CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`
`208144Orig1s000
`
`SUMMARY REVIEW
`
`Eye Therapies Exhibit 2066, 1 of 41
`Slayback v. Eye Therapies - IPR2022-00142
`
`

`

`Eye Therapies Exhibit 2066, 2 of 41
`Slayback v. Eye Therapies - IPR2022-00142
`
`

`

`Cross Discipline Team Leader Review
`NDA 208144 Brimonidine tartrate ophthalmic solution
`
`Highlights of the Submission and Approval Recommendation:
`
` The approval recommendation is for the indications and the intended populations the sponsor has requested. All discipline
`reviewers recommended approval or did not make a recommendation.
`
` This application is an original NDA resubmission (NDA 208144). This application relies in part on the Agency’s prior findings of
`nonclinical safety for the approved listed drug product, Alphagan 0.2% (brimonidine tartrate 0.2%, NDA 020613) which was
`approved in 1996 for the treatment of glaucoma and increased intraocular pressure (IOP) in adults and children 5 years of age and
`over. Alphagan was approved for use in the pediatric population 2 years of age in 2001.
`
` The sponsor withdrew its original name request for Luminesse following a teleconference with FDA on November 7, 2017. An
`approved replacement name is pending at the time of this review, although the sponsor has proposed “
` as its first choice,
`with “Lumify” as a backup.
`
` The sponsor conducted 2 pivotal clinical efficacy trials, 1 safety trial, and a label interpretation study in support of this application.
`An additional study contributed safety information, yielding safety data from 4 clinical studies with 426 subjects on drug and 209
`on placebo. This application relies in part on the safety and efficacy established for NDA 20613, as well as supportive studies from
`the published literature regarding the efficacy of the active ingredient.
`
` The sponsor’s summary of clinical safety, which included literature and postmarket safety from the Bausch and Lomb internal
`database, FAERS and WHO through 2016, and DAWN (through 2011), did not raise safety concerns.
`
` Brimonidine tartrate ophthalmic solution 0.025% did not show tachyphylaxis or rebound congestion in clinical trials. The absence
`of tachyphylaxis or rebound congestion with an OTC ophthalmic vasoconstrictor to relieve redness of the eye is a potential
`advantage for the OTC consumer.
`
`CDER Cross Discipline Team Leader Review Template 2015 Edition
`Version date: June 9, 2015. For initial rollout (NME/original BLA reviews)
`
`Reference ID: 4187475
`
`2
`
`(b) (4)
`
`Eye Therapies Exhibit 2066, 3 of 41
`Slayback v. Eye Therapies - IPR2022-00142
`
`

`

`Cross Discipline Team Leader Review
`NDA 208144 Brimonidine tartrate ophthalmic solution
`
`Dimension
`
`Evidence and Uncertainties
`
`Conclusions and Reasons
`
`Ocular Redness
`
`Analysis of
`Condition
`
`Current
`Treatment
`Options
`
` Ocular redness can be caused by an inflammation in the conjunctiva
`which may be due to exposure to allergens, environmental irritants, or a
`reaction to infectious agents (e.g., bacteria or virus). There are non-
`allergic and non-infectious causes of redness caused by minor eye
`irritations.
`
`There can be a negative impact of eye redness,
`which may have eye irritation associated with
`it. Also, eye redness is noticeable to the
`individual and others and has a cosmetic
`importance.
`
`Pharmacotherapy has been the mainstay of
`treatment for conjunctival irritation and the
`fact that most sufferers self-treat for minor eye
`irritations, highlight the importance of OTC
`treatments for control of some of the
`symptoms.
`
` OTC drug treatments used to relieve ocular redness are
`commonly topical vasoconstrictor agents. These vasoconstrictor
`agents are all α-adrenergic receptor (AR) agonists and induce
`contraction of smooth muscle. The α-ARs are further
`differentiated pharmacologically into α1-ARs and α2-ARs, both
`of which can induce vasoconstriction, but through different
`mechanisms.
`
` There are 2 classes of vasoconstrictors: sympathomimetic amines
`and imidazolines. Sympathomimetic amines (e.g., ephedrine,
`pseudoephedrine, and phenylephrine) activate the sympathetic
`nerves by the pre-synaptic release of endogenous norepinephrine.
`
` The active ingredients in current OTC ophthalmic solutions
`commonly used to relieve ocular redness are mixed alpha-
`adrenergic and vasoconstrictive imidazolines.
`
`CDER Cross Discipline Team Leader Review Template 2015 Edition
`Version date: June 9, 2015. For initial rollout (NME/original BLA reviews)
`
`Reference ID: 4187475
`
`3
`
`Eye Therapies Exhibit 2066, 4 of 41
`Slayback v. Eye Therapies - IPR2022-00142
`
`

`

`Cross Discipline Team Leader Review
`NDA 208144 Brimonidine tartrate ophthalmic solution
`Dimension
`Evidence and Uncertainties
`
`Conclusions and Reasons
`
` Of note, prescription drug treatments are also available (e.g.
`olopatadine). It is unclear whether the Rx drug(s) are more
`effective than OTC drugs as redness relievers.
` Brimonidine tartrate is a relatively selective alpha-2 adrenergic receptor
`agonist that has a peak ocular hypotensive effect that occurs two hours
`post-installation in the eye. Fluorophotometric studies in animals and
`humans indicate that brimonidine tartrate may have a mechanism of
`action of reducing aqueous humor production and increasing
`uveoscleral outflow. At the proposed over-the-count (OTC)
`concentration of 0.025% (one-eighth the common prescription strength
`of 0.20%), the drug has a vasoconstrictive effect that can relieve redness
`of the eye
`
` The sponsor is relying on preclinical and toxicology data and
`clinical studies for prior NDA submissions to support safety. For
`additional clinical support for the OTC indication, the sponsor
`performed 4 studies to evaluate effectiveness of brimonidine
`0.025% ophthalmic solution (1 Phase 1 with 14 subjects, 2 Phase
`2 with 57 subjects and 2 Phase 3 with 60 subjects and 507
`subjects respectively). The clinical studies with brimonidine
`tartrate ophthalmic solution, 0.025% demonstrate that
`brimonidine tartrate 0.025% provides rapid and effective relief
`for ocular redness, while minimizing the side effects of
`tachyphylaxis (tolerance or loss of effectiveness) or rebound
`congestion that are commonly associated with OTC products
`currently on the market for reduction of ocular redness and that
`restrict long-term use.
`
`Benefit
`
`The effectiveness of the product has been
`established for conditions other than glaucoma
`or to relieve eye redness. Consumers who
`experience eye redness related to seasonal
`allergies may need other therapy such as a
`product incorporating an antihistamine.
`
`This combination product provides an
`additional choice for consumers to eye redness
`due to lack of sleep, minor irritation from
`contact lenses and other minor eye irritants.
`
`Risk
`
` For a risk assessment in this application, the sponsor submitted a
`Summary of Clinical Safety (ISS) and Postmarket safety data
`from December 2011 to December 2016, plus a 4-month safety
`update.
`
`Brimonidine tartrate has a satisfactory safety
`profile in the prescription environment based
`on 14 years of clinical use and postmarketing
`experience in the United States.
`
`CDER Cross Discipline Team Leader Review Template 2015 Edition
`Version date: June 9, 2015. For initial rollout (NME/original BLA reviews)
`
`Reference ID: 4187475
`
`4
`
`Eye Therapies Exhibit 2066, 5 of 41
`Slayback v. Eye Therapies - IPR2022-00142
`
`

`

`Cross Discipline Team Leader Review
`NDA 208144 Brimonidine tartrate ophthalmic solution
`Dimension
`Evidence and Uncertainties
`
` Exposure was adequate in clinical trials: subjects in studies 11-
`100-0015 and 13-100-0005 were dosed 4 times daily (QID) for
`approximately four weeks. Subjects in study 13-100-0006 were
`dosed QID for approximately four weeks and subjects in study
`13-100-0007 were dosed QID for approximately one week.
`
` Serious adverse events have been reported infrequently for the
`product in adults in the postmarket setting. See Clinical, Section
`7 of this review and Dr. Kelty’s review.
`
` The most common adverse events are related to the site of
`administration and include Ocular Hyperemia, Eye Irritation,
`Intraocular Pressure Increased (maybe drug ineffective), and Eye
`Pain. Non-ocular events reported across 4 databases include
`Dizziness, Fatigue, Headache, and Hypotension. In the clinical
`development program, the most common non-ocular adverse
`events were Nasopharyngitis and Sinusitis, both below 1%.
`Bradycardia; hypotension; iritis; miosis; skin reactions (including
`erythema, eyelid pruritus, rash, and vasodilation); and
`tachycardia. Apnea, bradycardia, hypotension, hypothermia,
`hypotonia, and somnolence have been reported in infants
`receiving brimonidine tartrate ophthalmic solution 0.2%.
`
` Brimonidine tartrate is a Pregnancy Category B drug. Studies in
`rats with oral doses 189 times higher than seen in humans after
`multiple ophthalmic doses revealed no evidence of fetal harm
`This drug is excreted in breast milk.
`
` Safety in pediatric patients ≤ 2 years of age as not been
`established at 0.2%. SAEs have been reported with 0.2%
`brimonidine tartrate ophthalmic solution.
`
`
`CDER Cross Discipline Team Leader Review Template 2015 Edition
`Version date: June 9, 2015. For initial rollout (NME/original BLA reviews)
`
`Reference ID: 4187475
`
`Conclusions and Reasons
`
`Serious adverse events (SAEs) are uncommon
`with labeled use in adults for lowering of
`intraocular pressure at a 0.2% strength.
`
`For the pediatric age group, SAEs were
`uncommon in clinical trials down to age 5 at a
`0.025% strength used as an eye redness
`reliever.
`
`The potential for alpha agonist effects, local or
`centrally mediated from absorption, is
`generally low in the doses contained in the
`proposed product.
`
`Relative safety of the prescription strength
`brimonidine tartrate ophthalmic solution 0.1-
`0.2% has been established in adults.
`
`The safety of brimonidine tartrate ophthalmic
`solution 0.025% for OTC use is supported by
`the clinical studies and overall safety profile
`demonstrated in the evaluation of
`postmarketing safety data and published
`literature from the higher concentration
`prescription brimonidine tartrate ophthalmic
`products (0.1-0.2%).
`
`5
`
`Eye Therapies Exhibit 2066, 6 of 41
`Slayback v. Eye Therapies - IPR2022-00142
`
`

`

`Cross Discipline Team Leader Review
`NDA 208144 Brimonidine tartrate ophthalmic solution
`Dimension
`Evidence and Uncertainties
`
`Conclusions and Reasons
`
` Brimonidine tartrate ophthalmic solution 0.025% shows no
`difference from placebo in its effect on IOP in subjects with
`normal IOP.
` The proposed OTC labeling has the essential warnings translated
`from the current Alphagan Rx label (brimonidine tartrate 0.2%)
`into the OTC Drug Facts Label (DFL). Some of the warnings are
`translated into the DFL out of an abundance of caution, since they
`refer to a higher strength (Rx).
`
`Risk
`Management
`
`Warnings provided in the proposed OTC
`labeling may help mitigate the risk of serious
`adverse events.
`
`CDER Cross Discipline Team Leader Review Template 2015 Edition
`Version date: June 9, 2015. For initial rollout (NME/original BLA reviews)
`
`Reference ID: 4187475
`
`6
`
`Eye Therapies Exhibit 2066, 7 of 41
`Slayback v. Eye Therapies - IPR2022-00142
`
`

`

`Cross Discipline Team Leader Review
`NDA 208144 Brimonidine tartrate ophthalmic solution
`
`Background
`2.
`Current Submission NDA 208144
`The sponsor, Bausch & Lomb, submitted a 505(b)(2) application as a 505(b)(2) under NDA
`208144 on February 27, 2017 to market brimonidine tartrate ophthalmic solution 0.025%
`under the proposed name Luminesse, for the treatment of red eye, or relieving redness of the
`eye due to minor eye irritations.
`
`The sponsor relied on FDA’s prior findings of safety and efficacy for the approved product
`under NDA 020613, brimonidine tartrate 0.20% ophthalmic solution (Alphagan). Alphagan
`was withdrawn from marketing but not for safety or effectiveness, and is still a RLD. Several
`generics (5 as of November 22, 2017 per the Orange Book) with brimonidine tartrate 0.2%
`will remain on the market with no changes to the current approved Rx labeling for the
`treatment of glaucoma and ocular hypertension.
`
`CDTL Comment
`The majority of safety data comes from the Rx drug which has been on the market for
`approximately 20 years. For this switch, efficacy also needed to be established, which DTOP
`assessed as being proven in 2 pivotal trials.
`
`Source of CDTL Review Information
`This review is written from the following primary FDA reviews in Table 1 below:
`
` Table 1: Primary reviews reflected in this CDTL review
`Materials Reviewed
`Name of Discipline Primary Reviewer
`DMEPA Human Factors Name Review
`Grace P. Jones, PharmD, BCPS
`DNDP Labeling Review
`Arlene Solbeck, BS
`DNDP Medical Officer Review
`Jenny Kelty, MD
`DNDP Pharmacology/Toxicology Review Donald C. Thompson, PharmD, PhD
`DNDP Social Science Review
`Amanda Pike-McCrudden, MAA
`
`Joo-Yeon Lee, PhD
`Office of Biostatistics Review
`Amit Somani, PhD
`Office of Clinical Pharmacology Review
`Swapan De, PhD (and 5 others from OPQ)
`OPQ CMC
`Martin Nevitt, MD, MPH
`DTOP
`Wonyul Lee, PhD
`DTOP-Statistics
`Sharon Gershon, PhD
`OSI (inspection)
` OPQ CMC = Office of Pharmaceutical Quality: Chemistry, Manufacturing and Controls
` DMEPA = Division of Medication Error Prevention and Analysis
` DNDP = Division of Nonprescription Drug Product
` DTOP = Division of Transplant and Ophthalmology Drug Products
` OSI = Office of Scientific Investigation (Compliance)
`
`Pre and Post Submission Regulatory Activity
`
`CDER Cross Discipline Team Leader Review Template 2015 Edition
`Version date: June 9, 2015. For initial rollout (NME/original BLA reviews)
`
`7
`
`Reference ID: 4187475
`
`Eye Therapies Exhibit 2066, 8 of 41
`Slayback v. Eye Therapies - IPR2022-00142
`
`

`

`Cross Discipline Team Leader Review
`NDA 208144 Brimonidine tartrate ophthalmic solution
`
`Six meetings were held with the sponsor regarding this application since September 2010.
`These major milestone meetings and select discussions from 5 other meetings are summarized
`in Table 2 below.
`
`Table 2. Key Interactions with the Applicant under NDA 208144
`Date
`Meeting
`Key Discussion Points/Action Items
`Type
`Pre-IND
`Meeting
`
`September 1, 2010
`
`December 20, 2010
`
`November 15, 2011
`
`IND 108524
`opened by Eye
`Therapies, LLC
`Pre-NDA
`Meeting
`
`May 15, 2013
`
`August 5, 2013
`
`October 24, 2014
`
`End of Phase 2
`Meeting
`
`Transfer of
`IND to Bausch
`& Lomb
`Pre-NDA
`Meeting (first
`meeting with
`Bausch &
`Lomb)
`
`March 31, 2015
`
`May 29, 2015
`
`NDA 208144
`filed
`Refusal to File
`(RTF) Letter
`
` Ora (agent for Eye Therapies) will file an IND with a study
`protocol using the Conjunctival Allergen Challenge (CAC)
`model
` Ora will provide clarification that it does not seek an OTC
`claim for IOP reduction and will submit information about
`brimonidine tartrate IOP reduction dose response
`Prepare for CAC model study
`
`
`
`
`
` Ora agreed to repeat the CAC study for onset and duration
`of action.
` Ora agreed to submit actual use data if there is a disparity
`between dosing directions and duration of action.
`Safety issues raised by FDA included:
`a)
`use in geriatric subjects
`b)
`safety in pediatric subjects,
`c)
`potential somnolence and lethargy
`d) potential “overuse” issues
` Ora agreed to provide an initial Pediatric Study Plan (iPSP)
`within 60 days of this End-of-Phase 2 meeting
` Ora agreed to utilize daily subject diaries
`
`
`
`Business reasons
`
`
`
`
`
`
`
`
`
`FDA recommended that the dosing regimen match the
`efficacy data of the proposed product.
`FDA expressed concern that the proposed product might be
`accidentally ingested by children. The sponsor confirmed
`that its product will be packaged with a child-resistant cap.
`FDA stated there have been case reports involving misuse
`of similar products as date rape drugs. The sponsor agreed
`to search for AEs and literature regarding misuse.
`The sponsor requested FDA’s comments regarding a label
`interpretation study to support inclusion of the phrase
`” on the principal display
`panel (PDP). FDA noted that claims beyond what is stated
`in the Drug Facts Label (DFL) are not allowed on the PDP.
`While truthful and non-misleading claims may be
`”
`permissible on the PDP,
`was probably not acceptable as it may overstate efficacy.
` NDA submitted
`
`
`
`Reason for RTF: failure to provide post marketing data
`critical for an adequate safety review of the proposed
`product for use in the OTC consumer population.
`
`CDER Cross Discipline Team Leader Review Template 2015 Edition
`Version date: June 9, 2015. For initial rollout (NME/original BLA reviews)
`
`8
`
`Reference ID: 4187475
`
`(b) (4)
`
`(b) (4)
`
`Eye Therapies Exhibit 2066, 9 of 41
`Slayback v. Eye Therapies - IPR2022-00142
`
`

`

`Cross Discipline Team Leader Review
`NDA 208144 Brimonidine tartrate ophthalmic solution
`
`July 29, 2015
`
`Post-Refusal to
`File Meeting
`
`December 17, 2015
`
`tcon
`
`
`
`
`
`
`
`
`
`
`
`
`
`FDA requires additional analyses, and specific AE
`information for the postmarketing surveillance/database.
`The literature review was to provide synthesized
`conclusions about safety with a focus on topics of special
`interest such as CNS depression, respiratory depression,
`and issues of misuse. More detailed safety narratives were
`to be included for discontinuations due to AEs.
`CMC issues included the provision of in-use stability data
`for the different presentations of the product, the proposed
`change in the color of the child-resistant cap, and the
`submission of validation and sterilization information
`associated with drug product manufacturing.
`
`FDA requested the addition of terms rape, sexual assault,
`victim, victim of sexual abuse, date rape to the
`postmarketing search strategy.
`FDA requested safety topics of special interest including
`breakdowns of AEs by preferred terms, serious and non-
`serious AE reports separately, inclusion of a discussion of
`medically significant AEs, even if rare, and a discussion of
`how these would/would not impact the suitability of the
`drug product for an OTC environment with labeling
`implications also to be addressed.
`FDA agreed to time period of January 1, 2001 through July
`31, 2015 for the literature and database searches based on a
`projected NDA resubmission date of March 2016
`The sponsor agreed to include the following safety issues in
`the postmarketing safety analysis:
`CNS depression
`
`Respiratory depressive effects, especially in young
`
`children and elderly
` Drug misuse and abuse
`Review cycle initiated
`
`February 27, 2017
`
`
`
`NDA
`resubmission*.
`IOP = intraocular pressure
`* NDA resubmitted by Bausch & Lomb, a subsidiary of Valeant Pharmaceuticals International, Inc.
`Source: Dr. Kelty’s review
`
`Information about the Prescription (Rx) Drug Product
`Brimonidine is an α2 adrenergic receptor (α2-AR)-specific agonist with an α2-AR/α1-AR
`binding affinity ratio ~1000:1.
`
`The brimonidine tartrate-containing ophthalmic solutions are approved with concentrations of
`0.1%, 0.15%, and 0.2% at a dose of one drop three times daily (TID) for lowering intraocular
`pressure (IOP). In addition to Alphagan, generic formulations of brimonidine tartrate 0.15%
`and 0.2% are approved at the same dosages.
`
`Long term ophthalmic dosing (two or three times daily dosing over years) with brimonidine
`tartrate 0.2% has been shown to be safe and effective in lowering IOP.
`
`CDER Cross Discipline Team Leader Review Template 2015 Edition
`Version date: June 9, 2015. For initial rollout (NME/original BLA reviews)
`
`9
`
`Reference ID: 4187475
`
`Eye Therapies Exhibit 2066, 10 of 41
`Slayback v. Eye Therapies - IPR2022-00142
`
`

`

`Cross Discipline Team Leader Review
`NDA 208144 Brimonidine tartrate ophthalmic solution
`
`CDTL Comment
`The approved ocular prescription-strength of brimonidine tartrate is 4-8 fold higher than the
`concentration proposed in this application, adding a margin of safety for the proposed OTC
`drug to be used to relieve eye redness.
`
`Nature of the proposed OTC condition (eye redness) and type of drug product
`Ocular redness can be caused by an inflammation in the conjunctiva which may be due to
`exposure to allergens, environmental irritants, or a reaction to infectious agents, such as a
`bacterium or virus). Topical vasoconstrictor agents are commonly used to relieve ocular
`redness, particularly non-allergic and non-infectious redness caused by minor eye irritations.
`
`These vasoconstrictor agents are all α-adrenergic receptor (AR) agonists and induce
`contraction of smooth muscle. The α-ARs are further divided pharmacologically into α1-ARs
`and α2-ARs, both of which can induce vasoconstriction through different mechanisms.
`Brimonidine tartrate is an imidazoline 2-adrenergic receptor (AR) agonist, a chemical class
`well known to cause vasoconstriction and that includes the active component in several over-
`the-counter (OTC) vasoconstrictors (e.g., Visine LR, Naphcon Forte, see Tables 4 and 5
`below).
`
`Specific Drug Product Information
`The proposed drug product is a preserved topical ophthalmic solution of composition as
`summarized in the Sponsor’s Table 2.3.P.1-1 below. The drug product will be packaged
`as nominal 2.5 and 7.5 mL fill volumes in 10 mL LDPE bottles using
` tips and
`two-piece child-resistant closures.
`
`Table 3 below summarizes the drug product information for the proposed OTC brimonidine
`tartrate ophthalmic solution, including the drug class, proposed dosing regimen, chemical
`structure, and formulation ingredients.
`
`Table 3. Drug product information (proposed OTC)
`Product Name
`Brimonidine Tartrate Ophthalmic Solution
`
`Applicant
`Class
`Formulation
`Dosing Regimen
`
`Proposed Indication
`NDA Type
`
`Bausch & Lomb
`Selective -2 adrenergic agonist
`0.025% ophthalmic solution
`Adults and children  5 years: 1 drop in affected eye(s) Q6-8 hrs, no more than
`4x/day
`Relieve redness of the eye due to minor eye irritations
`505(b)(2)
`
`CDER Cross Discipline Team Leader Review Template 2015 Edition
`Version date: June 9, 2015. For initial rollout (NME/original BLA reviews)
`
`10
`
`Reference ID: 4187475
`
`(b) (4)
`
`Eye Therapies Exhibit 2066, 11 of 41
`Slayback v. Eye Therapies - IPR2022-00142
`
`

`

`Cross Discipline Team Leader Review
`NDA 208144 Brimonidine tartrate ophthalmic solution
`
`Chemical Structure
`
`White powder freely soluble in water. Molecular Weight 442.22 g/mol
`
`Source: Dr. Kelty’s and Dr. De’s review
`Product Composition: see Table 8 below and the CMC section of this review
`See CMC primary review for further details about nomenclature and molecular formula
`
`Examples of OTC NDA eye redness relievers
`Dr. Kelty’s clinical review listed the some currently available OTC NDA or ANDA (generic)
`eye redness relievers (Table 4 below).
`
`Table 4. Currently available OTC NDA or ANDA drug products for relief of eye redness
`Product
`Active Ingredients
`Indication
`Sponsor Approval
`Date
`1/31/96
`
`Visine A N020485
`
`0.025% naphazoline HCl 0.3%
`pheniramine maleate
`
`Opcon-A N020065
`A078208
`
`0.02675% naphazoline HCl
`0.315% pheniramine maleate
`
`Naphcon A N020226
`A202795
`
`0.025% naphazoline HCl 0.3%
`pheniramine maleate
`
`Temporarily relieves itchy, red eyes
`due to:
`•
`•
`•
`•
`
`pollen
`ragweed,
`grass,
`animal hair and dander
`
`J & J
`
`Bausch &
`Lomb
`
`6/8/94
`
`Alcon
`
`6/8/94
`
`Visine LR N019407
`
`0.025% oxymetazoline HCl
`
`Relief of redness of the eye due to
`minor eye irritations
`
`J & J
`
`3/31/89
`
`Ocuclear N018471
`
`0.025% oxymetazoline HCl
`
`Bayer
`
`5/30/86
`
`Source: Dr. Kelty’s clinical review
`
`Dr. Kelty’s review also listed some OTC monograph eye redness relievers (Table 5 below).
`
`Table 5. OTC Final Monograph Ophthalmic Drug Products (21 CFR 349): GRASE*
`Ophthalmic Vasoconstrictors
` Ephedrine HCl
` Naphazoline HCl
` Phenylephrine HCl
` Tetrahydrozoline HCl
`
`0.12%
`0.01-0.03%
`0.08-0.2%
`0.01-0.05%
`
`CDER Cross Discipline Team Leader Review Template 2015 Edition
`Version date: June 9, 2015. For initial rollout (NME/original BLA reviews)
`
`11
`
`Reference ID: 4187475
`
`Eye Therapies Exhibit 2066, 12 of 41
`Slayback v. Eye Therapies - IPR2022-00142
`
`

`

`Cross Discipline Team Leader Review
`NDA 208144 Brimonidine tartrate ophthalmic solution
`
`Indication
`
`Relieves redness of the eye due to minor eye irritations
`
`Dosage
`
`Population
`Maximum Duration of Use
`Warnings
`
`1-2 drops in affected eye(s) every 6 hours
`up to 4 times/day
`Adults and children ** 6 years
`Unspecified
`Discontinue use for:
`eye pain
`
`vision changes
`
`condition worsens/persists for >72 hours
`
`Do not use
`glaucoma
`
`if solution becomes cloudy
`
` Overuse may produce increased redness of eye
`*GRASE general recognition of safety and effectiveness
`** OTC monograph vasoconstrictor eye drops typically are marketed with dosing down to 6 years of age;
`however, the monograph does not specify a lower age limit for use
`Source: Dr. Kelty’s clinical review
`
`CDTL Comments
`
`1. Table 5 above shows that OTC ophthalmic vasoconstrictors have dosing down to age 6;
`however, the sponsor requests dosing down to age 5 for brimonidine tartrate 0.025%
`ophthalmic solution.
`
`2. Dr. Kelty’s review addressed the difference between the lower age dosing for OTC
`ophthalmic vasoconstrictors by noting:
`“At the EOP2 Meeting held on May 15, 2013, it was agreed that adult findings of efficacy
`could be extrapolated to pediatric patients down to age 6 years provided safety is
`demonstrated. In the agreed initial Pediatric Study Plan (iPSP), the sponsor proposed that
`efficacy in pediatric patients 5-17 years of age can be extrapolated from brimonidine tartrate
`ophthalmic solution, 0.025% adult studies; and the Division agreed. There is unlikely to be a
`significant difference in efficacy with use of the proposed product between a 5 year old and a 6
`year old child for the proposed indication”.
`
`Clinical Studies to Support OTC Use:
`Six clinical studies were conducted to evaluate the safety and effectiveness of brimonidine
`tartrate ophthalmic solution, 0.025% in relieving ocular redness. These included: one dose-
`ranging safety and efficacy (phase 2) study; two safety and efficacy studies (one phase 2 and
`one phase 3 study); one intraocular pressure lowering study; one safety (phase 3) study; and
`one pharmacokinetics (phase 1) study. An overview of the clinical studies is summarized in
`Table 6 below.
`
`CDER Cross Discipline Team Leader Review Template 2015 Edition
`Version date: June 9, 2015. For initial rollout (NME/original BLA reviews)
`
`12
`
`Reference ID: 4187475
`
`Eye Therapies Exhibit 2066, 13 of 41
`Slayback v. Eye Therapies - IPR2022-00142
`
`

`

`Cross Discipline Team Leader Review
`NDA 208144 Brimonidine tartrate ophthalmic solution
`
`Study Title
`
`Table 6. Clinical Studies of Brimonidine Tartrate Ophthalmic Solution, 0.025%
`Study
`Type of
`Drug
`Number,
`Study/
`Treatment
`Title
`Population
`Duration
`(N subjects)
`Phase 2
`safety and
`efficacy
`(duration of
`action)
`Adult (68)
`Phase 2
`safety and
`efficacy
`
`A Single-center, Randomized, Double- Masked,
`Placebo and Active Controlled, Dose-Ranging
`Evaluation of the Duration of Action of
`Brimonidine Tartrate Ophthalmic Solution in
`the Prevention of Ocular Redness Induced by
`Conjunctival Allergen Challenge (CAC)
`A Single-Center, Double-Masked,
`Randomized, Vehicle-Controlled, Parallel-
`Group Study Evaluating the Safety and Efficacy
`of Brimonidine Tartrate 0.025% Ophthalmic
`Solution Used Four Times Daily in a
`Population of Adult and Geriatric Subjects
`A Single-Center, Randomized, Double-
`Masked, Cross-Over Pilot Study Evaluating
`Safety and IOP Lowering Response of
`Brimonidine Tartrate 0.025% Ophthalmic
`Solution versus Vehicle in Subjects with Open
`Angle Glaucoma or Ocular Hypertension
`A Single-Center, Double-Masked,
`Randomized, Vehicle-Controlled, Parallel-
`Group Study Evaluating the Efficacy and Safety
`of Brimonidine Tartrate Ophthalmic Solution
`0.025% Used Four Times Daily in a Population
`of Adult and Geriatric Subjects with Ocular
`Redness
`A Multi-Center, Double-Masked, Randomized,
`Vehicle-Controlled, Parallel-Group Study
`Evaluating the Safety of Brimonidine Tartrate
`Ophthalmic Solution 0.025% Used Four Times
`Daily in a Population of Pediatric, Adult, and
`Geriatric Subjects.
`
`14 days
`screening +
`single doses
`administered
`over 42 days
`of enrollment
`28 days
`
`~1-5 weeks
`screening +
`4 weeks QID
`dosing
`
`~5 weeks
`
`~4 weeks
`
`7 days
`
`10-100-0008
`
`11-100-0015
`
`12-150-0001
`
`Adult (45)
`Geriatric
`( 2)
`Pilot IOP
`study
`(safety)
`
`Adult (15)
`
`13-100-0005
`B&L
`Number 861
`
`Phase 3
`safety and
`efficacy
`
`Adult (50)
`Geriatric
`(10)
`Phase 3
`safety
`
`Pediatric
`(50)
`Adult (408)
`Geriatric
`Phase 1
`safety
`
`Adult (14)
`
`13-100-0006
`B&L
`Number 862
`
`13-100-0007
`B&L
`Number 863
`
`A Prospective, Single- Center, Open-Label
`Study of the Plasma Pharmacokinetics and
`Safety following Topical Administration of
`Brimonidine Tartrate Ophthalmic Solution
`0.025% Used Four Times Daily in Healthy,
`Adult Subjects
`Source: Adapted from sponsor’s Table 1 Clinical Studies of Brimonidine Tartrate Ophthalmic Solution 0.025%,
`ISE.
`
`CDER Cross Discipline Team Leader Review Template 2015 Edition
`Version date: June 9, 2015. For initial rollout (NME/original BLA reviews)
`
`13
`
`Reference ID: 4187475
`
`Eye Therapies Exhibit 2066, 14 of 41
`Slayback v. Eye Therapies - IPR2022-00142
`
`

`

`Eye Therapies Exhibit 2066, 15 of 41
`Slayback v. Eye Therapies - IPR2022-00142
`
`

`

`Eye Therapies Exhibit 2066, 16 of 41
`Slayback v. Eye Therapies - IPR2022-00142
`
`

`

`Cross Discipline Team Leader Review
`NDA 208144 Brimonidine tartrate ophthalmic solution
`
`Bearr reconsidered based on the in-use study and the drug stability study noted below, and
`concluded “Based on these data, DMA (Division of Microbial Assessment) recommends that
`standard labeling practices concerning discarding opened multi-dose ophthalmic products be
`followed.”
`
` An in-use study was conducted wherein 2 drops of the drug product were dispensed
`every other day for 121 days. The drug product was capable of passing AET after 121
`days of simulated use.
` AET was performed on drug product stability samples stored unopened at 25ºC for 24
`months (i.e. expiry for the “worst case” 7.5 mL drug product) and the samples met the
`acceptance criteria.
`
`Dr. De summarized as “regarding Chemistry Manufacturing and Controls, the application may
`be approved. And, “Regarding quality aspects of the application the drug substance, drug
`product, process, microbiology and facility sections are reviewed and found adequate to
`support the approval of the application. The drug product has been granted a shelf life of
`15 months for the 2.5mL fill and 24 months for the 7.5mL fill product configuration. In
`addition, 120 day in-use period is granted (i.e. once the bottle is opened it should be
`discarded after 120 days)”.
`
`See the Chemistry review for additional details.
`
`CDTL Comments
`1) At a team labeling meeting held on November 20, 2017, DNDP, DTOP, and the Product
`Quality (CMC and microbiology) team discussed the data and need or lack of need for a
`“discard 120 days after opening” statement. CMC recommended the statement because there
`is some water loss from the bottle after opening, leading to the concentration the preservative,
` being out of specifications after approximately 120 days. DTOP
`commented that a discard statement was atypical for an ophthalmic solution. Dr. Bearr from
`OPQ-microbiology commented that the preservative was still active at day 120 even at 10% of
`the concentration in the proposed drug product. Although actual antimicrobial
`activity/microbial growth was not measured after day 120 (following opening), the risk of
`bacterial contamination after day 120 is extremely low. Dr. Bearr commented she saw reason
`to either include or not include the discard statement.
`
`2) This CDTL reviewer believes that the discard statement is not needed on this OTC drug
`product based on the microbiology opinion that microbial growth is likely to be inhibited after
`120 days given that microbial growth was inhibited at day 120 at a preservative concentration
`10% of the actual in the OTC drug product.
`
`Nonclinical Pharmacology/Toxicology
`4.
`The Pharmacology / Toxicology review was conducted by Donald Thompson, RPh, PhD,
`DABT., who recommended approval. Dr. Thompson noted that no new nonclinical data were
`submitted with the application and the “application relies in part on prior FDA findings of
`
`CDER Cross Discipline Team Leader Review Template 2015 Edition
`Version date: June 9, 2015. For initial rollout (NME/original BLA reviews)
`
`16
`
`Reference ID: 4187475
`
`(b) (4)
`
`Eye Therapies Exhibit 2066, 17 of 41
`Slayback v. Eye Therapies - IPR2022-00142
`
`

`

`Cross Discipline Team Leader Review
`NDA 208144 Brimonidine tartrate ophthalmic solution
`
`nonclinical safety for the approved lis