CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICATION NUMBER:
`
`21-023
`
`MEDICAL REVIEW(S)
`
`
`
`
`
`

`

`
`
`Medical Officer’s Review of NBA 21-023
`Amendment
`
`NDA 21-023
`
`Submissions:
`
`December 20, 2002
`
`)[edical 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
`PO. Box 19534
`
`Irvine, CA 92623-9534
`
`Pharmacologic Category:
`
`immunomodulator
`
`Proposed Indication:
`
`Dosage Form and
`Route of Administration:
`
`Reviewer’s Comments:
`
`ophthalmic emulsion for topical ocular
`administration
`
`Revised labeling based on previous review, discussion with the applicant, discussion
`between ODE V and the Division, and a correctedpackage insert transmitted by the
`applicant on December 20, 2002.
`
`The applicant proposes inserting the word ”topical " before "anti-inflammatoty ” in the
`Clinical Evaluations and Indications and Usage sections of the label.
`
`This is acceptable.
`
`

`

`*1?”— Draft Labeling Page(s) Withheld
`
`

`

`l2
`
`;_;-_—.
`
`Recommendations:
`
`It 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 recommendations for additional postmarketing studies.
`
`
`
`William M. Boyd, MD.
`Medical Officer
`
`NDA 2 1-023
`HFD—SSO/Div Files
`
`HFD-SSO/MO/Boyd
`HFD—SSO/Dep DirectorJChambers
`HFD—YES/Stat/LuHo
`
`HFD-805fMicroijley
`HFD—SSO/Chem/Tso
`
`HFD—SSOlChem TUNg
`HFD-SSO/PMfGorski
`
`HFD—SSO/PharmToxJMukherjee
`HFD-SSO/Pharm Tox "IL/Yang
`HFD-880/ Biopharm TL/Bashaw
`
`Medical Officer‘s Review ofNDA Zl-023 Amendment: cyclosporine ophthalmic emulsion 0.05%
`Review #9
`
`

`

`
`
`:2:
`
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`noon-u-..-------------------------------------------------------------------------------------------------------------
`
`William Boyd
`12/23/02 10:27:00 AM
`MEDICAL OFFICER
`
`Wiley Chambers
`12/23/02 03:29:14 PM
`MEDICAL OFFICER
`
`
`
`
`
`

`

`Medical Officer’s Review of NBA 21-023
`Amendment
`
`NDA 21-023
`
`Submissions:
`
`September 7, 2001
`April 23, 2002
`June 17‘, 2002
`
`July 1 1, 2002
`September 6, 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
`PO. Box 19534
`
`_ Irvine, CA 92623—9534
`
`Pharmacologic Category:
`
`immunomodulator
`
`Proposed Indication:
`
`Dosage Form and
`Route of Administration:
`
`Reviewer’s Comments:
`
`ophthalmic emulsion for topical ocular
`administration
`
`Revised labeling is based on further discussion within the Division on December 19,
`2002, regarding the Clinical Pharmacology, Clinical Evaluations, and Indication and
`Usage sections and subsections ofthe labeling.
`
`
`
`

`

`f/D
`
`Draft Labeling Page(s) Withheld
`
`

`

`12
`
`Recommendations:
`
`It is recommended that NDA 21-023 be approved with the labeling revisions listed in this
`review.
`
` MM“—-.,_,,_.m—..._—nm--
`The application supports the safety and effectiveness of Restasis (cvclosporinc
`
`is
`"a"'
`h
`a
`‘m'
`'
`
`ophthalmic emulsion) 0.05%W” “‘ “ '“W'”"’k
`
`There are no recommendations for additional postmarketing studies.
`
`William M. Boyd, MD.
`Medical Officer
`
`
`
`NDA 21—023
`HFD-SSO/Div Files
`
`HFD-SSO/MO/Boyd
`HFD-SSO/Dep Director/Chambers
`HFD-725/Stat/LuHo
`
`HFD-SOS/Microi’Riley
`HFD-SSO/Chem/Tso
`
`HFD—SSO/Chem TL/Ng
`HFD-SSO/PM/Gorski
`
`HFD—SSO/PharmTox/Mukherjee
`HFD-SSO/Pharm Tox "FL/Yang
`HFD—SSO/ Biopharm TL/Bashaw
`
`Medical Officer’s Review ofNDA 2103 Amendment: cyclosporine Ophthalmic emulsion 0.05%
`Review #8
`
`

`

`
`
`2-
`
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`----————-—-__-_-—_------..--—----.._.._..--—__---_-——-—_-----u------------------------------------------------------------
`
`William Boyd
`12/20/02 02:42:36 PM
`MEDICAL OFFICER
`
`Wiley Chambers
`12/20/02 03:26:37 PM
`MEDICAL OFFICER
`
`

`

`
`
`Medical Officer’s Review of NBA 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:
`
`Cyclosporine ophthalmic emulsion, 0.05%
`
`Sponsor:
`
`Allergen, Inc.
`2525 Dupont Drive
`PO. Box 19534
`
`Irvine, CA 92623-9534
`
`Pharmacologic Category:
`
`immunomodulator
`
`Proposed Indication:
`
`
`
`Dosage Form and
`Route of Administration:
`
`Submitted:
`
`I 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 '5 review, dated 12/13/02 12:12:56 PM
`in DFS, were not included in the final drug product labeling.
`
`1) Under Description, “The amount as “" J should replace 0.05% for cyclosporine.”
`
`The proportion oftlze active ingredient, cyclosporine, is acceptable per CFR 201.100
`(WM)-
`
`2) Under How Supplied, “The word vial should be replaced by 57—- as the latter is the
`description for a sealed container as per C-DRR—OO907, Package Type, CDER Data
`Standards Manual.”
`
`Disagree. Per the CDER Data Standards manual, the proposed single—use LDPE
`container is a vial ("A container designedfor use with parenteral drug products ”).
`
`
`
`

`

`L Draft Labeling Page(s) Withheld
`
`

`

`
`
`all
`
`Recommendations:
`
`{/ \
`
`1: «37.3
`
`It is recommended that NDA "" be ap'proved with the labeling revisions listed in this
`review.
`
`The application supports the safety and effectiveness of Restasis (cyclosporine
`
`Ophthalmic emulsion) 0.05%
`
`There are no recommendations for additional postmarketing studies.
`
`William M. Boyd, MD.
`Medical Officer
`
`NDA 21-023
`
`HFD—SSO/Div Files
`
`HPD—SSO/MO/Boyd
`HFD-SSO/Dep Director/Chambers
`HFD—725/Stat/LuHo
`
`HFD-SOS/Micro/Riley
`HFD-SSO/Chemfl‘so
`
`HFD-SSO/Chem 'I‘UNg
`HFD-SSO/PM/Gorski
`
`HFD-SSO/PharrnTox/Mukheijee
`HFD—SSO/Pharrn Tox TUYang
`HFD-880/ Biopharm TUBashaw
`
`Medical Officer‘s Review of NDA 21-023 Amendment: cyclosporine ophthalmic emulsion 0.05%
`Review #7
`
`
`
`

`

`---nn-u----—--Q-’---—---------------—---------------—-.-."Ifl------------------—-----------.._---------n----------
`
`This is a representation of an electronic record that was signed eiectronicaiiy and
`this page is the manifestation of the electronic signature.
`.----—-—----------—----n----——-_--_-_-_____---_--unnun-u---_------—-p---.._-—-------------—---__-—_------- .........
`
`William Boyd
`12/16/02 02:33:44 PM
`MEDICAL OFFICER
`
`Wiley Chambers
`12/16/02 02:54:09 PM
`MEDICAL OFFICER
`
`

`

`l
`
`""
`
`22;. w;
`
`Medical Officer’s Review of NBA 21—023
`
`Office of Drug Safety Consultation
`
`NDA 21~023
`
`Submission:
`
`December 1 1, 2002
`
`Medical Officer’s Review #6
`
`Review Completed: December 1 l, 2002
`
`Proposed Tradename:
`
`Restasis
`
`Generic Name:
`
`Cyclosporine ophthalmic emulsion, 0.05%
`
`Sponsor:
`
`Allergan, Inc.
`2525 Dupont Drive
`PO. Box 19534
`
`Irvine, CA 92623—9534
`
`Pharmacologic Category:
`
`immunomodulator
`
`Proposed Indication:
`
`Dosage Form and
`Route of Administration:
`
`Submitted:
`
`w- «say-WM m""““’“ an kwMwyfia an.n
`
`ophthalmic emulsion for topical ocular
`administration
`
`Submitted is 3 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 reSponse to a previous consultation to the Office of Post—Marketing Drug Risk
`Assessment (response received August 28, 2000), OPDRA stated it had no objections to
`the use of the proprietary name, Restasis. Recommendations for labeling revisions were
`made to minimize potential errors with the use of this product.
`
`Office of Drug Safety Comments:
`
`Based upon review of the revised package insert labeling, DMETS acknowledges that
`packaging the product in single-use containers and labeling them as single-use addresses
`the concern surrounding the AW described in Appendix A (A.2.a. and
`A.2.b.). However, it appears that 0.4 mL is more than the amount needed for a single
`dose. The estimated volume required for two drops based on 15-20 dr0ps per milliliter
`is 0.1 — 0.13 mL. Therefore, there is a risk that patients may save the vial and use the
`remaining drug in 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
`
`

`

`
`
`especially since the product does not contain a preservative. Another way to minimize
`this risk is to use the least amount of overfill beyond the volume needed for two drops.
`Additionally, if Space permits, we recommend that the terminology
`~—--—-—--
`..._._ 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).
`
`Because of the material properties of the LDPE vial, this additional volume assists the
`patient in administering the correct amount of drug product. The additional volume is
`also requiredfor product stability.
`
`With every single—use, unpreserved product there is 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
`to practitioners, patients and caregivers within the Restasis package insert:
`
`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 irrmrediately after administration.
`
`Do not allow the tip of the vial to touch the eye or any surface, as this may
`contaminate the emulsion.
`
`The Restasis tray label is marked ”
`
`. .WWWw“'“
`
`_
`is marked'
`..,.______~_ ........a-~......
`“mm-HWW The
`WWWWWWG ”Both tray label and_ , >mmamm-mw
`indicate the drug product is W
`
`—-'
`
`Office of Drug Safety Comments:
`
`Since the initial review, DMETS identified two additional preprietary names with
`potential for confusion with Restasis since we conducted our initial review. However,
`DMETS does not anticipate that these product names will cause confission in the US
`marketplace at 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 ofNDA 21-023: cyclosporinc ophthalmic emulsion 0.05%
`Review #6
`
`Hi “i
`
`
`
`

`

`---------------------------------------------------------------------------------------------------------------------
`
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`_-----_--—----------------------------------------------------------------------------------------------------------
`
`Wiley Chambers
`12/23/02 05:06:41 PM
`
`
`
`

`

`We have safety concerns with the packaging of this product in a low-density
`polyethylene (LDPE) container. In particular, these concerns relate to the labeling that
`appears on the flange. This labeling should be clear and distinctive, since this type of
`packaging is being utilized in the manufacturing of other drug products. We also
`recommend that the WM , since the product will
`be loosely stored in bins within the institutional setting.
`
`Some of the products that are packaged in a like fashion include nonprescription
`ophthalmic lubricants and are utilized by the same patient 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 US. that are
`packaged in LDPE containers has been documented in numerous reports 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, and_ipratropiurn bromide 0.02% inhalation
`solution. Although the,volume of 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. “
`
`,
`
`. PM
`
`The proposed labeling on the Restasis vial is clear and distinctive. The proposed
`packaging of the tray and physician sample carton is clear and distinctive.
`
`Unlike the nonprescription ophthalmic lubricants packaged in a likefashion, Restasis is
`a white, opaque emulsion. There is no perceived additional risk to the indicated
`populationfrom the use ofa nonprescription ophthalmic lubricant. Based on the safety
`profile ofRestasis, there is no perceived safety riskfrom the inadvertent use ofRestasis in
`the population utilizing nonprescription ophthalmic lubricants.
`
`The volume andpackaging ofnon-ophthalmic products on the market in the US. is unlike
`the proposed packaging of the Restasis vial, carton, or tray. Again, the proposed
`labeling on the Restasis vial is clear and distinctive; the proposed packaging ofthe tray
`andphysician sample carton is clear and distinctive.
`
`Medicai Officer’s Review of NDA 21—023: cyclosporine ophthalmic emulsion 0.05%
`Review #6
`
`

`

`
`
`
`
`The phrase "
`’ is quite restrictive and could be confusing to the user.
`Some clarification should be provided regarding the following issues.
`
`How many doses or drops will each vial deliver? If more than two drops are
`deliverable, then the statement above seems to imply that
`r—-—-—-—-"’
`
`_ Wfiym-wafimunmmwfimuwlv .._ A
`,, .ufle-mae‘ M
`
`_
`_l_-,:,,,......._,.r;.,._,..,. HF. .,_,, WWW .m,
`
`n
`
`
`
`their“:
`user.
`
`7 according to the statement above, if strictly adhered to by the
`
`Medical Officer’s Comments:
`
`
`
`is no longerfound in the package insert, Restasis vial,
`The phrase ‘
`tray or-
`- "M“ It has been replaced, where appropriate with ‘ “*—
`
`' /W , or “
`These phases are
`intentionally more restrictive than " u——-—---..
`
`1n the interest of economy and conserving the drug product, it also seems likely
`that a patient be will inclined to use the remainder of the dropper, if the dosing is
`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 as the dosing interval, significant confusion and misuse seem
`likely.
`
`Medical Officer’s Comments:
`
`~
`.
`.
`See prewous comment regarding
`
`11- W ,
`.
`
`Again, with every single-use, unpreservedproduct there is 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
`to practitioners, patients and caregivers within the Restasis package insert:
`
`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 not allow the tip of the vial to touch the eye or any surface, as this may
`contaminate the emulsion.
`
`
`The Restasis tray label is marked ” «W -” and “ —--—""
`"
`" The
`JS marked ‘
`"“‘flfi W‘
`1
`W...
`‘Both trav label aria
`-—-—-——---~
`,.__...-—-—-r~
`
`indicate the drug product is
`
`Medical Officer’s Review ofNDA 21-023: cyclosporine ophthalmic emulsion 0.05%
`Review #6
`
`

`

`
`
`We have some concerns with the description of this package as a “vial”.
`
`Medical Officer’s Comments:
`
`
`
`Per the CDER Data Standards manual, the proposed single-use LDPE container is a
`vial.
`
`
`
`The
`
`.) is absent from the via] label (see 21 CFR 201.51).
`
`Medical Officer’s Comments:
`
`The container is a single—use vial, meant to deliver a single to drop to each eye.
`
`-——-—-—"':‘staten1ent to read: “ W
`On the tray label, revise
`W
`
`Medical Officer’s Comments:
`
`In the clinical trials performed by the applicant in support of the eflicacy and safety of
`the drug product, dosing took place approximately 12 hours apart.
`/ j
`.
`'
`
`This reviewer does notlagree that the suggested revision to the MM is
`appropriate.
`
`\Ve suggest substitution of the word "--" ’ for the Greek “pL”, as ML] is frequently
`mistaken for m[L}, particularly with scripted instructions.
`
`Medical Officer’s Comments:
`
`This reviewer does not agree that the suggested substitution of the word ” '-*- ’ for the
`Greek ”1.1L " is appropriate. There could be no substitution ofRestasis with a '—
`concentration since none exits.
`
`Topical ophthalmic prostaglandins are expressed in microliter concentrations with
`
`Under How Supplied, delete the phrase “fill in 0.9 mL LDPE vial”,'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 ofNDA 21~023: cyclosporine ophthalmic emulsion 0.05%
`Review #6
`
`
`
`

`

`
`
`RESTASISTM is packaged in single use vials. Each vial contains 0.4 mL fill in a
`0.9 mL LDPE vial; 32 vials are packaged in a polypropylene tray with an
`aluminum peelable lid.
`
`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 revisions listed in this
`Medical Officer’s Review#5 dated December 1, 2002.
`
`The application supports the safety and effectiveness of Restasis (cyclosporine
`ophthalmic emulsion) 0.05%
`. nmwmfl m: "
`
`I
`
`There are no recommendations for additional postmarketing studies.
`
`William M. Boyd, MD.
`Medical Officer
`
`
`
`NDA 21-023
`HFD—SSO/Div Files
`
`HFD—SSOMO/Boyd
`l-LFD-SSO/Dep Director/Chambers
`HFD—725/Stat/LuHo
`
`HFD—SOS/Micro/Riley
`HFD-SSO/Chemfl‘so
`
`HFD-SSO/Chem TUN g
`HFD-SSO/PM/Gorski
`
`HFD-SSO/Pharm'l‘ox/Mukherjee
`HFD—SSOfPharm Tox TUYang
`HPD-SSO/ Biopharm TUB ashaw
`
`Medical Officer‘s Review ofNDA 21-023: cyclosporine ophthalmic emulsion 0.05"»
`Review #6
`
`

`

` --- -----—--_--_-.-__---_-------——---q~----------.'--h—-----'D-nfi—--------"--------------------------------------
`
`C“
`
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`William Boyd
`12/13/02 04:29:39 PM
`MEDICAL OFFICER
`
`Wiley Chambers
`12/16/02 02:42:39 PM
`MEDI CAL OFFICER
`
`

`

`
`
`Medical Officer’s Review of NBA 21-023
`Amendment and
`
`Safety Update
`
`Submissions:
`
`NBA 21—023
`
`September 7, 2001
`April 23, 2002
`June 17,2002
`
`July 11, 2002
`September 6, 2002
`November 15, 2002
`
`Medical Officer’s Review #5
`
`Review Completed: December 13, 2002
`
`Proposed Tradename:
`
`Restasis
`
`Generic Name:
`
`Sponsor:
`
`CyCIOSporine ophthalmic emulsion, 0.05%
`
`Allergan, Inc.
`2525 Dupont Drive
`__ PO. Box 19534
`Irvine, CA 92623—9534
`
`Pharmacologic Category:
`
`immunomodulator
`
`Proposed Indication:
`
`'r‘W
`
`WW»
`
`Dosage Form and
`Route of Administration:
`
`Submitted:
`
`ophthalmic emulsion for topical ocular
`administration
`
`Responses dated September 7, 2001, April 23, 2002, June 17, 2002, July 1 1, 2002,
`September 6, 2002, and November 15, 2002, to items identified in the approvable letter
`dated March 25, 2000, for NBA 21-023 Restasis (cyclosporine ophthalmic emulsion)
`005%.
`
`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.
`
`

`

`
`
`
`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
`
`Overview of 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 NBA approval. The analysis is for patients who achieved
`an increase in Schjrmer wetting scores of 2 10 mm at the six-month timepoint.
`
`Also submitted, at the agency’s request, is a responder analysis of Allergan study
`192371—501 (Europe) and Allergen study 192371—503 (Europe).
`
`Validation of the clinical relevance of this clinical Sign (increase in Schirmer wetting
`scores of 2 10 mm at the six—month timepoint) is provided.
`
`
`
`Medical Officer‘s Review ofNDA 21-023 Amendment: cyclosporine ophthalmic emulsion 005%
`Review #5
`
`

`

`
`
`é --:—
`
`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 2 10 mm at the six-month timepoint).
`Per the sponsor, subjects with lower Schirmer scores have more disability due to dry eye
`and more ocular surface staining.
`
`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 1: Validation — Schirmer Score as Clinically Relevant Endpoint
`
`
`
`HFHS (OSDI)
`Group 2 Group 3
`p-value
`
`21 1
`
`N : 58
`
`
`0.24
`0.24 m 0.013
`
`
`N = 36
`
`N = 43
`
`I 0501 symptomfifi
`5‘ subscale
`
`OSD] overall
`score
`
`Corneal Stainin_
`
`analyses performed on data obtained at single visit
`analyses performed on data obtained at week 24
`
`7 "
`
`
`
`p—value
`
`m—
`
`
`
`
`
`Reviewer‘s Comments:
`
`Both the 031)] symptom subscale and the OSDI overall score are statistically
`significantly lower in subjects with Schirmer wetting scores ofz H mm. There are also
`Statistically significantly lower corneal staining scores in subjects with Schirmer wetting
`scores of 2 l 1 mm.
`
`Table 2: Correlation coefficients with confidence intervals for validation analyses on
`HFHS and 192371—503
`
`
`192371-503
`HFHS (OSDI)
`
`
`
`
`Group 2
`Group 3
`Gram—T
`Group 2
`Group 3
`
`
`
`55mm
`6—10
`211
`610
`211
`
`
`N=28
`N=89
`N=69
`N=47
`
`
`
`
`
`
`subscale
`OSDI overall
`score
`
`
`
`
`—0.54, 0.33
`-0.303
`-0.66, 0.16)
`
`-0.68, 0.13
`
`
`
`-0.56, 0.15
`~0.060
`-0.42, 0.32
`
`-0.25, 0.16
`0.001
`-0.21, 0.2]
`
`-0.38, 0.37
`
`-0.28, 0.13
`
`
`
`
`
`-0.32, 0.15
`
`—0.26, -0.03)
`
`{-0.33, 0.14)
`
`(-0.27, -0.02)
`
`-0.24, 0.23
`
`-0.43, 0.13
`
`
`
`Medical Officer’s Review ofNDA 21—023 Amendment: cyclosporine ophthalmic emulsion 0.05%
`Review #5
`
`

`

`Reviewer-‘3 Comments:
`
`None of the submitted correlation coeflicients approach 1 (or --1), and based on the
`confidence intervals provided, veryfew ofthe coefficients reach statistical significance.
`
`Table 3 summarizes additional analyses from the sponsor showing the percentage of
`subjects with a corneal staining score of O, grouped by absolute values of Schirmer, in the
`ITT population excluding ocular anti-inflammatory drugs and punctal plugs for 192371—
`002, -003, —501, —503.
`
`If an increase in Schirmer score above 11 mm were clinically relevant, these groups
`should Show less ocular surface staining in 192371-002, -003, -501, ~503.
`
`[N0te2 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
`
`192371-002
`
`
`
`*‘i92371—003
`
`Corneal Staining
`Group] Group2 Group3
`p-value
`
`SSmm
`6A1!)
`,
`211
`
`
`m
`2.1
`_-E-
`
`
`
`12
`11
`1
`34
`
`responder analyms is the number (percent) ofpatlcnts With a corneal staining score oft) at month GK_w_fi
`(15%)
`
`
`.
`,
`_
`.
`.
`.
`
`m1
`
`0-005
`
`
`
`192371-503”
`1923-3—50]
`
`
`
`Corneal Staining
`Group 1
`Group2 Group3 i p—value
`
`
`
`5 5mm
`
`
`
`
`
`(41%)_L
`__ _ (7%)
`(16%)
`(3 8%)
`(16%)
`(32%)
`
`responder analysis is the number (percent) ofpatients with a corneal staining score ofO at month 6
`
`
`
`12
`
`Reviewer’s Comments:
`
`Three of the clinical trials demonstrated statistical significance in the number
`(percentage) ofpatients with a corneal staining score of 0 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 2} 1 mm at month 6.
`
`[Note: responders here are patients who achieved a corneal staining score of0 at month
`6-]
`
`Medical Officer’s Review of NDA 21-023 Amendment: cyclosporinc ophthalmic emulsion 005%
`Review #5
`
`

`

`
`
`Responder Analysis:
`
`Table 4: Responder Analysis - Month 6 — 192371—002, —003
`
`
`
`192371-002
`
`
`
`
`
`20/11711/11311/109
`(17%)
`(10%
`(10%)
`10/109
`10/106
`8/97
`
`0.14735
`
`0.04825
`
`(18%)
`
`(9%)
`
`(8%)
`
`16/137— 11/131
`(12%)
`(8%)
`15/129
`11/125
`
`(12%)
`
`(9%)
`
`8/37
`(22%)
`8/34
`(24%)
`
`2/35
`(6%)
`
`0.00823
`
`m—Anti—
`
`Inflammatory Rx
`and Plugs
`ijigrens
`
`Sjfigrens - Anti-
`Inflammatory Rx
`and Plugs
`
`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, all of the popnlations trend towards higher responder ratesfor the 0. 05%
`cyclosporine treatment group.
`
`In two of the groups (127* anti—inflammatory Rx and punctal plugs and .Sjogrens — anti-
`inflammatory Rx and punctal plugs), the responder rates are statistically significant
`fm‘oring 0. 05 % cyclosporine in both trials.
`
`Table 5: Responder Analysis - Month 6 — 19237l-501, —503
`
`
` Inflammatory Rx
`and Flu s
`
`
`
`Reviewer’s Comments:
`
`The responder analyses of l 923 71 —5 01 and 192 3 7/ —5 03 (Table 2) do not achieve
`statistical significance for the specific dry eye population lflT— anti—inflammatory Rx and
`punctal plugs. The sample sizes are small.
`
`There is a trend towards higher responder rates for the 0.05% cyclosporine treatment
`groups.
`
`Although —5 01 and —503 analyses did not achieve statistical significance, the responder
`analyses are supportive of the findings in —002 and —003.
`
`Medical Officer’s Review of NDA 21-023 Amendment cyclosporine ophthalmic emulsion 0.05%
`Review #5
`
`

`

`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 conjunctival 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 emulsion in
`the W' ire not altered.
`
`IN
`3 HAY
`
`means TH
`6..—
`0itfi§iéfittfii
`
`
`
`Medical Officer’s Review ofNDA 21-023 Amendment: cyclosporme ophthalmic emulsion 0.05%
`Review #5
`
`

`

`Draft Labeling Page(s) Withheld
`
`

`

`
`
`Conclusions:
`
`1)
`
`A clinically relevant, dry eye population (ITT — ocular anti-inflammatory Rx and
`punctal plugs) demonstrated statistically significant differences in responder rates for
`the number of patients who achieved an increase in Schinner wetting scores 2 10 mm
`at the six~month timepoint in 192371-002 and —003.
`
`Although 750} and —503 analyses did not achieve statistical significance, the
`responder analyses are supportive of the findings in —002 and ——003.
`
`Regarding validation of this clinical Sign:
`
`Both the ()SDI symptom subscale and the OSDI overall score are statistically
`significantly lower in subjects with Schinner wetting scores of2 l 1 mm in the
`validation studies. There are also statistically significantly lower corneal staining
`scores in subjects with Schirmer wetting scores of> l l nun in the validation studies.
`
`Allergen has successfully demonstrated that the clinical sign (increase in Schirrner
`wetting scores 2 10 mm at the six—mOnth timepoint) is clinically relevant. Lower
`Schirmer scores seem to have more disability due to dry eye and more ocular surface
`staining.
`,w
`
`Original conclusions regarding the safety of 0.05% cyclosporine ophthalmic emulsion
`in
`
`
` -; are not aitered..._‘7, .i. *
`
`r’J v
`
`4)
`
`
`
`.
`can
`APPc-gxri T333 WA
`CW WHEESML
`
`Medical Officer’s Review ofNDA 21—023 Amendment: cyclosporine Ophthalmic emulsion 0.05%
`Review #5
`
`
`
`

`

`~:
`
`Recommendations:
`
`16
`
`
`
`"-‘..
`
`It is recommended that NDA 21—496 be approved with the labeling revisions listed in this
`review.
`
`The application supports the safety and effectiveness of Restasis (cyclosporine
`ophthalmic emulsion) 005% MW
`
`WI .
`
`There are no recommendations for additional postmarketing studies.
`
`William M. Boyd, MD.
`Medical Officer
`
`NDA 21-023
`HFD-SSO/Div Files
`
`HFD-SSO/MO/Boyd
`HFD-SSO/Dep Director/Chambers
`llFD-725/Stat/LuHo
`
`HFD—SOS/Micro/Riley
`HPD-SSO/Cheinrfso
`
`HPD-SSO/Chem TUNg
`HFD—SSO/PM/Gorski
`
`HFD-SSO/PhannTofoukheijee
`HFD—SSO/Pharm Tox TLfYang
`HFD-880/ Biophann TUBashaw
`
`Medical Ofiiccr's Review ofNDA 21—023 Amendment: cyclosporine ophthalmic emulsion 0.05%
`Review #5
`
`

`

`-—----.--------------------------------------------------------------------------------------------------------------
`
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`sun's---“-----------------------------------------------------------------------------------------------------------
`
`William Boyd
`12/13/02 04:24:16 PM
`MEDICAL OFFICER
`
`Wiley Chambers
`12/16/02 02:18:24 PM
`MEDICAL OFFICER
`
`

`

`
`
`Medical Officer’s Review of NBA 21-023
`
`Amendment
`
`NDA 21-023
`
`Medical Officer’s Review #4
`
`Submission:
`
`10/3/00
`
`Review Completed:
`
`10/5/00
`
`Proposed Tradename:
`
`Restasis
`
`Generic Name:
`
`Sponsor:
`
`Cyclosporine Ophthalmic emulsion, 0.05%
`
`Allergen, Inc.
`2525 Dupont Drive
`PO. Box 19534
`
`Irvine, CA 92623—9534
`
`Pharmacologic Category:
`
`Immunomodulator
`
`Proposed Indication:
`
`$.qume
`fl-‘mi'J-r-w-mwwwmwm ,
`
`Ophthalmic emulsion for topical ocular
`administration
`
`Dosage Form and
`Route of Administration:
`
`Submitted:
`
`Response dated October 3, 2000, to items identified in the approvable letter dated March
`25, 2000, for NBA 21—023 Restasis (cyc103porine ophthalmic emulsion) 0.05%.
`
`Sponsor’s Clinical Response Overview:
`
`This response presents study data from a keratoconjunctivitis sicca subpopuiation at high
`risk for more severe disease to demonstrate that studies 192371—002 and —003 are
`replicative and that 0.05% cyclosporine Ophthalmic emulsion is effective.
`
`To demonstrate replication in the two Phase 3 studies and to demonstrate the efficacy of
`0.05% cyciosporine emulsion, Allergan has performed new analyses beyond the 6-month
`IT'I‘ analyses originally submitted in NDA 21-023.
`
`

`

`
`
`
`
`A clinically relevant keratoconjunctivitis sicca subpopulation consisting of two
`subgroups has been defined:
`
`1) Sjogren’s patients and patients with other autoimmune connective tissue diseases
`2) Women 65 years of age or 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
`4) use ofprohibited ocular ointments, pilocarpine, ocular NSAID, beta-blocker, or
`ocular steroids.
`7 H
`'
`'
`
`Analyses were limited to presenting the proportions of patients with zero severity score
`for one sign (temporal corneal staining) and one symptom (blurred vision) at Month 6.
`
`Description of Patients in the High-Risk Patient Subpopulation:
`
`There are no statistically significant differences in the subpopulation demographic
`variables between treatment groups for age, age-by-group, sex, race, or iris color in
`studies 192371—002 and —003.
`
`Table 1 - Numbers of Patients in the High-Risk Patient Subpopulation
`
`
`
`
`
`
`"heatment Group
`
`mm
`
`
`
`Study 192371-002
`
`Subpopulation
`
`Original Intent-to-
`Treat Population
`
`
`
`Study 192371—003
`
`Subpopulation
`
`Original Intent-to-
`Treat Population
`
`
`
`
`
`
`"m
`
`
`
`
`Across both studies, 374 (43%) of the original 877 ITT patients were retained in the high-
`ris