ALCON 2004
`Argentum Pharm. LLC v. Alcon Research, Ltd.
`Case IPR2017-01053
`
`001
`
`

`

`Clinical Review
`
`Martin P. Nevitt, MD‘, MPH.
`NDA 21-994; N—000
`Travatan Z (travoprost ophthalmic solution) 0.004%
`
`
`CLINICAL REVIEW
`
`Application Type
`Submission Number
`
`NDA 21-994
`000
`
`Submission Code
`
`Letter Date
`
`Stamp Date
`PDUFA Goal Date
`
`Original
`
`11/18/05
`11/21/05
`09/21/06
`
`Reviewer Name
`
`Review'Completion. Date
`
`Martin P. Nevitt, M.D., MZPH.
`5/09/06
`
`Established Name
`
`travoprost ophthalmic solution 0.004%
`
`(Proposed) Trade Name
`Therapeutic Class
`Applicant
`
`Travatan Z
`
`Prostaglandin F2m analogue
`Alcon Research, Ltd.
`6201 South Freeway
`PO. Box 19534
`Fort Worth, TX 76134—2099
`817-551-4933
`'
`
`Angela C. Kothe, OD, PhD
`Associate Director, Regulatory Affairs
`
`Priority Designation
`
`S
`
`' Structure
`
`C26H35F306
`
`H
`
`(3H3
`
`Q/i\ CM;
`
`o
`
`(7
`l“
`
`f,
`
`L4
`
`H .5?on
`
`
`
`:
`‘E'l
`
`H5:
`
`. Dosing Regimen
`
`One drop in the affected eye(s) once-daily in the evening
`
`Indication
`
`Reduction of intraocular pressure (IOP) in patients with
`open-angle glaucoma or ocular hypertension who are
`intolerant of intraocular lowering medications or are
`insufficiently responsive (failed to achieve target IOP
`determined after multiple measurements over time) to another
`intraocular pressure lowering medication
`
`Intended Population
`
`Patients 18 years or older with open angle glaucoma or ocular
`hypertension
`
`002
`
`002
`
`

`

`Clinical Review
`Martin P. Nevitt, M.D., M.P.H.
`NDA 21—994; N—000
`Travatan Z (travoprost ophthalmic solution) 0.004%
`
`Table of Contents
`
`1
`
`EXECUTIVE SUMMARY................................................................................................................................4
`
`1.1
`1.2
`
`1.3
`
`RECOMMENDATION ON REGULATORY ACTION ........................................................................................... 4
`RECOMMENDATION ON POSTMARKETING ACTIONS .................................................................................... 4
`
`1.2.1 Risk Management Activity ......... i ............................................................................................................ 4
`.................................................................................... 5
`SUMMARY OF CLINICAL'FINDINGS
`
`1.3.1 Brief Overview of Clinical Program . .......................................................................................................... 5
`1.3.2Efficacy................................................................................................... 5
`1.3.3Safety ........................ 6
`1.3.4 Dosing Regimen and Administration ......................................................................................................... 6
`1.3.5 Drug-Drug Interactions .............................................................................................................................. 7
`1.3.6 Special Populations......................................................- .............................................................................. 7
`
`2
`
`INTRODUCTION AND BACKGROUND ......................................................................................................8
`
`2.1
`2.2
`2.3
`2.4
`2.5
`2.6
`
`PRODUCT INFORMATION ................................................................................................................ '. ............ 8
`CURRENTLY AVAILABLE TREATMENT FOR INDICATIONS ............................‘.....
`
`AVAILABILITY OF PROPOSED ACTIVE INGREDIENT IN THE UNITED STATES .....
`
`IMPORTANT ISSUES WITH PHARMACOLOGICALLY RELATED PRODUCTS ..........
`
`PRESUBMISSION REGULATORY ACTIVITY .................................................
`
`OTHER RELEVANT BACKGROUND INFORMATION ........................ -. ............................................................. 1 1
`
`SIGNIFICANT FINDINGS FROM OTHER REVIEW DISCIPLINES ........_........:................................... 11
`
`CMC (AND PRODUCT MICROBIOLOGY, IF APPLICABLE) ........... 11
`ANIMAL PHARMACOLOGY/TOXICOLOGY .................................................................................................. 1 1
`
`3.1
`3.2
`
`DATA SOURCES, REVIEW STRATEGY, AND DATA INTEGRITY..................................................... 12
`SOURCES OF CLINICALDATA .......................................................... 12
`TABLES OF CLINICAL STUDIES .................................................................................................................. 13
`REVIEW STRATEGY ............‘....................................................................................................................... 13
`
`DATA QUALITY AND INTEGRITY ............................................................................................................... 13
`COMPLIANCE WITH GOOD CLINICAL PRACTICES ....................................................................................... 14
`FINANCIAL DISCLOSURES .......................................................................................................................... 14
`
`4.1
`. 4.2
`4.3
`
`4.4
`-4.5
`4.6
`
`CLINICAL PHARMACOLOGY (FROM THE CLINICAL PHARMACOLOGY REVIEW) ............... 14
`
`5.1
`5.25
`5.3
`
`PHARMACOKINETICS ........................‘......................................................................._......................................
`PHARMACODYNAMICS .............................................................................................................................. 15
`EXPOSURE-RESPONSE RELATIONSHIPS
`...................................................................................... 15
`
`INTEGRATED REVIEW OF EFFICACY ................................................................................................... 15
`
`6. 1
`
`INDICATION ........................................................................................... .................................................... 15
`6.1.1 Methods ......................................................_............................................................................................. 15
`6.1.2 General Discussion of Endpoints ............................................................................................................. 15
`6.1.3 Study Design........................................................-...................................... 16
`
`6.1.4 Efficacy Findings .................................................................................................................................... 24
`6.1.5 Clinical Microbiology ..................................................................................................................... _. ........ 26
`6.1.6 Efficacy Conclusions ..........................-..................................................................................................... 26
`
`INTEGRATED REVIEW OF SAFETY............................................. 26
`
`_ 7.1
`
`METHODS AND FINDINGS .......................................................................................................................... 26
`7.1.1 Deaths ......................................'............'. ................................................................................................... 26
`7.1.2 Other Serious Adverse Events ................................................................................................................. 27
`
`7. 1. 3 Dropouts and Other Significant Adverse Events ..................................................................................... 28
`
`2 0
`
`03
`
`003
`
`

`

`.
`Clinical Review
`Martin P. Nevitt, M.D., M.P.H.
`NDA 21-994; N-OOO
`Travatan Z (travoprost ophthalmic solution) 0.004%
`
`7.1.4 Other Search Strategies ............................................................................................................................ 29
`7.1.5 Common Adverse Events......................................................................................................................... 30
`
`7.1.6 LessCommon Adverse Events ............................................................................................ . ........ 31
`7.1.7 LaboratoryFIndIngs...........................31
`7.1.8 Vital Signs................................................................................................................................................32
`
`97.1.9 Electrocardiograms (ECGS) ............................................................................................................... 32
`7.1.10 Immunogenicity.................... .................................................................................................................32
`7.1.11 Human Carcinogenicity .........................................................................................................................32
`
`7.1.12 Special Safety Studies ...........................................................
`'
`........._.........33
`7.1.13 Withdrawal Phenomena and/0r Abuse Potential .................................................................................... 33
`7.1.14 Human Reproduction and Pregnancy Data ............................................................................................33
`
`7.1.15 Assessment of Effect on Growth .................................................................................................. 33
`............ 33
`7.1.16 Overdose Experience
`
`7.1.17 Postmarketing Experience.................................................................................................................. 33.
`ADEQUACY or PATIENT EXPOSURE AND SAFETY ASSESSMENTS ............................. _. ................................34
`7.2.1 Description of Primary Clinical Data Sources (Populations Exposed and Extent of Exposure) Used to
`Evaluate Safety ..........................................................................................................................................34
`7.2.2 Description of Secondary Clinical Data Sources Used to Evaluate Safety .............................................. 36
`7.2.3 Adequacy of Overall Clinical Experience................................................................................................ 37
`7.2.4 Adequacy of Special Animal and/or In Vitro Testing...................... ..................................................... 37
`7.2.5 Adequacy of Routine Clinical Testing .....................................................................................................37
`7.2.6 Adequacy OfMetabolic, Clearance, and Interaction Workup .................................................................. 37
`7.2.7 Adequacy of Evaluation for Potential Adverse Events for Any New Drug and Particularly for Drugs in
`the Class Represented by the New Drug; Recommendations for Further Study ...:.... ............................... 37
`7.2.8 Assessment of Quality and Completeness of Data......-........'....................................................................37
`7.2.9 Additional Submissions, Including SafetyUpdate ..................................38 '
`SUMMARY OF SELECTED DRUG-RELATED ADVERSE EVENTS, IMPORTANT LIMITATIONS OF DATA, AND
`CONCLUSIONS ........................................................................................................................................... 38
`
`GENERAL METHODOLOGY ..............................................................‘.
`...'..38
`7.4.1Pooling Data Across Studies to Estimate and Compare Incidence ...........................................................38
`
`7.2
`
`7.3
`
`7.4
`
`8
`
`ADDITIONAL CLINICAL ISSUES
`
`.................38
`
`8.1
`8.2
`8.3
`8.4
`8.5
`8.6
`8.7
`8.8
`
`DOSING REGIMEN AND ADMINISTRATION .............................................
`
`DRUG-DRUG INTERACTIONS ...........................
`
`SPECIAL POPULATIONS .......................................... .................................................................................... 39
`PEDIATRICS ........................................................................._. .....................................................................39
`
`‘
`. ADVISORY COMMITTEE MEETING .............................
`............................................................... 39
`LITERATURE REVIEW ................................................................................................................................ 39
`POSTMARKETING RISK MANAGEMENT PLAN ............................................................................................ 39
`OTHER RELEVANT MATERIALS .................................................................................................................39
`
`9
`
`OVERALL ASSESSMENT.............................................................................................................................40
`
`9. 1
`9.2
`9.3
`9.4
`9.5
`
`CONCLUSIONS ........................................................................................................................................... 40
`RECOMMENDATION ON REGULATORY ACTION
`....................................40
`
`RECOMMENDATION ON POSTMARKETING ACTIONS ........................................................................ 40
`LABELING REVIEW ............................. . ................................................................................................41
`COMMENTS To APPLICANT..................................;.....................................................................................4'1
`
`9.4 LINE—BY-LINE LABELING REVIEW ............................................................................................................42
`
`004
`
`004
`
`

`

`Clinical Review
`
`Martin P. Nevitt, M.D., M.P.H.
`NDA 21-994; N-000
`'
`Travatan Z (travoprost ophthalmic solution) 0.004%
`
` 1
`
`EXECUTIVE SUMMARY
`
`1.1 Recommendation on Regulatory Action
`
`From a clinical perspective, NDA 21—994 is recommended for approval for the treatment of
`elevated intraocular pressure (IOP) in patients with open angle glaucoma or ocular hypertension
`who are intolerant of intraocular lowering medications or insufficiently responsive (failed to
`achieve target IOP determined after multiple measurements over time) to another intraocular
`pressure lowering medication.
`
`The submitted bioequivalence trial (study C-04—Il7) supports approval of Travatan Z, aka
`Travatan BAC—free. Travatan Z was developed for those patients who may be intolerant of the
`preservative benzalkonium chloride.
`
`Study C—04—17 was a multicenter, phase 3 safety and efficacy trial. This safety/efficacy study
`was designed to demonstrate bioequivalence of Travatan Z (the BAC-free formulation of
`travoprost ophthalmic solution, 0.004%) to the marketed formulation of travoprost ophthalmic
`solution, 0.004% (Travatan), with both dosed once-daily in the evening in patients with open- ~
`angle glaucoma or ocular hypertension.
`
`The primary efficacy endpoint, mean intraocular pressure, is demonstrated to be equivalent when
`comparing travoprost ophthalmic solution, 0.004% (Travatan Z); to the previously approved
`drug, travoprost ophthalmic solution, 0.004% (Travatan). Equivalence is defined as 'the two sided
`95% confidence interval being less than 1.5 mmHg at each direct group comparison over
`multiple times over a three month period and being less than 1.0 mmHg for the majority of direct
`group comparisons. Travatan (NDA 21-257) was first approved in March 2001 for the reduction
`of elevated [OP in patients with open-angle glaucoma or ocular hypertension who are intolerant
`of intraocular lowering medications or are insufficiently responsive (failed to achieve target [OP
`determined after multiple measurements over time) to another intraocular pressure lowering
`medication.
`
`The recommended dosing regimen is one drop in the affected eye(s) once daily in the evening.
`
`1.2 Recommendation on Postmarketing Actions
`
`1.2.1 Risk Management Activity
`
`No additional clinical trials or postmarketing surveillance studies are required.
`
`005
`
`005
`
`

`

`-
`Clinical Review
`Martin P. Nevitt, M.D., MPH.
`NDA 21-994; N-OOO
`Travatan Z (travoprost ophthalmic solution) 0.004%
`
`
`1.3 Summary of Clinical Findings
`
`1.3.1 Brief Overview of Clinical Program
`
`Established Name
`(Proposed) Trade Name
`Therapeutic Class
`
`travoprost ophthalmic solution, 0.004%
`Travatan Z
`Prostaglandin FZQ analogue
`
`Glaucoma is a disease characterized by optic nerVe damageand visual field loss often associated
`'with increased intraocular pressure (IOP). [OP is an important risk factor for developing open
`angle glaucoma. Ocular hypertension is a condition characterized by increased IOP in the
`absence of identifiable optic nerve damage and visual field loss.
`
`In this clinical trial, reduction in IOP was the proposed primary efficacy endpoint studied in
`patients with open angle glaucoma or ocular hypertension. The proposed indication for this drug
`product was for the reduction of intraocular pressure in male or female patients, l8 years or
`older, with open angle glaucoma or ocular hypertension who are intolerant of intraocular
`lowering medications Or are insufficiently responsive (failed to achieve target IOP determined
`after multiple measurements over time)‘to another intraocular pressure lowering medication,
`
`The protocol for study C-04-l7 was submitted to the FDA in July 2004 for Special Protocol
`Assessment to confirm the appropriateness of the clinical study design, analysis plan, selection
`of comparative agent and total number of patients to be included~in the study. With this prior
`FDA agreement, a single multicenter clinical trial (study C—04-l7) comparing travoprost
`ophthalmic solution, 0.004% (Travatan Z) with travoprost ophthalmic solution, 0.004%
`(Travatan) would be acceptable as clinical suppOrt if travoprost ophthalmic solution, 0.004%
`(Travatan Z) demonstrated equivalence to travoprost ophthalmic solution, 0.004% (Travatan).
`
`Study C-04-l7 was a multicenter, double masked, randomized, parallel-group, active control
`design with the following scheduled visits: Screening/Eligibility with a washout phase, and exam
`Visits at week 2, week 6, and month 3. The study objectives were to evaluate the safety and
`efficacy of Travantan Z given once daily at 8 PM compared with Travatan also given once daily
`at 8 PM. Additional safety and secondary parameters examined were visual acuity, ocular signs
`(cornea, iris/anterior chamber, lens, aqueous flare and inflammatory cells), ocular hyperemia,
`dilated fundus parameters (vitreous, retina/macula/choroids, optic nerve, cup/disc ratio),
`automated perimetry, endothelial cell density and adverse events.
`
`1.3.2 Efficacy
`
`The primary measure of efficacy was mean IOP at 8 AM, 10 AM and 4 PM at exam visits on
`weeks 2 and 6, and month 3. If only one of a patient’s eyes was closed, the dosed eye was
`selected for analysis; if both of a patient’s eyes were dosed, the worse evaluable eye was selected
`for analysis.
`
`006
`
`006
`
`

`

`Clinical Review
`Martin P. Nevitt, M.D., M.P.H.
`NDA 21-994; N-000
`Travatan Z (travoprost ophthalmic solution) 0.004%
`
`
`The demographic characteristics between the two treatment groups (Travatan Z and Travatan
`groups) showed no significant differences. The efficacy results of the trial demonstrated there
`were no statistically significant differences between the 2 treatment groups at any follow-up
`timepoint for mean IOP at each visit and at each time interval. The new formulation, Travatan Z,
`_ demonstrated equivalence to Travatan in IOP lowering ability.
`
`1.3.3 Safety
`
`The most frequently reported adverse events (3 5% in either treatment group) were ocular
`hyperemia and ocular pruritis. A similar adverse event profile was observed comparing the most
`common adverse events observed in the Travatan Z and Travatan groups.
`
`Common ocular adverse events occurring at an incidence of 2.0% to 5.5% in the Travatan Z
`group versus the Travatan group included ocular pruritus (5.5% vs. 3.5%), ocular discomfort
`(3.8% vs. 1.4%), foreign body sensation (2.6% vs. 1.2%) and ocular pain (2.3% vs. 1.4%). All'of
`these events occurred at slightly higher incidences in the Travatan Z group than in the Travatan
`group; however, individual characteristics of these adverse events were similar between
`treatment groups. Decreased visual acuity and dry eye occurred at a slightly higher incidence in
`the Travatan group than the Travatan Z group, (both adverse events occurring at 2.0% vs. 1.7 %,
`' 4
`respectively.)
`" ‘
`"
`'
`
`Few serious adverse events were reported in the clinical trial. None of the events were ocular,
`and none were considered to be related to the study medications. There were two deaths reported
`during the clinical trial both occurring in the Travatan Z group but were not related to treatment;
`one patient died frommultiple myeloma and another'from septic shock. Other serious, non-fatal
`adverse events all unrelated to-therapy were reported for 12 patients. This included 9 elderly
`patients with exposure to Travatan Z and 3 elderly patients withexposure to Travatan. Overall,
`although there was a higher incidence of serious adverse events in the Travatan Z group,.none of
`these events were related to therapy'and no common factors were noted in the non-fatal serious
`adverse events reported which would indicate a safety concern for Travatan Z.
`
`Additionally, no safety concerns were identified based upon an analysis of change from baseline
`for visual acuity, ocular signs (cornea, iris/anterior chamber, lens, aqueous flare and
`inflammatory cells), ocular hyperemia, dilated fundus parameters (vitreous,
`retinalmacula/choroids, optic nerve), cup/disc ratio, visual fields and endothelial cell density
`measurements in either treatment group in the overall safety population, adult population, or
`elderly population.
`'
`I
`
`1.3.4 Dosing Regimen andAdministration '
`
`Dose-response efficacy has been studied previously with travoprOSt, the active ingredient in
`Travatan and Travatan Z, in concentrations of 0.004% and 0.0015% in NDA 21-257. Although
`both concentrations demonstrated efficacy in lowering IOP, travoprost 0.004% lowered [OP
`more than travoprost 0.0015%. The amount of [GP reduction produced by travoprost 0.004% (7-
`
`007
`
`007
`
`

`

`Clinical Review
`
`Martin P. Nevitt, M.D., MPH.
`NDA 21-994; N—OOO
`Travatan Z (travoprost ophthalmic solution) 0.004%
`
`8 mmHg) as compared to travoprost 0.0015% (6—7 mmHg) was not statistically and clinically
`significant. Travoprost 0.004% was granted approval on March 2001 (NDA 21—257).
`
`'
`
`The recommended dosing regimen is one drop in the affected eye(s) once daily in the evening.
`
`1.3.5 Drug-Drug Interactions
`
`There were no important drug-drug interactions noted that would affect the product’s clinical
`use.
`.
`
`1.3.6 Special Populations
`
`No overall differences in safety or effectiveness have been observed between elderly and adult
`patients.
`'
`'
`
`No patients with hepatic or renal impairment were studied.
`
`There are no adequate and well-controlled studies in pregnant woman. It is not known whether
`this drug or its metabolites are excreted. in human milk; although in an animal study of lactating
`rats radiolabeled travoprost and/or its metabolites were excreted in milk.
`
`Safety and effectiveness in pediatric patients have not been established.
`
`Reviewer’s comments:
`
`Travoprost ophthalmic solution, 0.004%1in NDA 21-257 (Travatan), was evaluated in patients
`with hepatic impairment and also renal impairment in clinical trials. N0 clinically relevant
`changes in hematology, blood chemistry or urinalysis data were observed in these patients.
`
`Appears Thls Way
`On Original
`
`008
`
`008
`
`

`

`Clinical Review
`
`Martin P. Nevitt, MD, MPH.
`NDA 21-994; N—000
`Travatan Z (travoprost ophthalmic solution) 0.004%
`
` 2
`
`INTRODUCTION AND BACKGROUND
`
`2.1 Product Information
`
`Established Name
`(Proposed) Trade Name.
`Therapeutic Class
`Formulation
`
`.
`
`travoprost ophthalmic solution, 0.004%
`Travatan Z
`
`ProStaglandin FZa-analogue
`C26H35F306
`
`
`
`tilt)
`
`
`on
`
`-
`
`f;
`
`H
`
`‘ Proposed Indication
`
`Reduction of intraocular pressure (IOP) in patients
`18 years or older with open angle glaucoma or
`ocular hypertension who are intolerant of
`intraocular loweringmedications or are
`insufficiently responsive (failed to achieve target
`[OP determined after multiple measurements over
`time) to another intraocular pressure lowering
`medication
`
`_
`
`Appears This Way
`On Original
`
`009
`
`009
`
`

`

`Clinical Review
`
`Martin P. Nevitt, M.D., MPH.
`NDA 21-994; N-000
`Travatan Z (travoprost ophthalmic solution) 0.004%
`
`
`Composition of Travatan Z (FIDa 107047)
`
`
`
`Cnmpendial
` Component
`Designation
`
`
`
`, iramprost(ALUGZEI )
`1
`Non-Compendial
`7e
`r”
`m:
`A Poiyoxyl 4O Hydrogenated ;
`
`
`
`. Castor Oil (1460—40)
`1
`Alternate: Alcon Glob-at
`'
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`l
`Alfonograpii
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`USP
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`i
`USP
`
`
`1
`, L.
`Sodium H ydtoxide
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`ndi
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`*
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`we
`gh‘”
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`k
`. Hydroehlorie Acid
`
`
`E
`Purified Water
`
`. _,...
`,c m
`i
`.-
`, W m. ..,.m... -_-.,
`‘1 FED= formulation identification number
`.
`b Adjust to fiased on purity of the raw material
`
`, 4 capaoity. Pl‘féélTaEiOn of the drug product in
`‘ The combination of ”a” fifithDtGV-idc tin
`
`tiw-container is acinevcd h) the
`,
`M
`
`Active
`
`,
`
`
`
`'
`
`'
`
`
`
`
`
`
`
`Reviewer’s Comments:
`
`The Travatan Zformulation contains the same active ingredient in the same concentration
`previously approved in Alcon ’s Travatan (travoprost ophthalmic solution) 0.004% (NDA 21-
`572). The preservative benzylkonium chloride (BAC) has been removed.
`~
`
`2.2 Currently Available Treatment for Indications
`
`There are currently available numerous topical treatments for open angle glaucoma and ocular
`hypertension either as first or second line therapy These treatments include Beta--adrenergic
`antagonists (beta-blockers) Adrenergic agonists, Parasympathomimetic (miotic) agents,
`Carbonic anhydrase inhibitors and Prostaglandin analogues.
`
`2.3 Availability of Proposed ActiVe Ingredient in the United States
`
`Travoprost[S the active ingredient1n the currently approved product Travatan (travoprost
`ophthalmic solution 0004%)
`
`010
`
`010
`
`

`

`Clinical Review
`
`Martin P. Nevitt, M.D., MPH.
`NDA 21-994; N-OOO
`,
`Travatan Z (travoprost ophthalmic solution) 0.004%
`
`
`
`
`'
`
`'
`
`Same
`
`The following table provides a comparison of the previously approved formulation of Travatan
`(travoprost ophthalmic solution, 0.004%) with Travatan Z '(travoprost ophthalmic solution,
`0.004%).
`.Comgarison of Compo_sitions of Travatan Z and Travatan
`
`Component -
`% of Com 0 osition
`
`
`
`Travatan Z
`
`
`Travoprost
`0.004
`
`Benzalkonium Chloride
`—
`
`i
`
`'
`
`“I
`
`HCO-40
`
`Boric Acid
`
`Disodium Edetate
`Zinc Chloride
`
`' Tromethamine
`
`Sorbitol
`
`Mannitol
`
`Propylene Glycol
`Sodium Hydroxide
`and/or
`
`Hydrochloric Acid
`
`
`
`
` Purified Water - u . 2
`
`
`
`
`
`Reviewers’ comments:
`
`The clinical studyforming the basis ofthis NDA, is a bioequivalence trial that compared
`Travatan (travoprost ophthalmic solution, 0.004%) with Travatan Z (travoprost ophthalmic
`solution, 0.004%).
`
`In addition to removal ofbenzalkonium chloride (BAC), theformulation was modified to remove
`disodium edetate (EDTA) and mannitol and to include propylene glycol, zinc chloride and
`
`sorbitol. The concentration ofboric acid is also
`from wefimwana. Savefor the
`absence ofBAC, the changes are considered relatively minor, relate to known excipients of
`ophthalmic preparations, and do not pose a concern with regard to ocular toxicity or local
`tolerance.
`
`2.4
`
`Important Issues With Pharmacologically Related Products
`
`There have been no additional safety issues raised with this class of agents outside of those
`identified in this review.
`
`In an effort to maintain effective [OP reduction while enhancing tolerability, Travatan Z
`ophthalmic solution has been developed. This new formulation will provide improved
`tolerability for those patients who are intolerant of benzalkonium chloride (BAC) used in
`ophthalmic medications.
`
`'
`
`10
`
`011
`
`011
`
`

`

`Clinical Review
`
`Martin P. Nevitt, M.D., M.P.H.
`NDA 21-994; N-OOO
`Travatan Z (travoprost ophthalmic solution) 0.004%
`
`
`Reviewer’s comments:
`
`The class efi’ectsfor the prostaglandin analogues, including travoprost ophthalmic solution,
`0.004% have been reported to include changes to pigmented tissues. The mostfrequently
`reported changes have been increased pigmentation 0fthe iris and the periorbital tissue (eyelid)
`and increased pigmentation and growth ofeyelashes. These changes may be permanent.
`
`2.5 Presubmission Regulatory Activity
`
`The protocol for study C-04-l7 was submitted to the FDA in July 2004 for Special Protocol
`Assessment to confirm the appropriateness of the clinical study design, analysis plan, selection
`of comparative agent and total number of patients to be included in the study.
`
`Based on this review the following changes to the study protocol and/or agreements were made:
`
`0 The Division agreed that Travatan would be an appropriate control group
`I The Division agreed that 300 patients per treatment arm followed for 3 months would be
`an adequate number of patients to support the efficacy and safety of Travantan Z
`(Travatan BAC—free)
`g
`_
`..
`-.
`,
`0 The Division recommended patients with particularly thick corneas be excluded because
`applanation tonometry may not accurately reflect changes in intraocular pressure in these
`patients (with pachymetry measurements included at baseline exam)
`0 Endothelial cell density measurements were added at baseline and exit at selected sites
`
`2.6 Other Relevant Background Information
`
`The sponsor has not submitted any international labeling regarding approval or pending approval
`for Travatan Z.
`
`3
`
`SIGNIFICANT FINDINGS FROM OTHER REVIEW DISCIPLINES
`
`3.1 CMC (and Product Microbiology, if Applicable)
`
`NDA 21-994 is recommended for approval pending CMC review.
`
`3.2 Animal Pharmacology/Toxicology
`
`In nonclinical studies, the formulation Travatan Z showed a similar toxicity profile as the
`marketed formulation Travatan. The drug product showed a low irritation potential when
`administered topically to the rabbit eye. Studies with impurities including meand ' _ WW
`showed no biologically relevant toxicity.
`
`11
`
`012
`
`012
`
`

`

`Clinical Review
`
`Martin P. Nevitt, M.D., MPH.
`NDA 21-994; N—OOO
`Travatan Z (travoprost ophthalmic solution) 0.004%
`
`
`The NDA is approvable from a nonclinical perspective.
`
`4
`
`DATA SOURCES, REVIEW STRATEGY, AND DATA-INTEGRITY
`
`4.1 Sources of Clinical Data
`
`The submitted clinical study report and protocol for study C-04- l 7 and relevant literature reports
`were reviewed. The submitted study report forms the basis for the majority of this application.
`
`The application was submitted in paper and electronic format.
`
`A PubMed electronic literature search‘wasperformed to supplement the review, and no new
`information was found.
`
`Appears This Way
`On Original
`
`12
`
`013
`
`013
`
`

`

`Clinical Review
`
`Martin P. Nevitt, M.D., MPH.
`NDA 21-994; N—OOO
`Travatan Z (travoprost ophthalmic solution) 0.004%
`
`42' Tables of Clinical Studies
`
`Phase 3 Glaucoma/Ocular Hypertension Study
`Utilized in MD. Safety and Efficacy Review
`
`Study
`Study
`Study
`# Patients Dura-
`MIF
`Diagnosis
`Safety
`Design
`Treat-
`Objective
`by arm
`tion of
`Inclusion
`Variables
`ment
`treat—
`mean
`Criteria
`ment
`age
`(range)
`
`Type
`
`
`
`
`
`
`
`
`
`
`
`48
`centers
`-
`USA
`
`Study
`Period
`
`Total
`Enrollment
`[Target
`Enrollment
`Oct. 2004 to
`June 2005
`
`Total
`enrollment
`N=690
`
`Target
`enrollment
`N=600
`'
`
`Patients :
`18 yrs. Of
`either sex
`and of any
`race
`diagnosed
`with open
`angle
`glancoma
`(with or
`without
`pseudoex-
`foliation
`or
`pigment
`dispersion
`com pon-
`em) or
`confirmed
`ocular
`hyper-
`tension
`
` .M'
`M = Male, F = Female; yrs = years, IOP = intraocular pressure
`
`Randomiz
`-ed, multi-
`center,
`double-
`masked,
`parallel,
`active
`control
`
`
`Travatan
`BAC-free
`(Travatan
`Z)
`
`
`
`
`Travatan
`
`Compare
`the safety
`and [OP-
`lowering
`efficacy
`of
`Travatan
`BAC—free
`to
`Travatan
`in patients
`with
`open-
`angle
`glaucoma
`or ocular
`hyperten-
`sion
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`3
`months
`
`Travatan
`BAC-free
`N=344
`
`Travatan
`N=346
`
`\
`
`Race
`M 320
`
`F 370
`56.8%
`
`63. l
`yrs.
`(18—94)
`
`Extent of
`exposure,
`adverse
`events,
`visual
`acuity,
`ocular
`signs,
`ocular
`hyperemia,
`dilated
`fundus,
`automated
`perimetry,
`endothelial
`cell density
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reviewer’s Comments:
`
`The design ofthe clinical trial and the number ofcenters is acceptable.
`
`4.3 Review Strategy
`
`The submitted clinical study report and protocol for study C-04- l 7 and relevant literature reports
`were reviewed. The submitted study report forms the basis of this application.
`
`The entire application was submitted in electronic and paper format.
`
`4.4 Data Quality and Integrity
`
`The medical officer has reviewed all Case Report Forms for discontinued subjects in study C-04—
`17. There were no problems noted with data quality and integrity.
`
`13
`
`L 014
`
`014
`
`

`

`Clinical Review
`
`Martin P. Nevitt, M.D., MPH.
`NDA 21 -994; N-000
`Travatan Z (travoprost ophthalmic solution) 0.004%
`
`4.5 C