CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`206276Orig1s000
`
`
`CROSS DISCIPLINE TEAM LEADER REVIEW
`
`

`

`Cross-Discipline Team Leader Review
`
`Date
`From
`Subject
`NDA#
`Applicant
`Date of Submissions
`PDUFA Goal Date
`
`Proprietary Name /
`Established (USAN)
`names
`Dosage forms / Strength
`Proposed Indication(s)
`
`Recommended:
`
`1. Introduction
`
`January 29, 2015
`William M. Boyd, M.D.
`Cross-Discipline Team Leader Review
`206276
`Alcon Research Ltd
`July 30, 2014
`January 30, 2016
`
`Pazeo (olopatadine hydrochloride ophthalmic
`solution) 0.7%
`
`Topical ophthalmic solution
`Treatment of ocular itching associated with allergic
`conjunctivitis
`Recommended for Approval
`
`Olopatadine is a sterile, multi-dose ophthalmic solution containing olopatadine for topical administration
`to the eyes. Olopatadine is a relatively selective histamine H1 antagonist and it inhibits the release of
`histamine from the mast cells. The active ingredient in the formulation, Olopatadine, is the same as in
`the US approved products, PATADAY 0.2% (NDA 21-545) and PATANOL Ophthalmic Solution, 0.1%
`(NDA 20-688).
`
`This is a 505(b)(1) application.
`2. Background
`
`Clinical studies were conducted by Alcon under IND 60,991. Two Pre-NDA meetings were held between
`Alcon and the Agency. One meeting was held on July 30, 2012, and the second was held on August 26,
`2013.
`
`Alcon Research, Ltd. (Alcon) developed PATANOL (olopatadine hydrochloride ophthalmic solution),
`0.1% for the treatment of allergic conjunctivitis (NDA 20-688). PATADAY (olopatadine hydrochloride
`ophthalmic solution), 0.2% was subsequently developed to provide a once daily treatment regimen for
`itching associated with allergic conjunctivitis (NDA 21-545). PATANASE (olopatadine 0.6%) was
`developed for the treatment of nasal allergy symptoms (NDA 21-861). The currently proposed product
`(olopatadine hydrochloride ophthalmic solution, 0.7%) was intended by Alcon to increase the duration of
`efficacy over the existing marketed products (PATANOL and PATADAY).
`
`Reference ID: 3694323
`
`

`

`Cross-Discipline Team Leader Review
`William M. Boyd, M.D.
`NDA 206276
`Pazeo (olopatadine hydrochloride ophthalmic solution) 0.7%
`
`The safety information for this application is primarily derived from Study C-12-028, a 6 week,
`multicenter, randomized, double-masked, vehicle-controlled, parallel-group study. Subjects at risk for
`developing allergic conjunctivitis, at least 2 years of age or older with asymptomatic eyes at the time of
`study entry were randomized in a 2:1 ratio to, Olopatadine HCl Solution, 0.7% or vehicle respectively.
`Subjects younger than 6 years of age were randomized from 1 randomization schedule; subjects 6 years
`of age or older were randomized from another randomization schedule.
`
`The applicant has requested a partial waiver of the Pediatric Assessment requirements. The waiver would
`be for children less than two years of age because necessary studies are impossible or highly impractical,
`e.g., because the number of patients with allergic conjunctivitis in that age group is so small or
`geographically dispersed.
`
`3. Product Quality
`
`Olopatadine hydrochloride is a white, crystalline, water-soluble powder with a molecular weight of
`373.88 and a molecular formula of C21H23NO3•HCl.
`
`The chemical structure is presented below:
`
`Reference ID: 3694323
`
`2
`
`(b) (4)
`
`(b) (4)
`
`

`

`Cross-Discipline Team Leader Review
`William M. Boyd, M.D.
`NDA 206276
`Pazeo (olopatadine hydrochloride ophthalmic solution) 0.7%
`
`Chemical Name: 11-[(Z)-3(Dimethylamino) propylidene]-6-11dihydrodibenz[b,e] oxepin-2-acetic acid,
`hydrochloride
`
`. Additional information was requested from the
`Mannitol is described in the USP as
`applicant to support this claim. On October 17, 2014, Alcon stated that although mannitol itself is not a
` boric acid
`solution.
`
`
`
`
`
`Reference ID: 3694323
`
`3
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Cross-Discipline Team Leader Review
`William M. Boyd, M.D.
`NDA 206276
`Pazeo (olopatadine hydrochloride ophthalmic solution) 0.7%
`
`INSPECTIONS:
`
`The Office of Compliance has given an acceptable recommendation for both the drug substance
`manufacturing facility
` and the drug product
`manufacturing facility (Alcon Research, LTD., Fort Worth, Texas and Alcon- Covreour nv, Puurs,
`Belgium).
`
`Product Quality recommends approval.
`
`Reference ID: 3694323
`
`4
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b)
`(4)
`
`(b)
`(4)
`
`(b)
`(4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Cross-Discipline Team Leader Review
`William M. Boyd, M.D.
`NDA 206276
`Pazeo (olopatadine hydrochloride ophthalmic solution) 0.7%
`
`4. Nonclinical Pharmacology/Toxicology
`
`From the original Pharmacology/Toxicology Review:
`
`Olopatadine is a H1 receptor antagonist, an inhibitor of pro-inflammatory mediator release from human
`conjunctival mast cells, and an inhibitor of histamine stimulated cytokine production by human
`conjunctival epithelial cells. Most of the nonclinical studies to determine the pharmacologic properties
`of olopatadine were previously submitted under NDA 20-688 and 21-545.
`
`The applicant conducted pharmacology, ocular distribution and up to a 3- month ocular toxicity study to
`support the new formulation. Olopatadine exhibited significantly greater anti-allergy efficacy in vivo
`when administered topically in a 0.7% solution as compared with olopatadine, 0.2%. In pigmented
`rabbits, no adverse or toxic effects were attributed to olopatadine, 0.77% when administered up to four
`times daily for 3 months. The NOAEL, 0.7% QID, represents a ~4-fold ocular safety margin over the
`proposed clinical dose of 0.7%, QD. The formulation used also qualifies the excipients hydroxypropyl-
`γ-cyclodextrin and povidone K29/32 to
`%, respectively, for topical ophthalmic solutions.
`
`Pharmacology/Toxicology recommends s approval.
`
`5. Clinical Pharmacology
`
`From the original Clinical Pharmacology Review:
`
`The applicant conducted PK Study C-11-036 to determine the plasma exposures to olopatadine and its
`two (N-oxide and mono-desmethyl) metabolites following single and repeated topical ocular
`administration of the proposed commercial ophthalmic solution in 24 healthy adult subjects; 19 subjects
`had a complete set of PK profiles on Days 1 and 7. The plasma olopatadine (parent drug) concentrations
`were higher with topically applied PAZEO (olopatadine hydrochloride ophthalmic solution ) 0.7%
`administered as 1 drop per eye once daily for 7 days, compared to that reported for 0.15% olopatadine
`ophthalmic solution administered as 1 drop per eye twice daily for 2 weeks (see the PATADAY® and
`PATANOL® US package inserts), although no apparent accumulation of olopatadine was observed
`following repeated topical ocular administration of the proposed product.
`
`The mean steady state plasma olopatadine Cmax and AUC0-12 measured with PAZEO in this PK study
`were lower (by 90% to 93%, and by 85% to 88%, respectively) than that reported in adult healthy
`subjects and seasonal allergic rhinitis patients following administration of PATANASE (olopatadine
`hydrochloride 0.6%) Nasal Spray given 2 sprays per nostril twice daily for 14 days. The N-oxide
`metabolite of olopatadine (M3) was detected in less than 10% of the total plasma samples in
`approximately half of the study participants; the maximum plasma concentration was 0.174 ng/mL
`measured during the first 4 hours post-dosing. Plasma concentrations of desmethyl olopatadine (M1)
`were below the LLOQ (0.05 ng/mL) of the PK assay.
`
`Reference ID: 3694323
`
`5
`
`(b) (4)
`
`

`

`Cross-Discipline Team Leader Review
`William M. Boyd, M.D.
`NDA 206276
`Pazeo (olopatadine hydrochloride ophthalmic solution) 0.7%
`
`Clinical Pharmacology recommends approval.
`
`6. Sterility Assurance
`
`The drug product will be
`
`filled into 4 ml LDPE dropper bottles. The HPMC solution will be
`
`
`
`
`
`The container closure system for olopatadine hydrochloride ophthalmic solution, 0.7% consists of a 4 mL
`low density polypropylene (LDPE) oval bottle with a LDPE dispensing plug and a polypropylene
`closure. Bottles will be filled with either 0.5 mL or 2.5 mL of drug product. The oval bottle and
`dispensing plug
` The closure will be
`
`
`
`Product Quality Microbiology recommends approval.
`
`7. Clinical/Statistical - Efficacy
`
`From the original Medical Officer Review:
`
`All submitted studies were adequate and well controlled studies. The cross-over study (C-10-127)
`provided information on the “acceptability” of the product but was not designed to demonstrate efficacy.
`The two conjunctival antigen challenge (CAC) studies (C-10-126 and C-12-053) provided data to
`support the initial efficacy of the drug product and the duration of its action. The six week safety study
`(C-12-028) provided safety information in subjects who may use the product in the future.
`
`The efficacy studies, C-10-126 and C-12-053, were multicenter, randomized, double-masked, vehicle
`controlled, parallel-group studies and used the CAC model. The CAC design has been used to support
`the majority of drug products approved for the treatment of ocular itching. The study design includes a
`study visit in which patients with an allergic history are conjunctively challenged in both eyes with
`progressively higher doses of antigen until they demonstrate a ≥2+ itching and redness reaction. These
`patients return for a second visit in which the dose which elicited a ≥2+ reaction is administered and
`only patients who demonstrate a reproducible ≥2+ reaction continue in the study. Patients return for a
`third visit, during which the test drug product is administered to both eyes and after 24 hours, the antigen
`which reproducibly elicited a ≥2+ reaction is again administered. The patient’s itching reactions are
`recorded at 3, 5 and 7 minutes after antigen administration, the patient’s redness reactions are recorded
`7, 15 and 20 minutes after antigen administration. The patient’s fourth visit is a repeat of the third visit
`except that the time after test product administration is reduced to 16 hours. The patient’s fifth visit is a
`repeat of the third visit, except that the time after test product administration is reduced to27 minutes.
`
`Reference ID: 3694323
`
`6
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Cross-Discipline Team Leader Review
`William M. Boyd, M.D.
`NDA 206276
`Pazeo (olopatadine hydrochloride ophthalmic solution) 0.7%
`
`The study designs were similar for both studies with the exception that C-12-053 did not include the 16
`hour duration efficacy evaluation visit and had an additional active comparator, PATANOL. Both
`studies evaluated the same efficacy endpoints (itching and redness) for the onset of action and the 24
`hours duration of action. Study C-10-126 included PATADAY (olopatadine hydrochloride ophthalmic
`solution) 0.2% and Vehicle as comparators; Study C-12-053 included PATADAY, PATANOL
`(olopatadine hydrochloride ophthalmic solution) 0.1% and Vehicle as comparators. The randomization
`ratio in C-10-126 was 1:1:1 and in C-12-053, it was 2:2:2:1 (olopatadine hydrochloride ophthalmic
`solution, 0.7%: PATADAY: PATANOL: Vehicle). In past CAC Studies, differences of
`approximately1 unit between test product and vehicle observed in the majority of time points (two out of
`three in the case of these studies) has been considered clinically significant.
`
`Reference ID: 3694323
`
`7
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Cross-Discipline Team Leader Review
`William M. Boyd, M.D.
`NDA 206276
`Pazeo (olopatadine hydrochloride ophthalmic solution) 0.7%
`
`Study C-10-126 - Itching
`
`Efficacy over vehicle for itching has been demonstrated 30 minutes after administration and continues for
`a duration of at least 24 hours after administration. The effectiveness of Olopatadine 0.7% is relatively
`similar to Olopatadine 0.2% (Pataday) at the onset of action, but is slightly more evident at 24 hours.
`
`Reference ID: 3694323
`
`8
`
`

`

`Cross-Discipline Team Leader Review
`William M. Boyd, M.D.
`NDA 206276
`Pazeo (olopatadine hydrochloride ophthalmic solution) 0.7%
`
`Study C-12-053 - Itching
`
`Efficacy over vehicle for itching has been demonstrated 30 minutes after administration and continues for
`a duration of at least 24 hours after administration. The effectiveness of Olopatadine 0.7% is relatively
`similar to Olopatadine 0.2% (Pataday) and Olopatadine 0.1% (Patanol) at the onset of action but is
`slightly more evident at 24 hours.
`
`Reference ID: 3694323
`
`9
`
`2 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`

`

`Cross-Discipline Team Leader Review
`William M. Boyd, M.D.
`NDA 206276
`Pazeo (olopatadine hydrochloride ophthalmic solution) 0.7%
`
`Summary Efficacy Statement
`
`Adequate and well controlled studies support the efficacy of Pazeo (olopatadine hydrochloride
`ophthalmic solution) 0.7% for the treatment of ocular itching associated with allergic conjunctivitis.
`
`
`
`8. Safety
`
`From the original Medical Officer Review:
`
`The six week safety study (C-12-028) provided safety information in subjects who may use the product
`in the future. The population was an appropriate population to monitor for the potential to develop an
`adverse reaction.
`
`Categorization of Adverse Events
`
`Reference ID: 3694323
`
`12
`
`(b) (4)
`
`

`

`Cross-Discipline Team Leader Review
`William M. Boyd, M.D.
`NDA 206276
`Pazeo (olopatadine hydrochloride ophthalmic solution) 0.7%
`
`Deaths/Significant Adverse Events
`
`None.
`
`Drug- Specific Safety Explorations
`
`There were no clinically significant changes noted in visual acuity, intraocular pressure, slit lamp or
`funduscopy in any trial.
`
`Visual Acuity
`
`Reference ID: 3694323
`
`13
`
`

`

`Cross-Discipline Team Leader Review
`William M. Boyd, M.D.
`NDA 206276
`Pazeo (olopatadine hydrochloride ophthalmic solution) 0.7%
`
`IOP
`
`Safety Summary Statement
`
`The three clinical studies (C-10-126, C-12-053, C-12-028) were used to establish the safety of the drug
`product. An adequate safety profile has been established
`
`The most commonly reported adverse reactions seen in the six-week trial C-12-028 occurred in 2-5% of
`patients treated with either PAZEO or vehicle. These events were blurred vision, dry eye, superficial
`punctate keratitis, dysgeusia and an abnormal sensation in the eye.
`
`9. Advisory Committee Meeting
`
`No Advisory Committee Meeting was held. There were no new issues raised in the review of the
`application which were thought to benefit from an Advisory Committee Meeting.
`
`10. Pediatrics
`
`The applicant received a Written Request for pediatric studies with olopatadine hydrochloride ophthalmic
`solution, 0.7% dated 10/3/2013. In this application, the applicant has requested a partial waiver of the
`Pediatric Assessment requirements. The waiver would be for children less than two years of age because
`necessary studies are impossible or highly impractical, e.g., because the number of patients in that age
`group with allergic conjunctivitis is so small or geographically dispersed.
`
`This application was reviewed by the Pediatric Review Committee on November 12, 2014. The
`committee agreed that the waiver of children less than two years of age was appropriate.
`14
`
`Reference ID: 3694323
`
`

`

`Cross-Discipline Team Leader Review
`William M. Boyd, M.D.
`NDA 206276
`Pazeo (olopatadine hydrochloride ophthalmic solution) 0.7%
`
`The Pediatric Exclusivity Board determined on 12/16/14 that exclusivity should be granted for the single
`moiety.
`
`11. Other Relevant Regulatory Issues
`
`BIOSTATISTICS
`Per the original Biostatistics review:
`
`In order to support the approval of this new formulation, the applicant submitted two Phase 3 efficacy
`studies: Study C-10-126, and Study C- 12-053.
`
`Studies C-10-126 and C-12-053 were similarly designed phase 3 studies. Both were multicenter,
`randomized, double-masked, active and vehicle controlled, parallel-group studies and used the
`conjunctival allergen challenge (CAC) model to evaluate the safety and efficacy of Olopatadine 0.7%
`versus Vehicle or active comparators in the treatment of ocular itching associated with allergic
`conjunctivitis.
`
`The primary efficacy variable for both studies was patient-evaluated ocular itching severity scores
`(assessed using a 0-4 scale with 0.5 unit increments: 0 = none, 4 = incapacitating itch). In Study C-10-
`126, the primary efficacy endpoints were patient-evaluated ocular itching at 3, 5, and 7 minutes post-
`CAC at both Visits 4B (16-hour duration-of-action) and 5 (onset-of-action). In Study C-12-053, the
`primary efficacy endpoints were patient-evaluated ocular itching at 3, 5, and7 minutes post-CAC at both
`Visit 3B (24-hour duration-of-action) and Visit 4 (onset-of-action).
`
`Based on the efficacy results (Table 1):
`In both Study C-10-126 and Study C-12-053, Olopatadine 0.7% was superior to Vehicle for treating
`
`ocular itching associated with allergic conjunctivitis at onset-of-action, and 24-hour duration-of-action.
`In Study C-10-126, at 24-hour duration-of-action, Olopatadine 0.7% was superior to PATADAY for
`
`the treatment of ocular itching associated with allergic conjunctivitis. In Study C-12-053, Olopatadine
`0.7% was superior to PATADAY for ocular itching associated with allergic conjunctivitis at 24-hour
`duration-of-action at 2 (3 and 5 minutes) out of 3 post CAC time points. The point estimate for the
`treatment difference at 7 minutes post-CAC was in favor of Olopatadine 0.7% but did not demonstrate
`statistical significance.
`
`Reference ID: 3694323
`
`15
`
`

`

`Cross-Discipline Team Leader Review
`William M. Boyd, M.D.
`NDA 206276
`Pazeo (olopatadine hydrochloride ophthalmic solution) 0.7%
`
`Biometrics recommends approval.
`
`OPDP
`The Office of Prescription Drug Products (DPDP) provided a labeling review of the proposed, clean,
`substantially complete version of the package insert. Edits were incorporated into the labeling document
`on the SharePoint site
`
`Reference ID: 3694323
`
`16
`
`

`

`Cross-Discipline Team Leader Review
`William M. Boyd, M.D.
`NDA 206276
`Pazeo (olopatadine hydrochloride ophthalmic solution) 0.7%
`
`DMEPA
`Office of Medication Error Prevention and Risk Management found the proprietary name, Pazeo,
`acceptable, on 12/10/2014.
`
`DMEPA provided a labeling review of the original carton and container labeling (without preparatory
`name) on 11/19/2014.
`
`FINANCIAL DISCLOSURE
`The applicant has adequately disclosed financial interests/arrangements with clinical investigators. The
`one reported interest (see Medical Officers review dated 12/14/2014) is not likely to raise questions
`about the integrity of the data because the studies were multicenter, masked trials and the one
`investigator with a potential interest was responsible for a small percentage of the overall application.
`
`OSI
`An Office of Scientific Investigations (OSI) audit was requested.
`
`The pivotal studies, C-10-126 entitled, “A Multicenter, Randomized, Double-Masked, Vehicle and
`Active Controlled, Parallel-Group Efficacy and Safety Study of AL-4943A Ophthalmic Solution, 0.77%
`in Patients with Allergic Conjunctivitis Using the Conjunctival Allergen Challenge (CAC) Model”, and
`C-12-028 entitled “A Multicenter, Randomized, Double-Masked, Vehicle-Controlled, Parallel-Group
`Study Evaluating the Safety of AL-4943A Ophthalmic Solution 0.77% Administered Once Daily”, were
`inspected in support of this application.
`
`Drs. Torkildsen’s and Rand’s clinical sites were selected for inspection because of high subject
`enrollments and previous inspection histories.
`
`Neither Dr. Torkildsen nor Dr. Rand was issued a Form FDA 483, and these inspections were classified
`No Action Indicated (NAI). Per OSI, the data generated by these clinical sites appear adequate in support
`of the respective indication.
`
`17
`
`Reference ID: 3694323
`
`

`

`Cross-Discipline Team Leader Review
`William M. Boyd, M.D.
`NDA 206276
`Pazeo (olopatadine hydrochloride ophthalmic solution) 0.7%
`
`12. Labeling
`
`The labeling found in the Appendix (carton and Container labeling and package insert submitted on
`1/29/2015) is acceptable.
`
`13. Recommendations/Risk Benefit Assessment
`
`RECOMMENDED REGULATORY ACTION:
`NDA 206276 for Pazeo (olopatadine hydrochloride ophthalmic solution) 0.7% is recommended for
`approval for the treatment of ocular itching associated with allergic conjunctivitis.
`
`Adequate and well controlled studies support the efficacy of Pazeo (olopatadine hydrochloride
`ophthalmic solution) 0.7% for the treatment of ocular itching associated with allergic conjunctivitis.
`
`
`The most commonly reported adverse reactions seen in the six-week trial C-12-028 occurred in 2-5% of
`patients treated with either PAZEO or vehicle. These events were blurred vision, dry eye, superficial
`punctate keratitis, dysgeusia and an abnormal sensation in the eye.
`
`The benefits of using this drug product outweigh the risks for the above indication.
`
`RECOMMENDATION FOR POSTMARKETING RISK MANAGEMENT ACTIVITIES:
`There are no risk management activities recommended beyond the routine monitoring and reporting of all
`adverse events.
`
`There are no recommended Postmarketing Requirements or Phase 4 Commitments.
`
`Reference ID: 3694323
`
`18
`
`10 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`(b) (4)
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`WILLIAM M BOYD
`01/29/2015
`
`WILEY A CHAMBERS
`01/29/2015
`
`Reference ID: 3694323
`
`