CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`21-023
`
`MEDICAL REVIEW(S)
`
`
`
`1
`
`ALL 2078
`MYLAN PHARMACEUTICALS V. ALLERGAN
`IPR2016-01132
`
`1
`
`ALL 2078
`MYLAN PHARMACEUTICALS V. ALLERGAN
`IPR2016-01132
`
`

`

`
`
`Medical Officer’s Review of NDA 21-023
`Amendment
`
`NDA. 21-023
`
`Submissions:
`
`December 20, 2002
`
`Medical Officer’s Review #9
`
`Review Completed: December 23, 2002
`
`Proposed Tradename:
`
`Restasis
`
`Generic Name:
`
`Sponsor:
`
`Cyclosporine ophthalmic emulsion, 0.05%
`
`Allergan,Inc.
`2525 Dupont Drive
`P.O. Box 19534
`{rvine, CA 92623-9534
`
`Pharmacologic Category:
`
`immunomodulator
`
`ProposedIndication:
`
`Dosage Form and
`Route of Administration:
`
`Reviewer’s Comments:
`
`ophthalmic emulsionfor topical ocular
`administration
`
`Revisedlabeling based onprevious review, discussion with the applicant, discussion
`between ODEDand the Division, and a correctedpackageinsert transmitted bythe
`applicant on December 20, 2002.
`
`The applicant proposes inserting the word “topical” before “anti-inflammatory” in the
`Chnical Evaluations andIndications and Usage sections ofthe label
`
`This is acceptable.
`
`2
`
`

`

`/0
`
`Draft Labeling Page(s) Withheld
`
`3
`
`

`

`
`
`Recommendations:
`
`{t is recommended that NDA 21-023 be approved with the labeling revisions listed in this
`review.
`
`The application supports the safety and effectiveness of Restasis (cyclosporine
`ophthalmic emulsion) 0.05% to increase tear production in patients whose tear production
`is presumed to be suppressed due to ocular inflammation associated with
`keratoconjunctivitis sicca.
`
`There are no recommendationsfor additional postmarketing studies.
`
`William M. Boyd, M.D.
`Medical Officer
`
`NDA 21-023
`HFD-550/Div Files
`HFD-550/MO/Boyd
`HFD-550/Dep Director/Chambers
`HFD-725/Stat/LuHo
`HFD-805/Micro/Riley
`HFD-550/Chem/Tso
`HFD-550/Chem TL/Ng
`HFD-550/PM/Gorski
`HFD-550/PharmTox/Mukherjee
`HFD-550/Pharm Tox TL/Yang
`HFD-880/ Biopharm TL/Bashaw
`
`Medical Officer’s Review of NDA 21-023 Amendment: cyclosporine ophthalmic emulsion 0.05%
`Review #9
`
`4
`
`

`

` Reeeeeenennenaneeeeee Beeneeeeeeeeeeene2esereeeeeeeeeeeeenseeeeeeeeeenenaee
`
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`/s/
`
`William Boyd
`12/23/02 10:27:00 AM
`MEDICAL OFFICER
`
`Wiley Chambers
`12/23/02 03:29:14 PM
`MEDICAL OFFICER
`
`
`
`
`
`5
`
`

`

`Medical Officer’s Review of NDA 21-023
`Amendment
`
`NDA21-023
`
`Submissions:
`
`September7, 2001
`April 23, 2002
`June 17, 2002
`July 11, 2002
`September6, 2002
`November 15, 2002
`December 16, 2002
`
`Medical Officer’s Review #8
`
`Review Completed: December 19, 2002
`
`Proposed Tradename:
`
`Restasis
`
`Generic Name:
`
`Cyclosporine ophthalmic emulsion, 0.05%
`
`Sponsor:
`
`Allergan,Inc.
`2525 Dupont Drive
`P.O. Box 19534
`_ Irvine, CA 92623-9534
`
`Pharmacologic Category:
`
`unmunomedulator
`
`Proposed Indication:
`
`Dosage Form and
`Route of Administration:
`
`Reviewer’s Comments:
`
`ophthalmic emulsion for topical ocular
`administration
`
`Revised labeling is based onfurther discussion within the Division on December 19,
`2002, regarding the Clinical Pharmacology, Clinical Evaluations, and Indication and
`Usage sections and subsectionsofthe labeling.
`
`
`
`6
`
`

`

`10
`
`Draft Labeling Page(s) Withheld
`
`7
`
`

`

`Recommendations:
`
`It 1s recommended that NDA 21-023 be approved with the labeling revisions listed in this
`review,
`
`The application supports the safety and effectiveness of Restasis (cyclosporine
`
`ophthalmic emulsion) 0.05%
`arerneem
`eeINeEtBeARCOaRETtNOII
`
`There are no recommendations for additional postmarketing studies.
`
`William M. Boyd, M.D.
`Medical Officer
`
`NDA 21-023
`HFD-550/Div Files
`HFD-550/MO/Boyd
`HFD-550/Dep Director/Chambers
`HFD-725/Stat/LuHo
`HFD-805/Micro/Riley
`HFD-550/Chem/Tso
`HFD-550/Chem TL/Ng
`HFD-550/PM/Gorski
`HFD-550/PharmTox/Mukherjee
`HFD-550/Phann Tox TL/Yang
`HFD-880/ Biopharm TL/Bashaw
`
`Medical Officer’s Review of NDA 21-023 Amendment: cyclosporine ophthalmic emulsion 0.05%
`Review #8
`
`8
`
`

`

` SeeennSeseeeHeeeeDOEEEESEEES CoNyeRRSOAROROESRSSCSEEESSOSESSNSEEEE BSEeaseensTeeeeReRRs eeeene
`
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`eeeeeeeeenaeeee8eeeeeeeeeReneEsweeSereROEeeeeeeneneeeee Aeneannennerore Seenena
`
`/s/
`
`William Boyd
`12/20/02 02:42:36 PM
`MEDICAL OFFICER
`
`Wiley Chambers
`12/20/02 03:26:37 PM
`MEDICAL OFFICER
`
`9
`
`

`

`
`
`Medical Officer’s Review of NDA 21-023
`Amendment
`
`NDA 21-023
`Medical Officer’s Review #7
`
`December 16, 2002
`Submissions:
`Review Completed: December 16, 2002
`
`Proposed Tradename:
`
`Restasis
`
`Generic Name:
`
`Sponsor:
`
`Cyclosporine ophthalmic emulsion, 0.05%
`
`Allergan, Inc.
`2525 Dupont Drive
`P.O. Box 19534
`Irvine, CA 92623-9534
`
`Pharmacologic Category:
`
`immunomodulator
`
`Proposed Indication:
`
`Dosage Form and
`Route of Administration:
`
`Submitted:
`
`
`
`. ophthalmic emulsion for topical ocular
`administration
`
`Revised labeling based on previous review, discussion with the applicant, and a clean-
`corrected package insert transmitted by the applicant on 12/16/02.
`
`Reviewer’s Comments:
`
`Two labeling comments appearing in the Chemist's review, dated 12/13/02 12:12:56 PM
`in DFS, were not includedin thefinal drugproduct labeling.
`
`1) Under Description, “The amount as —~ , should replace 0.05%for cyclosporine.”
`
`The proportion ofthe active ingredient, cyclosporine, is acceptable per CFR 201.100
`(B)(4).
`
`2) Under How Supplied, “The word vial should be replaced by --—— asthelatter is the
`description for a sealed container as per C-DRR-00907, Package Type, CDER Data
`Standards Manual.”
`
`Disagree. Per the CDER Data Standards manual, the proposed single-use LDPE
`containeris a vial ("‘A container designedfor use with parenteral drug products”).
`
`10
`
`
`
`10
`
`

`

`Sf Draft Labeling Page(s) Withheld
`
`11
`
`

`

`Recommendations:
`
`st‘
`
`U-023
`It is recommended that NDA ~~_be approved with the labelingrevisionslisted in this
`review.
`
`
`
`The application supports the safety and effectiveness of Restasis (cyclosporine
`
`ophthalmic emulsion) 0.05%
`
`There are no recommendationsfor additional postmarketing studies.
`
`William M. Boyd, M.D.
`Medical Officer
`
`NDA 21-023
`HFD-550/Div Files
`HFD-550/MO/Boyd
`HFD-550/Dep Director/Chambers
`HFD-725/Stat/LuHo
`HFD-805/Micro/Riley
`HFD-550/Chem/Tso
`HFD-550/Chem TL/Ng
`HFD-550/PM/Gorski
`HFD-550/PharmTox/Mukherjee
`HFD-550/Pharm Tox TL/Yang
`HFD-880/ Biopharm TL/Bashaw
`
`Medical Officer’s Review of NDA 21-023 Amendment: cyclosporine ophthalmic emulsion 0.05%
`Review #7
`
`12
`
`12
`
`

`

`etererrrnn 2SEeereeeEeeeESSEESFOOeeeeEeOEEeeeeneSeeeenaseneeeeseeeeeeeeeee
`
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`{sf
`
`William Boyd
`12/16/02 02:33:44 PM
`MEDICAL OFFICER
`
`Wiley Chambers
`12/16/02 02:54:09 PM
`MEDICAL OFFICER
`
`13
`
`

`

`—__|
`
`
`
`Proposed Indication: ELIEENOTCRte
`aleeee
`
`=e
`
`Medical Officer’s Review of NDA 21-023
`Office of Drug Safety Consultation
`
`NDA21-023
`
`Submission:
`
`December 11, 2002
`
`Medical Officer’s Review #6
`
`Review Completed: December 11, 2002
`
`Proposed Tradename:
`
`Restasis
`
`Generic Name:
`
`Sponsor:
`
`Cyclosporine ophthalmic emuision, 0.05%
`
`Allergan,Inc.
`2525 Dupont Drive
`P.O. Box 19534
`irvine, CA 92623-9534
`
`Pharmacologic Category:
`
`immunomodulator
`
`Dosage Form and
`Route of Administration:
`
`Submitted:
`
`ophthalmic emulsionfor topical ocular
`administration
`
`Submitted is a Office of Drug Safety memorandum in response to a November 19, 2002
`request from the Division of Anti-inflammatory, Analgesic, and Ophthalmologic Drug
`Products for a re-review of the proprietary name, Restasis.
`
`In responseto 4 previous consultation to the Office of Post-Marketing Dnig Risk
`Assessment (response received August 28, 2000), OPDRA stated it had no objections to
`the use of the proprietary name, Restasis. Recommendationsfor labeling revisions were
`made to minimize potential errors with the use of this product.
`
`Office of Drug Safety Comments:
`
`Based upon review ofthe revised package insert labeling, DMETSacknowledgesthat
`packaging the productin single-use containers and labeling them as single-use addresses
`the concern surrounding the9-“"""~------- described in Appendix A (A.2.a. and
`A.2.b.). However, it appears that 0.4 mL is more than the amount neededfor a single
`dose. The estimated volume required for two drops based on 15-20 drops per milliliter
`is 0.1 - 0.13 mL. Therefore, there is a risk that patients may save the vial and use the
`remaining drugin the interest of saving money. The risks of using the drug beyond the
`single dose needs to be clearly communicated to practitioners, patients and caregivers
`
`14
`
`14
`
`

`

`
`
`if Qf
`
`especially since the product does not contain a preservative. Another way to minimize
`this risk is to use the least amountofoverfill beyond the volume neededfor two drops.
`Additionally, if space permits, we recommendthat the terminology—~—_ee—eanm
`~~ be added to the labels and labeling.
`
`Medical Officer’s Comments:
`
`Single-use, unpreserved topical ophthalmic drug products uniformly contain a volume
`exceeding the amount neededfor a single dose (including overfill).
`
`Becauseofthe material properties ofthe LDPE vial, this additional volumeassists the
`patient in administering the correct amountofdrug product. The additional volumeis
`also requiredfor product stability.
`
`With every single-use, unpreserved productthereis the risk that patients may save the
`vial and use the remaining drug at a later time. The risks of using the cyclosporine
`ophthalmic emulsion single-use vial beyond the single dose is adequately communicated
`fo practitioners, patients and caregivers within the Restasis package insert:
`
`The emulsion from one individualsingle-use vial is to be used immediately after
`opening for administration to oneor both eyes, and the remaining contents should
`be discarded immediately after administration.
`
`Do notallow the tip of the vial to touch the eye or any surface,as this may
`contaminate the emulsion.
`
`The Restasis tray label is marked © ._--rs-wewnmncenomennennpertcntcite PO
`Ores ees
`
`encnncmennnent TACaeteIS marked ' wae
`
`
`
`elMaharLATASAAtttary‘Both fray label and.TSE _ ERRORCERr
`indicate the drug productis
`-—~
`(erences
`
`Office of Drug Safety Comments:
`
`Since the initial review, DMETSidentified two additional proprietary names with
`potential for confusion with Restasis since we conducted our initial review. However,
`DMETSdoesnotanticipate that these product names will cause confusion in the US
`marketplaceat this time.
`
`Medical Officer’s Comments:
`
`Agree.
`
`Office of Drug Safety Comments:
`
`Regarding consultation Appendix A (Labeling, Packaging and Safety Related Issues from
`Initial ODS (OPDRA) Consult:
`‘
`
`Medical Officer’s Review of NDA 21-023: cyclosporine ophthalmic emulsion 0.05%
`Review #6
`
`15
`
`
`
`15
`
`

`

`eeewe eeaee eewee Beeeeles Bee BereeESSESNeEreseeeORRBESSOne ESESETReHS Fae EeeRees ERNERennSESeS
`
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`eeeweeeeees Be Fenneeeenee een eeeeROREEeeEES BEESeeHrEee OReeeeee een eeeSeesee eee weeeeeeeesseees
`
`Wiley Chambers
`12/23/02 05:06:41 PM
`
`
`
`16
`
`

`

`Wehave safety concerns with the packaging of this productin a low-density
`polyethylene (LDPE) container. In particular, these concernsrelate to the labelingthat
`appears on the flange. This labeling should be clear anddistinctive, since this type of
`packagingis being utilized in the manufacturing of other drug products. We also
`recommend that the =esince the productwill
`be loosely stored in bins within the institutionalsetting.
`
`Someof the products that are packagedin a like fashion include nonprescription
`ophthalmic lubricantsand are utilized by the samepatient population. These products
`include the following: AquaSite, Bion Tears, Celluvisc, Hypo Tears PF, Preservative
`Free Moisture Eyes, Refresh, Refresh Plus, OcuCoat PF, and Tears Natural Free. The
`possibility exists for a patient or health care provider to confuse one product with the
`other. The patient would then receive an underdose or overdose of Restasis in the
`process.
`
`Confusion between other non-ophthalmic products on the market in the U.S. that are
`packaged in LDPEcontainers has been documented in numerousreports to the FDA.
`These products are generally pulmonary inhalation solutions from various manufacturers
`and include the following generic substances: albuterol sulfate 0.083% inhalation
`solution, sodium chloride inhalation solution, andipratropium bromide 0.02% inhalation
`solution. Although the volumeof these products is generally larger (2.5 to 3 mL) than
`the single-use ophthalmic droppers proposed for Restasis (0.4 mL),it is possible that
`these products could be confused with Restasis, or vice versa.
`
`Medical Officer’s Comments:
`
`The LDPE vial will be
`—
`
`°
`
`with,
`
`‘
`
`. a
`
`The proposed labeling on the Restasis vial is clear and distinctive. The proposed
`packaging of the tray andphysician sample cartonis clear and distinctive.
`
`Unlike the nonprescription ophthalmic lubricants packagedin a likefashion, Restasis is
`a white, opaque emulsion. There is no perceived additionalrisk to the indicated
`populationfrom the use ofa nonprescription ophthalmic lubricant. Based on the safety
`profile ofRestasis, there is no perceived safety riskfrom the inadvertentuse ofRestasis in
`the population utilizing nonprescription ophthalmic lubricants.
`
`The volume andpackaging ofnon-ophthalmic products on the marketin the U.S. is unlike
`the proposedpackaging ofthe Restasis vial, carton, or tray. Again, the proposed
`labeling on the Restasis vial is clear and distinctive; the proposedpackaging ofthe tray
`andphysician sample carton is clear and distinctive.
`
`Medical Officer’s Review of NDA 21-023: cyclosporine ophthalmic emulsion 0.05%
`Review #6
`
`17
`
`17
`
`

`

`
`
`BS
`
`The phrase “
`* is quite restrictive and could be confusing to the user.
`Someclarification should be provided regarding the followingissues.
`
`How many dosesor dropswill each vial deliver? If more than two drops are
`deliverable, then the statement above seems to imply that
`.————
`
` Ararest
`oo
`. ed
`rateee
`Se meTe areAIRth auguriA
`wane tage
`_ according to the statement above,if strictly adhered to by the
`User.
`
`Medical Officer’s Comments:
`
`
`
`The phrase‘
`is no longerfoundin the packageinsert, Restasis vial,
`it has been replaced, where appropriate with‘ ~~~
`tray or.Te
`rrr eee, These phasesare
`intentionally more restrictive than <nuenmmemmnn,
`
`In the interest of economy and conserving the drug product, it also seemslikely
`that a patient be will inclined to use the remainderofthe dropper, if the dosingis
`close to a 12-hour interval. Given the nature of cyclosporin (sic) therapy in an
`ophthalmic, preservative-free solution, can a local infection result from droppers
`used within, for example, 13 hours? Because the stated time to expiration of the
`product is the same asthe dosing interval, significant confusion and misuse seem
`likely.
`
`Medical Officer’s Comments:
`
`Again, with every single-use, unpreservedproduct thereis the risk that patients may save
`the vial and use the remaining drug ata later time. Therisks ofusing the c'yclosporine
`ophthalmic emulsion single-use vial beyond the single dose is adequately communicated
`{0 practitioners, patients and caregivers within the Restasis packageinsert:
`
`The emulsion from one individual single-use vial is to be used immediately after
`opening for administration to one or both eyes, and the remaining contents should
`be discarded immediately after administration.
`
`Do notallow thetip of the vial to touch the eye or any surface, as this may
`contaminate the emulsion.
`
`* wLenee ®. .
`
`
`
`See previous comment regarding
`“"—
`_-.
`
`
`
`The Restasis tray label is marked “-—-—_” and“ —-———
`
`” The.
`“
`‘smarked ‘7
`
`a
`* Both tray label ana _—_
`_.___ indicate the drug productis=———"~
`
`
`
`Medical Officer’s Review of NDA 21-023: cyclosporine ophthalmic emulsion 0.05%
`Review #6
`
`18
`
`18
`
`

`

`Wehave someconcerns with the description of this package as a “vial”.
`
`Medical Officer’s Comments:
`
`Per the CDER Data Standards manual, the proposed single-use LDPE containeris a
`vial.
`
`The
`
`
`;
`-
`
`) is absent from the vial label (see 2] CFR 201.51).
`
`Medical Officer’s Comments:
`
`The containeris a single-use vial, meant to deliver a single to drop to each eye.
`
`—_—————"T Statement to read: “OOo
`Onthe tray label, revise
`eel
`
`Medical Officer’s Comments:
`
`In the clinicaltrials performed by the applicantin support ofthe efficacy and safety of
`the drug product, dosing took place approximately 12 hours apart.
`sfe
`This reviewer does not agree that the suggested revision to the
`appropriate.
`
`ums”mmcnmnmensoiS
`
`Wesuggest substitution of the word “-— ‘for the Greek “pL”, as p[L]is frequently
`mistaken for m{L}, particularly with scripted instructions.
`
`Medical Officer’s Comments:
`
`
`
`This reviewer does not agree that the suggested substitution ofthe word “——~‘for the
`Greek “pL”is appropriate. There could be no substitution ofRestasis witha —
`concentration since none exits.
`
`Topical ophthalmic prostaglandins are expressed in microliter concentrations with
`
`Under How Supplied, delete the phrase “fill in 0.9 mL LDPEvial”, as inclusion of the
`empty container size frequently creates confusion over the actual contents and has
`resulted in medication errors on numerous occasions.
`
`Medical Officer’s Comments:
`
`The How Supplied section ofthe labeling accurately describes the packaging ofthe
`product:
`
`Medical Officer’s Review of NDA 21-023: cyclosporine ophthalmic emulsion 0.05%
`Review #6
`
`19
`
`19
`
`

`

`
`
`RESTASIS™is packaged in single use vials. Each vial contains 0.4 mLfill in a
`0.9 mL LDPEvial; 32 vials are packaged in a polypropylene tray with an
`aluminum peelable Sid.
`
`All topical prescription ophthalmic products are similarly described. Since the LDPE
`vial is a sealed containerfor single-use, it is unclear how confusion over its contents
`could result in a medication error.
`
`Recommendations:
`
`It is recommended that NDA 21-023 be approved with the labeling revisionslisted in this
`Medical Officer’s Review#5 dated December 1, 2002.
`
`The application supports the safety and effectiveness of Restasis (cyclosporine
`nceso
`ophthalmic emulsion) 0.05%
`netUOmapeetesanastRIAIAS atte
`
`*an
`
`There are no recommendations foradditional postmarketing studies.
`
`
`
`William M. Boyd, M.D.
`Medical Officer
`
`NDA 21-023
`
`HFD-550/Div Files
`HFD-550/MO/Boyd
`HFD-550/Dep Director/Chambers
`HFD-725/Stat/LuHo
`HFD-805/Micro/Riley
`HFD-550/Chem/Tso
`HFD-550/Chem TL/Ng
`HFD-550/PM/Gorski
`HFD-550/PharmTox/Mukherjee
`HFD-550/Pharm Tox TL/Yang
`HFD-880/ Biopharm TL/Bashaw
`
`Medical Officer’s Review of NDA 21-023: cyclosporine ophthalmic emulsion 0.05%
`Review 46
`
`20
`
`20
`
`

`

`
`
`wae eeeweeeeeeaerasereneeseeeneeeeeeneeneeneseSESESeeSeeBaeeeebenoFSEEREEESReeeereeERsHwebeneeeeee
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`PRReeneenaReeeeeeeee8eeennReteneeeereeeeeenebeneenreneeneeeeeeens enews eee eeeeee
`
`/s/
`
`William Boyd
`12/13/02 04:29:39 PM
`MEDICAL OFFICER
`
`Wiley Chambers
`12/16/02 02:42:39 PM
`MEDICAL OFFICER
`
`a1
`
`
`
`21
`
`

`

`Medical Officer’s Review of NDA 21-023
`Amendment and
`Safety Update
`
`NDA 21-023
`
`Submissions:
`
`September 7, 2001
`April 23, 2002
`June 17, 2002
`July 11, 2002
`September6, 2002
`November 15, 2002
`
`Medical Officer’s Review #5
`
`Review Completed: December 13, 2002
`
`Proposed Tradename:
`
`Restasis
`
`Generic Name:
`
`Sponsor:
`
`Cyclosporine ophthalmic emulsion, 0.05%
`
`Allergan, Inc.
`2525 Dupont Drive
`P.O. Box 19534
`‘Irvine, CA 92623-9534
`
`Pharmacologic Category:
`
`immunomodulator
`
`
`
`atenrnpeeeaent
`Proposed Indication:
`
`Dosage Form and
`Route of Administration:
`
`Submitted:
`
`Oetenants
`
`ophthalmic emulsion for topical ocular
`administration
`
`Responses dated September7, 2001, April 23, 2002, June 17, 2002, July 11, 2002,
`September 6, 2002, and November 15, 2002,to itemsidentified in the approvable letter
`dated March 25, 2000, for NDA 21-023 Restasis (cyclosporine ophthalmic emulsion)
`0.05%.
`
`Submitted in the November 15, 2002 submission is a revised draft labeling, revised
`annotated labeling, and safety updates for Studies 192371-005, 192371-501, and 192371-
`503.
`
`22
`
`22
`
`

`

`
`
`
`TABLE OF CONTENTS
`
`Overview of the Sponsor’s Clinical Response
`
`Validation of the Clinical Relevance of the Clinical Sign
`
`Page 2
`
`Page 3
`
`Page 5
`Page 6
`
`Page 7
`
`Page 15
`
`Responder Analyses
`
`Safety Update
`
`Labeling
`
`Conclusions
`
`
`
`Recommendations
`
`Page 16
`
`Overviewof the Sponsor’s Clinical Response:
`
`This response presents study data from an analysis of the two Phase 3 studies 192371 -002
`and 192371-002 in support of NDA approval. The analysis is for patients who achieved
`an increase in Schirmer wetting scores of = 10 mm atthe six-month timepoint.
`
`Also submitted, at the agency’s request, is a responderanalysis of Allergan study
`192371-501 (Europe) and Allergan study 192371-503 (Europe).
`
`Validation ofthe clinical relevance ofthis clinical sign (increase in Schirmer wetting
`scores of > 10 mm at the six-month timepoint) is provided.
`
`eHigudNOWISsaaAyaSiBLS
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`Medical Officer’s Review of NDA 21-023 Amendment: cyclosporine ophthalmic emulsion 0.05%
`Review #5
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`Validation of the Clinical Relevance of the Clinical Sign:
`
`The sponsor has reviewed available databases to validate clinical relevance of proposed
`clinical sign (increase in Schirmer wetting scores > 10 mm atthe six-month timepoint).
`Per the sponsor, subjects with lower Schirmer scores have moredisability due to dry eye
`and more ocular surfacestaining.
`
`These databases included the Henry Ford Heath System validation study of the OSDI
`(Ocular Surface Disease Index), Allergan study 192371-501 (Europe), and Allergan study
`192371-503 (Europe).
`
`Table i: Validation — Schirmer Score as Clinically Relevant Endpoint
`
`192371-503"
`
`
` OSDI symptom_
`
`
`
`0.24 aie 0.013
`' OSDI overall
`score
`
`
`
`
`analyses performed on data obtainedatsingle visit
`analyses performed ondata obtained at week 24
`
`i subscale
`
`7 ~
`
`°
`
`Reviewer’s Comments:
`
`Both the OSDI symptom subscale and the OSD] overallscorearestatistically
`significantly lower in subjects with Schirmer wetting scores of211 mm. There are also
`statistically significantly lower cornealstaining scores in subjects with Schirmer wetting
`scores of > 11 mm.
`
`
`
`
`
`0.25, 0.16
`
`-0.32, 0.15
`
`-0.26,-0.03)
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`Medical Officer’s Review ofNDA 21-023 Amendment: cyclosporine ophthalmic emulsion 0.05%
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`Table 2: Correlation coefficients with confidence intervals for validation analyses on
`HFHSand 192371-503
`
`
`
`
`HFHS(OSDI)
`192371-503
`
`
`Group 2
`Group 3
`Group 2
`6-10
`211
`6-10
`
`
`
`N=28
`N=89
`N=69
`
`
`Group 3
`2H
`N=47
`
`
`
`
`
`
`
`-0.56, 0.15
`-0.54, 0.33
`subscale
`-0.060
`-0.303
`OSDIoverall
`
`
`score (-0.66, 0.16)|(-0.42, 0.32)|(0.21, 0.21
`
`(0.33, 0.14)|(-0.27, -0.02)
`
`
`Corneal Staining
`-0.332
`
`-0.68, 0.13)|(-0.38, 0.37)|(-0.28, 0.13
`-0.24, 0.23
`-0.43, 0.13
`
`
`
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`

`

`Reviewer’s Comments:
`
`Noneof the submitted correlation coefficients approach | (or --1), and based on the
`confidenceintervals provided, veryfew ofthe coefficients reach statistical significance.
`
`Table 3 summarizesadditional analyses from the sponsor showing the percentage of
`subjects with a cormeal staining score of 0, grouped by absolute values of Schirmer, in the
`ITY population excluding ocular anti-inflammatory drugs and puncta! plugs for 192371-
`002, -003, -501, -503.
`
`If an increase in Schirmer score above 1! min wereclinically relevant, these groups
`should show less ocular surface staining in 192371-002, -003, -501, -503.
`
`[Note: responders here are patients who achieved an increase in Schirmer wetting scores
`2 10 mm at the six-month timepoint.]
`
`Table 3: Corneal Staining at Month 6
`Percent of Patients with a Corneal Staining Score of Zero
`
`
`
`¥92371-002
`
`192371-003
`
`
`Group11|Group 2|Group 3
`Corneal Staining
`Group ||Group 2|Group 3|p-value
`
`
`<se 6-10
`f-
`<5mmn_
`*~
`
`
`
`
`
`3% 1%)
`
`
`0.022
`|
`
`_|
`
`
`
`16
`(28%)
`
`57
`id
`
`Group I|Group 2 Group 3 | p-value
`
`< 5mm 6-10
`
`103__
`53
`2.0
`1.2
`
`16
`17
`
`(16%)|(32%) | (41%)
`
`responder analysisiis the number(percent) ofpatients with a comealstaining score of 0 at month 6
`
` 192371-503__
`
`
`
`Reviewer’s Comments:
`
`Threeofthe clinical trials demonstratedstatistical significance in the number
`(percentage) ofpatients with a cornealstaining score of0 at month 6 when subjects are
`grouped by absolute values ofSchirmer. The remaining trial demonstrates a trend
`favoring less corneal staining when Schirmer’s is 211 mm at month 6.
`
`[Note: responders here are patients who achieved a cornealstaining score of0 at month
`6]
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`Responder Analysis:
`
`Fable 4: Responder Analysis - Month 6 — 192371-002, -003
`
`
`192371-002 492371-003
`
`
`
`Irr 20/137}11/113|11/09 [0.14735|16/137|14/131
`
`
`
`(17%)|(0%) (12%)|(8%)
`
`
`
`TTT ~ Anti- 10/109|10/106 0.04825|15/129|11/125 0.00767
`Inflammatory Rx
`(18%)
`(9%)
`(12%)
`(9%)
`and Plugs
`Sjigrens
`
`
`
`8/37
`(22%)
`8/34
`(24%)
`
`Sjégrens - Anti-
`Inflammatory Rx
`and Plugs
`
`0.01920
`
`0.00823
`
`0.06704
`
`Reviewer’s Comments:
`
`Specific dry eye populations are identified and analyzedfor patients who achieved an
`increase in Schirmer wetting scores 2 10 mm at the six-month timepoint (responders). In
`Table 1, ail of the populations trend towards higher responder ratesfor the 0.05%
`cvclosporine treatment group.
`
`In two ofthe groups (ITT — anti-inflammatory Rx and punctal plugs and Sjégrens- anti-
`inflammatory Rx andpunctal plugs), the responder rates are statistically significant
`favoring 0.05% cyclosporine in both trials.
`
` ITT— Anti-
`
`Inflammatory Rx
`and Plugs
`
`Table 5: Responder Analysis - Month 6 — 192371-501, -503
`
`
`192371-501
`°
`""192371-503
` 0.53511
`Refresh
` 0.05%
`
`
`__cyclo
`
`11/93
`(12%)
`
`Reviewer’s Comments:
`
`The responder analyses of192371-501 and 192371-503 (Table 2) do not achieve
`statistical significancefor the specific dry eye population ITT— anti-inflammatory Rx and
`punctal plugs. The sample sizes are small.
`
`There is a trend towards higher responderrates for the 0.05% cyclosporine treatment
`groups.
`
`Although —501] and -503 analyses did not achieve statistical significance, the responder
`analyses are supportive ofthefindings in -002 and -003.
`
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`Review #5
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`a
`
`Safety Update
`
`Information contained in this safety update is comparable to previous safety information
`reviewed for the original NDA.
`
`The most common adverse event following the use of this drug product is ocular burning
`(17%). Other events reported in 1% to 5% of patients include conjunctiva! hyperemia,
`discharge, epiphora, eye pain, foreign body sensation,pruritus, stinging, and visual
`disturbance (most often blurring).
`
`Original conclusions regarding the safety of 0.05% cyclosporine ophthalmic emulsionin
`
`theanaETLPnEEAOEa are not altered.
`
`APPEARS THIS WAY
`OM ORIGINAL
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`LhoO Draft Labeling Page(s) Withheld
`
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`
`
`Conclusions:
`
`t) A chmically relevant, dry eye population (ITT — ocularanti-inflammatory Rx and
`punctal plugs) demonstratedstatistically significant differences in responderrates for
`the numberof patients who achieved an increase in Schirmer wetting scores > 10 mm
`at the six-month timepoint in 192371-002 and -003.
`
`Although —501 and —503 analyses did not achievestatistical significance, the
`responderanalyses are supportive of the findings in -002 and —003.
`
`2) Regarding validation ofthis clinical sign:
`
`Both the OSDI symptom subscale and the OSDI overall score are statistically
`significantly lower in subjects with Schirmer wetting scores of 2 11 mm im the
`validation studies. There are alsostatistically significantly lower corneal staining
`scores in subjects with Schirmer wetting scores of > 11 mm in thevalidation studies.
`
`+) Allergan has successfully demonstrated that the clinical sign (increase in Schirmer
`wetting scores > 10 mm at the six-month timepoint)is clinically relevant. Lower
`Schirmerscores seem to have more disability due to dry eye and more ocular surface
`staining.
`/
`
`+) Original conclusions regarding the safety of 0.05% cyclosporine ophthalmic emulsion
`in
`
`
`
`APPE2PS Ti10 A
`AY
`Cl ORGINAL
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`Medical Officer’s Review of NDA 21-023 Amendment: cyclosporine ophthalmic emulsion 0.05%
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`Recommendations:
`
`ft ts recommended that NDA 21-496 be approved with the labelingrevisions listed in this
`review.
`
`The application supports the safety and effectiveness of Restasis (cyclosporine
`ophthalmic emulsion) 0.05%=
`
`nettamenAAoo
`
`
`
`There are no recommendations for additional postmarketing studies.
`
`William M. Boyd, M.D.
`Medical Officer
`
`NDA 21-023
`HFD-550/Div Files
`HFD-550/MO/Boyd
`HFD-550/Dep Director/Chambers
`HFD-725/Stat/LuHo
`HFD-805/Micro/Riley
`HFD-550/Chem/Tso
`HFD-550/Chem TL/Ng
`HFD-550/PM/Gorski
`HFD-550/PharmTox/Mukherjee
`HFD-550/Pharm Tox TL/Yang
`HFD-880/ Biopharm TL/Bashaw
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`Medical Officer's Review of NDA 21-023 Amendment: cyclosporine ophthalmic emulsion 0.05%
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`oneaweeeasseeneeeeneeeeeeeeeeeeneneeeenenee8eee eeeeneeeeeeeeeeeeeeeecenaeenncen ene
`
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`10OOONeweeoeSeeSeeee80OOERESheeeeSeeeeeeeeeee Beeee ceeeeewesseeeeeneneeeeenenn nenaeensnce
`
`/s/
`
`William Boyd
`12/13/02 04:24:16 PM
`MEDICAL OFFICER
`
`Wiley Chambers
`12/16/02 02:18:24 PM
`MEDICAL OFFICER
`
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`Medical Officer’s Review of NDA 21-023
`Amendment
`
`NDA 21-023
`Medical Officer’s Review #4
`
`Submission:
`Review Completed:
`
`10/3/00
`10/5/00
`
`Proposed Tradename:
`
`Restasis
`
`Generic Name:
`
`Sponsor:
`
`Cyclosporine ophthalmic emulsion, 0.05%
`
`Allergan, Inc.
`2525 Dupont Drive
`P.O. Box 19534
`Irvine, CA 92623-9534
`
`Pharmacologic Category:
`
`Immunomodulator
`
`ProposedIndication:
`
`Dosage Form and
`Route of Administration:
`
`Submitted:
`
`Ophthalmic emulsion for topical ocular
`administration
`
`Response dated October 3, 2000, to itemsidentified in the approvableletter dated March
`25, 2000, for NDA 21-023 Restasis (cyclosporine ophthalmic emulsion) 0.05%.
`
`Sponsor’s Clinical Response Overview:
`
`This response presents study data from a keratoconjunctivitis sicca subpopulation at high
`risk for more severe disease to demonstrate that studies 192371002 and —003 are
`replicative and that 0.05% cyclosporine ophthalmic emulsionis effective.
`
`To demonstrate replication in the two Phase 3 studies and to demonstrate the efficacy of
`0.05% cyclosporine emulsion, Allergan has performed new analyses beyond the 6-month
`ITT analyses originally submitted in NDA 21-023.
`
`32
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`
`
`A clinically relevant keratoconjunctivitis sicca subpopulation consisting of two
`subgroupshas been defined:
`
`1) Sjégren’s patients and patients with other autoimmune connectivetissue diseases
`2) Women65 years of ageor older
`
`This subpopulation excludes patients with major protocol violations including the use of
`topical ocular corticosteroids.
`
`Reviewer’s Comments:
`
`Significant protocol violations included:
`
`1) prohibited diseases (severe acne rosacea, severe migraine, Grave's disease)
`2) prohibited surgeries during study
`3) use ofprohibited medicationsfor surgeries
`use ofprohibited ocular ointments, pilocarpine, ocular NSAID,beta-blocker, or
`ocular steroids.
`
`Analyses were limited to presentingthe proportionsofpatients with zero severity score
`for one sign (temporal cornealstaining) and one symptom (blurred vision) at Month 6.
`
`Description of Patients in the High-Risk Patient Subpopulation:
`
`There are nostatistically significant differences in the subpopulation demographic
`variables between treatmentgroups for age, age-by-group, sex, race, or iris color in
`studies 192371—002 and —003.
`
`Table 1 - NumbersofPatients in the High-Risk Patient Subpopulation
`
`
`
`
`
`
`Study 192371-003
`Study 192371-002
`
`Treatment Group Subpopulation|Original Intent-to- Subpopulation Original Intent-to-
`
`
`
`
`
`Treat Population
`Treat Population
`[o0s% Gamo|7|ss
`escape [TePees
`
`
`
`Acrossboth studies, 374 (43%) of the original 877 ITT patients were retained in the high-
`risk subpopulation ofpatients. This subpopulation contains less than halfof the patients
`enrolled in each study.
`
`
`
`Medical Officer’s Review of NDA 21-023 Amendment: cyclosporine ophthalmic emulsion 0.05%
`Submission dated October 3, 2000
`
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`Table 2 ~ Disease History of the High Risk Patient Subp