqueous humor to demonstrate bioequivalence.44 And FDA has consistently recommended an in vivo approach to demonstrate bioequivalence for ophthalmic corticosteroids across other complex dosage forms, including for dexamethasone/tobramycin ophthalmic ointment.45 Likewise, FDA has recommended clinical 41 FDA, Draft Guidance on Prednisolone Acetate (rev. June 2016), http://www.fda.gov/downloads/ Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM384160.pdf [hereinafter Draft Guidance on Prednisolone Acetate].

42 Draft Guidance on Loteprednol Etabonate.

43 FDA, Draft Guidance on Rimexolone (rev. June 2016), http://www.fda.gov/downloads/Drugs/ GuidanceComplianceRegulatoryInformation/Guidances/UCM347035.pdf [hereinafter Draft Guidance on Rimexolone].

44 FDA recently revised its product-specific bioequivalence draft guidances for two strengths of dexamethasone/tobramycin ophthalmic suspension (collectively, “Draft Guidances on Dexamethasone/Tobramycin Ophthalmic Suspension”) to include an in vitro option for demonstrating bioequivalence. FDA, Draft Guidance on Dexamethasone; Tobramycin (rev. June 2016), http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM199633.pdf (providing proposed recommendations for dexamethasone 0.05%/tobramycin 0.3% ophthalmic suspension); FDA, Draft Guidance on Dexamethasone; Tobramycin (rev. June 2016), http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM194598.pdf (providing proposed recommendations for dexamethasone 0.1%/tobramycin 0.3% ophthalmic suspension). To Petitioners’ knowledge, no other draft bioequivalence guidance for an ophthalmic corticosteroid suspension includes an in vitro option. We disagree with the revised approach in the Draft Guidances on Dexamethasone/Tobramycin Ophthalmic Suspension and believe that in vitro testing alone is not sufficient to demonstrate bioequivalence of ophthalmic suspensions containing dexamethasone, for similar reasons to those set forth in this petition. Petitioners are considering making a submission to the docket for the revised Draft Guidances on Dexamethasone/Tobramycin Ophthalmic Suspension, Docket No. FDA-2007-D-0369-0386.

45 E.g., FDA, Draft Guidance on Dexamethasone; Tobramycin Ophthalmic Ointment (rev. June 2016), http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM308032.pdf (recommending for dexamethasone/tobramycin ophthalmic ointment an in vivo pharmacokinetic study in aqueous humor to demonstrate bioequivalence of the dexamethasone component and an in vitro microbial kill rate study to evaluate the bioequivalence of the tobramycin component).

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endpoint studies in each of the product-specific bioequivalence draft guidances for ophthalmic suspensions that do not contain corticosteroids, i.e., brinzolamide,46 brimonidine tartrate/brinzolamide,47 nepafenac,48 and betaxolol hydrochloride49 ophthalmic suspensions. FDA has recommended in vitro bioequivalence testing for one ophthalmic emulsion drug product, cyclosporine ophthalmic emulsion,50 which is not a corticosteroid. But unique considerations underlie this recommendation for cyclosporine and are not applicable to Durezol, as described below.

FDA’s general practice of recommending in vivo bioequivalence testing for ophthalmic corticosteroids products is consistent with FDA’s regulations recognizing that in vivo testing is generally a more accurate, sensitive, and reproducible method of measuring bioavailability and establishing bioequivalence than in vitro testing. 51 Specifically, FDA’s regulation notes that, generally, in vivo studies comparing drug/metabolite concentrations in an accessible biological fluid, such as aqueous humor, will be a more accurate, sensitive, and reproducible measure of differences in bioavailability than in vitro testing, where the in vitro testing has not been shown to correlate with and be predictive of human in vivo bioavailability.52 To our knowledge, the in vitro testing described in the Draft Guidance on Difluprednate has not been proven to correlate with, and be predictive of, in vivo bioavailability of difluprednate. Further, we are aware of no in vitro test that has been correlated with and is predictive of human in vivo bioavailability data for difluprednate ophthalmic emulsion. Thus, an in vivo pharmacokinetic study in aqueous humor is expected to be the most accurate, sensitive, and reproducible method for establishing bioequivalence to Durezol.

C. FDA Should Require an In Vivo Pharmacokinetic Study to Demonstrate Bioequivalence for All Generic Difluprednate Ophthalmic Emulsion Products and Abandon the Proposed In Vitro Testing Option.

Petitioners request that FDA require, for all proposed generic versions of Durezol, in vivo pharmacokinetic bioequivalence testing in aqueous humor using DFB as the analyte. Given the insufficient evidence supporting the proposed in vitro option and the availability of a

46 FDA, Draft Guidance on Brinzolamide (rev. Mar. 2015), http://www.fda.gov/downloads/Drugs/ GuidanceComplianceRegulatoryInformation/Guidances/UCM384099.pdf.

47 FDA, Draft Guidance on Brimonidine Tartrate; Brinzolamide (rev. Mar. 2015), http://www.fda.gov/ downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm428201.pdf.

48 FDA, Draft Guidance on Nepafenac (Dec. 2014), http://www.fda.gov/downloads/Drugs/ GuidanceComplianceRegulatoryInformation/Guidances/UCM428230.pdf (providing proposed recommendations for nepafenac ophthalmic suspension 0.1%); FDA, Draft Guidance on Nepafenac (Dec. 2014), http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/ Guidances/UCM428231.pdf (providing proposed recommendations for nepafenac ophthalmic suspension 0.3%).

49 FDA, Draft Guidance on Betaxolol Hydrochloride (Jan. 2016), http://www.fda.gov/downloads/Drugs/ GuidanceComplianceRegulatoryInformation/Guidances/UCM481781.pdf.

50 Draft Guidance on Cyclosporine.

51 See 21 C.F.R. § 320.24.

52 Id.

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feasible, sensitive, and reliable in vivo option, the agency should not pursue its proposal to permit an in vitro testing option.

By recommending an in vivo pharmacokinetic study in aqueous humor for determining bioequivalence of certain proposed generic difluprednate ophthalmic emulsion products (i.e., those that are not Q1/Q2 the same as Durezol) as well as many other ophthalmic drugs as described above, FDA recognized that such a study is an accurate, sensitive, and reproducible method of measuring ocular bioavailability. Petitioners support revision of option two in the Draft Guidance on Difluprednate to apply to all proposed generic ophthalmic difluprednate emulsions. We also recommend that FDA revise option two to provide that the in vivo pharmacokinetic study should measure DFB rather than difluprednate as the analyte. This change is appropriate because difluprednate is rapidly hydrolyzed to the active metabolite DFB.

There is insufficient evidence supporting the proposed in vitro option. FDA has recognized that suspensions and emulsions present “similarly difficult[] challenges to the development of in vitro bioequivalence methods.”53 Just as there is not a sufficient basis to conclude that bioequivalence can be accurately determined based on in vitro data alone for the above ophthalmic corticosteroid products and ophthalmic suspension products,54 there are insufficient data to support an in vitro-only approach to demonstrating bioequivalence for ophthalmic difluprednate emulsions. For example, demonstration of drug release rate from the oil phase to aqueous phase is critical to demonstrating bioequivalence to Durezol, given that the residence time of drug product after instillation in eye is very short (less than five minutes).55 Nevertheless, FDA has acknowledged the “lack of compendial or biorelevant in vitro drug release assays for topically applied ocular suspension and emulsion dosage forms.”56 Moreover, in ongoing FDA-funded57 research conducted by Dr. Palakurthi of Texas A&M University, it was noted that the nature of the dialysis method used to investigate the in vitro release rates of different difluprednate emulsion formulations had a significant effect on the observed release profiles.58 Research to differentiate the release profiles of different

53 Second Restasis Citizen Petition Response, at 36.

54 See, e.g., id. (noting that, in the cases of brinzolamide suspension, brimonidine tartrate/brinzolamide suspension, and nepafenac suspension, the agency has not concluded that its existing knowledge of the products’ physiochemical properties is sufficient to determine bioequivalence based on in vitro data alone).

55 Reimondez-Troitiño S. et al., Nanotherapies for the treatment of ocular diseases, Eur. J. Pharmaceutics & Biopharmaceutics 279 (2015) (Exhibit A); Wilson C.G. & Tan L.E., Nanostructures overcoming the ocular barrier: physiological considerations and mechanistic issues, in Nanostructured Biomaterials for Overcoming Biological Barriers, 173 (Maria Jose Alonso & Noemi S. Csaba eds., 2012), https://books.google.com/books?id=4BveZLfcDVMC&printsec=frontcover&dq=naonstructured+biomaterials+for+overcoming+biological+barriers&hl=en&sa=X&ved=0ahUKEwj6-aOvj_7OAhWL2R4KHQ4lCPIQ6AEIIDAA#v=onepage&q&f=false.

56 Department of Health and Human Services, Grant Announcement RFA-FD-14-009, Dissolution Methods for Suspension and Emulsion Ocular Drug Products (March 28, 2014), http://grants.nih.gov/grants/guide/rfa-files/RFA-FD-14-009.html. This grant was awarded to Dr. Palakurthi, and this research is ongoing.

57 Id.

58 Palakurthi S. et al., Preparation and Evaluation of Difluprednate Topical Ocular Emulsions, American Association of Pharmaceutical Scientists Annual Meeting (2015), http://abstracts.aaps.org/Verify/AAPS2015/PosterSubmissions/M1271.pdf.

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difluprednate emulsion formulations is ongoing.59 Thus, there currently is no validated in vitro release rate test that would, in conjunction with other in vitro testing, ensure two ophthalmic difluprednate emulsion formulations are bioequivalent.

Further, as noted, neither the proposed in vitro testing nor any other in vitro testing has, to our knowledge, been proven to correlate with, and be predictive of, in vivo bioavailability of difluprednate. In vitro-in vivo correlation is, however, integral to ensuring that in vitro testing predicts similar tissue exposure between a proposed generic ophthalmic emulsion and RLD. For example, in vivo precorneal dynamics, such as shear forces caused by blinking and the dilutional potential caused by tear production, would not be captured in in vitro testing that has not been proven to correlate with in vivo bioavailability. Further, given that time frame for absorption into the ocular tissues from the formulation mixed with tear fluid is very short, ocular absorption depends on rapid dissolution and partitioning of drug into the cornea, with subsequent penetration into the anterior chamber (i.e., aqueous humor)—other characteristics not assessed in such in vitro testing. Consequently, the proposed in vitro testing might not accurately identify differences in the bioavailability of different difluprednate emulsion formulations. The potential for inaccuracies in the in vitro approach is concerning from a public health perspective, because lower exposure to difluprednate in target ocular tissues could result in a lack of efficacy, whereas higher exposure in comparison to Durezol could result in unintended consequences in some patients.

FDA’s proposed recommendation of in vitro testing to demonstrate bioequivalence to another topical ophthalmic emulsion, Restasis® (cyclosporine), does not support a similar approach for Durezol. First, FDA recommended in vitro testing over in vivo studies for proposed generic cyclosporine ophthalmic emulsions in part based on the agency’s conclusions, specific to the characteristics of Restasis, that in vivo studies were infeasible and unlikely to be a sensitive or accurate measure of differences in bioavailability.60 The agency emphasized that “given the modest clinical benefit shown for cyclosporine ophthalmic emulsion . . . a comparative clinical endpoint study could require more than 2,000 subjects with dry eye disease to pass the statistical tests for bioequivalence. Consequently, we recognize that a comparative clinical endpoint study may pose economic and logistical feasibility concerns.”61 A pharmacokinetic study in aqueous humor was not a viable option for determining bioequivalence for cyclosporine ophthalmic emulsion, which is not used in a surgical context. In contrast, an in vivo pharmacokinetic study of difluprednate ophthalmic emulsions in aqueous humor is not only feasible, it is the study type FDA recommends for the vast majority of other ophthalmic corticosteroids. Further, FDA reasoned that, for Restasis, “the recommended in vitro option likely is more sensitive than a comparative clinical endpoint study in detecting any differences between Restasis and a proposed generic product due to cyclosporine ophthalmic emulsion’s modest showing of clinical effect.”62 These concerns are not applicable to Durezol, which has robust efficacy. For example, in clinical studies evaluating ocular inflammation and pain after cataract surgery, 41% of Durezol patients achieved zero inflammation on day 15 compared to 11% of placebo patients, and 63% of Durezol patients were pain-free compared to

59 Id.

60 First Restasis Citizen Petition Response, at 12-13, 26.

61 Id. at 26.

62 Id. at 34 (emphasis added).

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35% of placebo patients on day 15.63 Also, Durezol demonstrated equal efficacy to prednisolone acetate ophthalmic suspension in studies of approximately 100 subjects with endogenous anterior uveitis.64 Thus, in contrast to FDA’s conclusions in the Restasis case, in vivo testing is both feasible and sensitive here.

Second, unlike in the Restasis situation, there appears to be no FDA testing supporting the proposed in vitro method for difluprednate bioequivalence. The agency’s recommended in vitro method for bioequivalence testing of generic cyclosporine ophthalmic emulsions was based, at least in part, on research conducted by the FDA Office of Testing and Research. FDA concluded that this research showed in vitro testing is capable of detecting differences in cyclosporine emulsion formulations’ physicochemical properties caused by different manufacturing processes and formulation steps.65 We are aware of no such data for difluprednate ophthalmic emulsion products. And these data generated with cyclosporine are not applicable to difluprednate given the many differences between Restasis and Durezol. The products have different sites of action,66 physiochemical properties (such as viscosity),67 and formulations.68 These differences may affect absorption of the active ingredient in the target tissue and consequently, efficacy and/or safety.

FDA also concluded that the lack of a validated in vitro release rate test method for cyclosporine emulsion did not preclude FDA from recommending in vitro bioequivalence testing only, because FDA expects ANDA applicants relying on this approach to develop and validate an appropriate in vitro release rate test method. But for a proposed generic difluprednate ophthalmic emulsion, a well-understood and accurate, sensitive, and reproducible method for demonstrating bioequivalence is available, i.e., an in vivo pharmacokinetic study. Therefore, in this case, FDA should not recommend alternative methods that have yet to be developed and appropriately validated.

In sum, the in vitro testing described in the Draft Guidance on Difluprednate will not reliably detect any bioavailability differences in different difluprednate emulsion formulations, and thus is not an appropriate method for demonstrating bioequivalence. FDA therefore should not depart from its general approach of requiring in vivo pharmacokinetic studies for ophthalmic corticosteroids in this case and potentially place patients at risk of not receiving correct therapeutic doses. We therefore request that the agency delete the in vitro option from the Draft Guidance of Difluprednate.

63 Durezol Prescribing Information § 14.1 (rev. May 2013) http://ecatalog.alcon.com/PI/Durezol_us_en.pdf.

64 Id. § 14.2 (describing study 1, n=110, and study 2, n=90).

65 First Restasis Citizen Petition Response, at 17.

66 As noted above, the site of action for Durezol is ocular tissues affected by inflammation, including the iris, ciliary body, cornea, and aqueous humor. FDA Pharmacology Review, at 9-10. Restasis is thought to work on the external tissues of the eye. Allergan, Inc., Citizen Petition, Docket No. FDA-2014-P-0304-0001, at 11, 17-18 (Feb. 28, 2014).

67 For example, Restasis contains a viscosity-enhancing ingredient, carbomer copolymer type A, as an emulsifier, and Durezol does not contain a similar viscosity-enhancing agent. See Allergan, Inc., Citizen Petition, Docket No. FDA-2014-P-0304-0001, at 19, 21, 44 (Feb. 28, 2014).

68 See id.

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IV. The Draft Guidance on Difluprednate Should Expressly State That a Clinical Endpoint Study May Be Necessary to Demonstrate Bioequivalence of Proposed Generic Products with Differences in Inactive Ingredients from Durezol.

Consistent with the agency’s regulations and draft guidance on other ophthalmic corticosteroid drug products, FDA should revise the Draft Guidance on Difluprednate to state that changes in inactive ingredients that cause a proposed generic drug not to be Q1/Q2 the same as Durezol may require an additional clinical endpoint study to demonstrate bioequivalence.

Because each ophthalmic product “represents an individual pharmaceutical system with its own characteristics and requirements,” FDA imposed “more stringent limitations on the variations permitted in the inactive ingredients in the formulation of . . . ophthalmic . . . drug products than on other dosage forms.”69 As noted, FDA regulations generally require generic ophthalmic drugs to contain the same inactive ingredients in the same concentration as the listed drug with a few exceptions. The ANDA must demonstrate that any allowable difference in an inactive ingredient or the composition of a proposed generic ophthalmic drug does not affect the safety or efficacy of the proposed product.70

In product-specific bioequivalence draft guidance for ophthalmic corticosteroid suspensions, FDA consistently has advised that changes in any inactive ingredient can affect the safety and efficacy of the ophthalmic drug product, and that an applicant may need to conduct an in vivo study with a clinical endpoint if the changes cause the products not to be Q1/Q2 the same.71 (This study is in addition to the in vivo pharmacokinetic study in aqueous humor.) For example, the Draft Guidance on Loteprednol Etabonate recommends that changes in inactive ingredients may require a clinical endpoint study.72 The Draft Guidance on Difluprednate refers to this Draft Guidance on Loteprednol Etabonate for “additional comments regarding the In Vivo pharmacokinetic study in aqueous humor,” indicating that FDA recognizes the similarities between the two drugs. 73

This cross-reference implies that the discussion in the Draft Guidance on Loteprednol Etabonate regarding the need for a clinical endpoint study upon inactive ingredient changes applies to proposed generic difluprednate ophthalmic emulsions; the recommendation appears in the section of the Draft Guidance on Loteprednol Etabonate entitled: “Additional comments regarding the in vivo pharmacokinetic study in aqueous humor.” Petitioners request that FDA make this point explicit in the Draft Guidance on Difluprednate. Specifically, FDA should include the following language in the Draft Guidance on Difluprednate: “Changes in any of the inactive ingredients can change the safety and efficacy of an ophthalmic drug product. Therefore, an applicant may need to also conduct an in vivo BE study with clinical endpoints for any difluprednate ophthalmic emulsion that has a different inactive ingredient or a difference of

69 ANDA Regulations, 54 Fed. Reg. 28872, 28883 (proposed July 10, 1989).

70 21 C.F.R. §§ 314.94(a)(9)(iv), 314.127(a)(8)(ii)(C).

71 See Draft Guidance on Prednisolone Acetate; Draft Guidance on Loteprednol Etabonate; see also Draft Guidances on Dexamethasone/Tobramycin Ophthalmic Suspension.

72 Draft Guidance on Loteprednol Etabonate, at 2.

73 Draft Guidance on Difluprednate, at 2.

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more than 5% in the amount of any inactive ingredient compared to that of the RLD. The sponsor is advised to submit a protocol to the Division of Clinical Review Team in the Office of Generic Drugs for review and concurrence prior to conducting the in vivo bioequivalence study with clinical endpoint for such a product.”

V. Alternatively, FDA Should Require ANDA Applicants to Conduct Additional In Vitro Testing to Qualify for Option 1 in the Draft Guidance on Difluprednate.

If, notwithstanding the discussion above, FDA retains the option to demonstrate bioequivalence to Durezol through in vitro testing alone, FDA should revise its recommendations for such testing to reflect the complex natures of in vivo precorneal dynamics and the release profiles of difluprednate emulsion products. The revised recommendations would increase the likelihood that any meaningful differences between the in vivo bioavailability of proposed generic difluprednate ophthalmic emulsion products and Durezol would be detected.

First, FDA should further clarify what constitutes an “acceptable comparative physiochemical characterization” of the test product and RLD. Although the Draft Guidance on Difluprednate recommends population bioequivalence with a 95% upper confidence bound for globule size distribution, it provides no information as to when the test product and RLD will be deemed acceptably comparable in the other parameters mentioned in the Draft Guidance on Difluprednate, including with respect to the in vitro release profile.

Second, FDA should require an ANDA applicant to demonstrate that its proposed generic difluprednate emulsion has the same drop size as Durezol. Drop size, which can be influenced by bottle design, is a critical determinant of the dose. As one article has noted, “[i]f a patient receives a different amount of drug than intended [due to drop size differences], efficacy may be affected and adverse events may result.”74 In particular, FDA should require that the ANDA applicant demonstrate that its proposed drug has the same drop size as the RLD in initial lots of the proposed generic drug as well as in stability lots (under long-term storage and accelerated stability conditions). An unstable emulsion may cream, affecting drop size. Therefore, even where initial lots of a proposed generic emulsion have the same drop size as the RLD, the drop size might diverge from that of the RLD over time.

Third, FDA should revise its recommendations for testing of globule size distribution and other parameters to make the Draft Guidance on Difluprednate consistent with the agency’s recommendations for in vitro bioequivalence testing for cyclosporine ophthalmic emulsion. FDA recently revised its recommendations for demonstrating bioequivalence for cyclosporine ophthalmic emulsion through in vitro testing75 in response to arguments that the proposed in vitro testing was insufficient.76 FDA should correspondingly revise its proposed recommendations in the Draft Guidance on Difluprednate, including by:

74 Zore M. et al., Generic Medications in Ophthalmology, 97 British J. Ophthalmology 253, 255 (2012) (Exhibit B).

75 See Draft Guidance on Cyclosporine.

76 Second Restasis Citizen Petition Response, at 5.

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• Recommending that applicants use complementary size characterization methods to capture the entire globule size range of the test and RLD formulations and provide comparable size distribution profiles for both undiluted samples and upon serial dilution.

• Noting that more than one size characterization method may be necessary to accurately detect the entire globule size distribution.

• Recommending that applicants provide the full profiles and raw data for the globule size distributions for all samples tested and information on the instrument, analysis mode, dilution medium, and level of dilution used to measure globule size.

• Recommending that equivalence between the test and RLD formulations in the shape of the globule size distribution should be demonstrated, including by comparison of D10, D50, D90, and D99 values or the globule size at each peak detected in the RLD.77

In addition, FDA should revise its proposed recommendations to call for a demonstration of equivalence between the test and RLD formulations in the shape of the globule size distribution in initial lots as well as in stability lots to ensure that stability of the emulsion does not affect globule size distribution over the shelf life of the product.

Fourth, applicants should evaluate microscopic structure, including phase structure and arrangement of emulsifier and coemulsifier in the emulsion, in comparison with the RLD using magnetic resonance, transmission electron microscopy, and atomic force microscopy. In addition to establishing similarity with the RLD in other physical and chemical parameters, establishing microscopic similarity to the RLD is important to assure appropriate product similarity, particularly because emulsions are heterogeneous systems.78

Fifth, FDA should require that the zeta potential testing be done on both initial lots and stability lots of the proposed generic product to demonstrate that its surface charge is comparable to the RLD over the shelf life of the product. Surface charge can be an important determinant of the bioavailability of emulsions in ocular tissue, potentially having a greater impact on intraocular drug delivery than the formulation itself.79

Finally, FDA should require that the in vitro release testing reflect that the safety and effectiveness of difluprednate ophthalmic emulsion is dependent upon the deacetylation of difluprednate to the active metabolite DFB in the epithelium. The release testing must demonstrate that the drug release from oil phase, its partition to the aqueous phase, and its subsequent transport to ocular tissue and conversion to active metabolite are not substantially different between the proposed generic difluprednate ophthalmic emulsion and Durezol to ensure bioequivalence of the two products. Demonstration of drug release rate from the oil

77 Id. at 14-15, 25, 31-32.

78 See Lawrence Yu, Office of Generic Drugs Research Program, FDA Center for Drug Evaluation and Research, “Bioequivalence of Topical Products - Discussion Points” (Oct. 22, 2003), http://www.fda.gov/ohrms/dockets/ac/03/slides/3996S2_09_Discussion%20Points.ppt.

79 Ying L. et al., Drug delivery to the ocular posterior segment using lipid emulsion via eye drop administration: Effect of emulsion formulations and surface modification, 453 Int’l J. of Pharmaceutics 329 (2013) (Exhibit C).

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phase to the aqueous phase is particularly important because, as noted, the residence time of drug product in the eye after instillation is very short (less than five minutes). Finally, release testing should reflect precorneal dynamics, including shear forces by blinking and dilutional potential caused by tear production. Accurate and sensitive release testing is critical, as the rate and extent of DFB exposure in the target ocular tissue is determinative of the safety and efficacy of difluprednate ophthalmic emulsion products.

VI. Conclusion

For the reasons set forth above, Petitioners request that FDA require an in vivo pharmacokinetic study in aqueous humor to establish bioequivalence for any ANDA that lists Durezol as the RLD. We also request that FDA explicitly acknowledge that a difference in the inactive ingredients between a proposed generic difluprednate ophthalmic emulsion and Durezol also may necessitate a clinical endpoint study. If FDA retains the option to establish bioequivalence to Durezol through in vitro testing only, Petitioners request that FDA revise the in vitro option as described above. Finally, we ask that the agency timely publish final product-specific bioequivalence guidance for difluprednate ophthalmic emulsion that incorporates these principles.

C. ENVIRONMENTAL IMPACT

The actions requested herein are subject to a categorical exclusion under 21 C.F.R. § 25.31(g).

D. ECONOMIC IMPACT

An economic impact statement will be submitted at the request of the Commissioner per 21 C.F.R. § 10.30(b).

E. CERTIFICATION

Pursuant to section sos(q)(1)(H) of the FDCA: I certify that, to my best knowledge and belief: (a) this petition includes all information and views upon which the petition relies; (b) this petition includes representative data and/ or information known to the petitioner which are unfavorable to the petition; and (c) I have taken reasonable steps to ensure that any representative data and/or information which are unfavorable to the petition were disclosed to me. I further certify that the information upon which I have based the action requested herein first became known to the party on whose behalf this petition is submitted on or about the following date: December 3, 2014 (information that an ANDA had been submitted) and January 27, 2016 (availability of the Draft Guidance on Difluprednate). If I received or expect to receive payments, including cash and other forms of consideration, to file this information or its contents, I received or expect to receive those payments from the following persons or organizations: my employer, Alcon Research, Ltd., and/or other affiliates of the Novartis group of companies (all of which are under common ownership and control), including without limitation Alcon Pharmaceuticals, Ltd. and Novartis Pharmaceuticals Corporation. I verify under penalty of perjury that the foregoing is true and correct as of the date of the submission of this petition.

Pursuant to 21 C.F.R. § 10.30(b): The undersigned certifies, that, to the best knowledge and belief of the undersigned, this petition includes all information and views on which the petition relies, and that it includes representative data and information known to the petitioner which are unfavorable to the petition. ·

Respectfully submitted,

Arthur A. Ciociola, Ph.D., F.A.C.G.so Vice President Global Franchise Head, Regulatory Affairs N ovartis Pharmaceuticals Ophthalmology 6201 South Freeway Fort Worth, TX 76134-2099 (817) 615-2442 arthur.ciociola@alcon.com

so Although Dr. Ciociola remains an employee of Alcon Research, Ltd., he has responsibility for coordinating global regulatory affairs matters for the newly created ophthalmology franchise within Novartis's global pharmaceuticals business unit. Dr. Ciociola will become an employee ofNovartis Pharmaceuticals Corporation on or around January 1, 2017.

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