CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICATION NUMBER:
`
`21-023
`
`MEDICAL REVIEWLS)
`
`
`
`1
`
`ALL 2078
`MYLAN PHARMACEUTICALS v. ALLERGAN
`|PR2016—01128
`
`1
`
`ALL 2078
`MYLAN PHARMACEUTICALS V. ALLERGAN
`IPR2016-01128
`
`

`

`
`
`Medical Officer’s Review of NBA 21-023
`Amendment
`
`NDA 21-023
`
`Submissions:
`
`December 20, 2002
`
`)ledical 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 ofAdministration:
`
`Reviewer-’5 Comments:
`
`ophthalmic emulsion for topical ocular
`administration
`
`Revised labeling based on previous review, discussion with {he appiicam‘, discussion
`between ODE V and the Division, and a correctedpackage inser! transmitted by Ike
`appiicant on December 20, 2002.
`
`The applicant proposes inserting the word "topical " before "anti—inflammatory " in the
`Clinical Evaluations and Indications and Usage sections ofihe iabei.
`
`This is acceptable.
`
`2
`
`

`

`/9
`
`Draft Labeling Page(s) Withheld
`
`3
`
`

`

`
`
`12
`
`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 siccar
`
`There are no recommendations for additional postmarketing studiest
`
`William M. Boyd, MD,
`Medical Officer
`
`NDA 21-023
`HFD-SSOIDiv Files
`
`HFD-SSO/MO/Boyd
`HFD—SSO/Dep Director/Chambers
`HFD-725/Stat/Lul—Io
`
`HFD-SOS/MicrofRiley
`HFD—S SOIChemeso
`
`HFD—SSO/Chem TUNg
`HFD-SSO/PM/Gorski
`
`HFD-SSO/PharrnTofoukherjee
`HFD-SSO/Pharm Tox TLlYang
`IIFD-880.’ Biopharm TUBashaw
`
`Medical Officer's Review of NBA 21-023 Amendment: cyclosporine ophthalmic emulsion 0.05%
`Review #9
`
`4
`
`

`

` -—-——-..------------------a-—m------_ -------p------------—_-.—-—--------------—----------——-.. .----.m.-....---_--- --
`
`1;
`
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`mun-- -__--_--_--—----—. --- ----------uu.__-_____--__----.-.-u----—-—----».-. -----n_-...--_-___--_———-.--.--- ----.-- .-.
`
`/8/
`
`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 NBA 21—023
`Amendment
`
`NDA 21—023
`
`Submissions:
`
`September 7, 2001
`April 23, 2002
`June 17, 2002
`July 1 l, 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
`
`_ Lrvine,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 onfitri'her discussion within the Divisimi on December 19,
`2002, regarding the Clinical Pharmacology, Clinical Evaluations, and Indication and
`Usage sections and subsections of the labeling.
`
`
`
`6
`
`

`

`/9
`
`Draft Labeling Page(s) Withheld
`
`7
`
`

`

`12
`
`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 (cyclosporinc
`ophthalmic emulsion) 0.05%
`“'”‘*““‘~-~..—-—---—-—-
`M~'wmmwym»——wwfl _ __ __
`
`There are no recommendations for additional postmarketmg studies.
`
`William M. Boyd, MD.
`Medical Officer
`
`NDA 21-023
`HFD—SSO/Div F iles
`
`HFD—SSO/MO/Boyd
`HFD-SSO/Dep Director/Chambers
`HFD-725/Stat/LuHo
`
`HFD-805/Miero/Riley
`HFD-SSO/Chem/Tso
`
`HFD-SSO/Chem TUNg
`HFD—SSO/PM/Gorski
`
`HFD—SSO/PhamiTox/Mukherjee
`HFD-SSO/Pharm Tox TL/Yang
`HFD—880/ Biopharm TL/Bashaw
`
`Medical Officer‘s Review of NBA 21—023 Amendment: Cyclosporine ophthalmic emulsion 0.05%
`Rmicw #8
`
`8
`
`

`

` _-----.--------—.—..---—-—--__-—-__--- -II-..IIIO-QII-l-I-D-I-n—--..--.-------—----- ..--------—------_-_- -- - - ----- ---
`
`1:7;
`
`This is a representation of an electronic record that was signéd electronically and
`this page is the manifestation of the electronic signature.
`"II-m.-—-----------I.--O.-------.----------------—--«-—------—----------—o—‘I-n" ..--------------- -___.,-_- ..___-__
`
`/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 NBA 21-023
`Amendment
`
`N DA 21-023
`Medical Officer’s Review #7
`
`December 16, 2002
`Submissions:
`Review Compieted: December 16, 2002
`
`Proposed Tradename:
`
`Restasis
`
`Generic Name:
`
`Cyclosporine ophthalmic emulsion, 0.05%
`
`Sponsor:
`
`Allergen, Inc.
`2525 Dupont Drive
`P.O. 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/} 3/02 1 2:! 2:56 PM
`in DFS, were not included in thefinal drugproduct labeling.
`
`1) Under Description, “The amount as ““ _, should replace 0.05% for cyclosporine.“
`
`The proportion ofthe active ingredient, cyclosporfne, is aeeeprabfe per CFR 201.100
`(WM)-
`
`2) Under How Supplied, “The word vial should be replaced by ~_~— as the latter 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
`conminer is or via! ("A container designedfor use with parenteral drug precincts ").
`
`10
`
`
`
`10
`
`

`

`_-_{___ Draft Labeling Page(s) Withheld
`
`11
`
`11
`
`

`

`a;
`
`Recommendations:
`
`(f‘
`
`11 .013
`
`It is recommended that NDA "“ be afiproved with the labeling revisions listed in this
`review.
`
`The application supports the safety and effectiveness of Restasis (cyclosporinc
`ophthalmic emulsion) 0.05%
`
`M
`
`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/Chem/l‘so
`
`HFD—SSO/Chem TUN g
`HFD-SSO/PM/Gorski
`
`HFD-SSO/PharmTox/Mukheijee
`HFD-SSO/Pharm Tox TL/Yang
`HFD-880/ Biopharm TUBashaw
`
`Medical Officer‘s Review of NDA 21-023 Amendment: cyclosporiue ophthalmic emulsion 0.05%
`Review #7
`
`12
`
`
`
`12
`
`

`

`_-_-_-.._____-_--_--_-_____ - --------~.-...---------------noon-u-----—--_-..-----------------.__--.--____._--—um-..
`
`«:7:
`
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`----- ——-—-.--------- -----------_-_--__--—————-—-.-u-un-u-uu-u.------------------ ---—----..... “up-nunnnnn-n u-u-uu -.-
`
`/8/
`
`William Boyd
`12/16/02 02:33:44 PM
`MEDICAL OFFICER
`
`Wiley Chambers
`12/16/02 02:54:09 PM
`MEDICAL OFFICER
`
`13
`
`13
`
`

`

`———-‘
`
`W
`
`Medical Officer’s Review of NBA 21-023
`
`Office of Drug Safety Consultation
`
`NDA 21—023
`
`Submission:
`
`December 1 l, 2002
`
`Medical Officer’s Review #6
`
`Review Completed: December 1 1, 2002
`
`
`
`Proposed Tradename:
`
`Restasis
`
`Generic Name:
`
`Cyclosporine ophthalmic emulsion, 0.05%
`
`Sponsor:
`
`Allergan, Inc.
`2525 Dupont Drive
`P.O. Box 19534
`
`lrvine,CA 92623-9534
`
`Pharmacologic Category:
`
`immunomodulator
`
`Proposed Indication:
`
`Dosage Form and
`Route ofAdrninistration:
`
`Submitted:
`
`ophthalmic cmulsion for topical ocular
`administration
`
`Submitted is a Office of Drug Safety memorandum in response to a November [9, 2002
`request from the Division of Anti-inflammatory, Analgesic, and Ophthalmologic Drug
`Products for a re-revicw 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 M described in Appendix A (Ala. 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 drops 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
`
`14
`
`14
`
`

`

`
`
`iii .,,
`
`
`
`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 ofthe 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 singlemse, 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 immediately after administration.
`
`Do not allow the tip ofthe vial to touch the eye or any surface, as this may
`contaminate the emulsion.
`
`. _WW_.HM
`Elie Restasrs tray label is marked
`“‘"e-b>m«*‘“ The
`-3h——-——.__._.fl"-—.
`is marked '
`MWMW [Both tray label and _
`indicate the drug product is W
`
`—’
`
`imam-mama”?
`
`Office of Drug Safety Comments:
`
`Since the initial review, DMETS identified two additional proprietary names with
`potential for confusion with Restasis since we conducted our initial review. However,
`DMETS does not anticipate that these product names will cause confusion 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 cyclosporine ophthalmic emulsion 0,05%
`Review #6
`
`15
`
`15
`
`

`

`----.--- -u--------- _----- ----------- --- ---—-----------—--.n----------n............................................
`
`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
`
`
`
`16
`
`16
`
`

`

`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, andtipratropium 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,
`
`'
`
`_ __
`
`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 like fashion, Resrasis is
`a while, opaque emulsion. There is no perceived additional risk to the indicated
`populationfrom the use of a nonprescription ophthalmic lubricant. Based on the safety
`profile ofReslasis, there is no perceived safety riskfrom the inadvertent use ofResrasis in
`the population utilizing nonprescription ophthalmic lubricants.
`
`The volume and packaging ofnon-ophthalmic products on the market in the US. is unlike
`the proposed packaging of (he Restasis vial, carton. or tray. Again, the proposed
`labeling on the Restasis vial is clear and distinctive; the proposed packaging ofrhe rroy
`andphysician sample carton is clear and distinctive.
`
`Medical Officer‘s Review ofNDA 21-023: cyclosporine ophthalmic emulsion 0.05%
`Review #6
`
`17
`
`17
`
`

`

`
`
`
`
`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
`,_..—-’
`
` Mm
`,
`.m-
`—'-'--—-- '---—-w —Wm H. fi-...._,..n-—- -—""‘
`
`Hfi‘m'h - a .
`
`_ _,
`
`
`
`-L.
`“SET.
`
`in,
`
`_ according to the statement above, if strictly adhered to by the
`
`Medical Officer’s Comments:
`
`
`
`The phrase ‘
`is no Iongerfonnd in the package insert, Restasis viai,
`tray 07"
`’ ,___......——-—.____.
`I! has been replaced, where appropriate with ‘ "“h-
`/W , or “
`~"""'"‘—"—'v
`These phases are
`intentionally more restrictive than "
`.,.__.._.........__
`
`In the interest of economy and censerving 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 tegardzng
`
`.r w“ .
`_
`
`Again, with every single—use, ttnpreservedproduct there is the risk that patients may save
`the via] and use the remaining drug at a later time. The risks ofusing the cyciosporine
`ophthalmic emulsion single-use vial beyond the single dose is adequateiy 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 " _,.._.s_——-»—-—. " and “
`"_‘*"’_' """"""—"‘
`" The,
`_
`"
`it: marked '
`
`i...
`'Both trap iabei am;
`-—---—.-—-—
`__ indicate the drug product is
`,——_———-—_-"‘
`
`.
`
`Medical Ofllcer‘s Review ofNDA 21-023: cyclospotine ophthalmic emulsion 0 05%
`Review #6
`
`18
`
`18
`
`

`

`
`
`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 l,DPE container is a
`vial.
`
`
`
`The
`
`.) is absent from the vial 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.
`
`fl—fi-‘Tslalement to read: “ '. “""'-""'-—"-—-
`On the tray label, revise
`W
`
`Medical Officer’s Comments:
`
`In the clinical trials performed by the applicant in support of the efficacy and safety of
`.rr
`the drug product, dosing took place approximately l2 hours apart.
`r
`
`This reviewer does not agree that the suggested revision to the .Wm. is
`appropriate.
`
`’ for the Greek “1.1L“, as l[.J.[L] is frequently
`\Vc suggest substitution of the word "~-*-
`mistaken for m[L], particularly with scripted instructions.
`
`Medical Officer’s Comments:
`
`This reviewer does not agree that the suggested substitution oftl'te word " ..__._ for the
`Greek "ML ” is appropriate. There could be no substitution (JRestasis 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: cyclospon'nc ophthalmic emulsion 0.05%
`Review #6
`
`19
`
`19
`
`

`

`
`
`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 confiisfon 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.
`
`'Ihe application supports the safety and effectiveness of Restasis {cyclosporine
`ophthalmic emulsion) 0.05%W
`. ‘mwmW‘g“ " u" I
`I
`
`There are no recommendations for additional postmarketing studies.
`
`William M. Boyd, M.D.
`Medical Officer
`
`
`
`NDA 21—023
`
`HFD~SSOfDiv Files
`
`HFD-SSO/MO/Boyd
`l-LFD-SSO/Dep Director/Chambers
`HFD-725/Stat/LuHo
`
`HFD—SOS/Microijley
`HFD-SSO/Chemll‘so
`
`HFD-SSO/Chem TUNg
`HFD-SSO/PMlGorski
`
`HFD-SSO/PhannTox/Mukherj ee
`HFD-SSO/Pharm Tox TUYang
`HFD-880/ Biopharm TUBashaw
`
`Medical Officer‘s Review of NDA 2l—023' cyclosporine ophthalmic emulsion 0.05%
`Review #6
`
`20
`
`20
`
`

`

` .-----_-___----—.-—-__---.—._-------.-------------------------_---.-a-.-..—-------..-------——-------_---------.
`
`\ll
`
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`------..—--------9----------.—_--__-_-nnu—————--------.--—-—-------------___..o—--——-—-——-—--.--nu-------------------
`
`/S/
`
`William Boyd
`12/13/02 04:29:39 PM
`MEDICAL OFFICER
`
`Wiley Chambers
`12/16/02 02:42:39 PM
`MED I CAL OFFI CER
`
`m
`
`
`
`21
`
`

`

`Medical Officer’s Review of NBA 21-023
`Amendment and
`
`Safety Update
`
`Submissions:
`
`NBA 21—023
`
`September 7, 2001
`April 23, 2002
`June I7, 2002
`July 1], 2002
`September I5, 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%
`
`Allergen, Inc.
`2525 Dupont Drive
`PO. Box 19534
`
`' Irvine, CA 92623-9534
`
`Pharmacologic Category:
`
`immunomodulator
`
`W ’
`
`fi—M
`
`ophthalmic emulsion for topical ocular
`administration
`
`Proposed Indication:
`
`Dosage Form and
`Route of Administration:
`
`Submitted:
`
`Responses dated September 7, 2001, April 23, 2002, June 17, 2002, July I I, 2002,
`September 6, 2002, and November 15, 2002, to items identified in the approvable letter
`dated March 25, 2000, for NDA 21-023 Restasis (eyelosporine 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, 1923714301, and 192311-
`503.
`
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`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 ofthe two Phase 3 studies 1923?] —002
`and 192371-002 in support of NBA approval. The analysis is for patients who achieved
`an increase in Schjmier wetting scores of 2 10 mm at the six—month timepoint.
`
`Also submitted, at the agency’s request, is a responder analysis of Allergen study
`192371-501 (Europe) and Allergan study 192371—503 (Europe).
`
`Validation of the clinical relevance of this clinical sign (increase in Sehirmer wetting
`scores of 2 10 mm at the six-month timepoint) is provided.
`
`n'13
`rd
`:7,
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`Oa
`
`:O 5
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`.3
`“3.5
`1:-
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`Fmasun5
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`Medical Officer‘s Review ofNDA 21—023 Amendment: cyclosporinc 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 2 10 mm at the six-month timepoint).
`Per the sponsor, subjects with lower Schinner 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
`,._.,_______
`
`.1
`102371-5032
`HFHS (OSDI)
`
`
`
`E1l,
`Group 2 Group 3
`p-value
`
`N=36 N=43 N=58
`
`
`
`1 OSDIsymptonT—
`0.31
`0.27
`0.004
`0.30
`0.025
`
`
`E subscale
`
`’OSDI overall
`0.24 -m 0.013
`0.35
`score
`
`
`
`analyses performed on data obtained at single visit
`analyses performed on data obtained at week 24
`
`
`
`1 ‘
`
`0.044
`
`Reviewer’s Comments:
`
`Both the OSDl symptom snbscale and the OSDl overall score are statistically
`significantly lower in subjects with Schirmer wetting scores (if?) H mm. There are also
`statistically significantly lower corneal staining scores in .sntgiects with Schirmer wetting
`scores of 2 l l mm.
`
`Table 2: Correlation coefficients with confidence intervals [or validation analyses on
`HFHS and 192371—503
`
`
`
`
`
`
`
`
`
`HFHS (osnn
`192371-503
`Group 2
`Group 3
`Group 2
`Group 3
`
`
`
`6-10
`211
`211
`6‘10
`
`
`
`N=28
`N=89
`N=69
`N=47
`
`
`
`
`
`
`
`
`subscale
`05]): overall
`score
`
`—O.S4, 0.33
`-0303
`-0.66, 0.16)
`
`-0.56, 0.15
`0.060
`-042, 0.32
`
`025, 0.16
`
`021, 0.21
`
`-0.68, 0.13
`
`
`
`038, 0.37
`
`023, 0.13
`
`
`
`
`
`
`
`-0.32, 0.15
`—0.104
`(—0.33, 0.14)
`
`-0.26, -0.03}
`0.008
`(-0.27. -0.02}
`
`'0-24. 0.23
`
`4143, 0.13
`
`Medical Officer‘s Review of NBA 21 023 Amendment: cyciosporinc ophthalmic emulsion 0.05%
`Re view #5
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`Reviewer’s Comments:
`
`None of the submitted correiotion coefiicients approach 1 (or --1), and based on the
`confidence intervois pmvided, veryfew ofthe coefficients reach stotisticmI significance.
`
`Table 3 summarizes additional analyses from the sponsor showing the percentage of
`subjects with a corneal staining score of 0, grouped by absolute values of Schirmer, in the
`HT population excluding ocular anti-inflammatory drugs and punctal plugs for 192371—
`002, -003, 601, -503.
`
`lfan increase in Schirmer score above ll mm were clinically relevant, these groups
`should show less ocular surface staining in 192371-002, -003‘ —50 l, «503.
`
`[Note: responders here are patients who achieved an increase in Schinner wetting scores
`2 10 mm at the six-month timepoint]
`
`Table 3: Corneal Slaining at Month 6
`Percent of Patients with a Corneal Staining Score of Zero
`
`
`
`
`i92371-002
`i92371-003
`
`Group 1 Group 2 Group 3
`p-value
`Corneal Staining
`Group 1 Group 2 Group 3
`
`
`-
`5 5mm
`6-10
`5 5mm;
`6—10
`
`
`234
`93
`
`
`_-I-
`241
`14
`
`|
`ll
`34
`22
`
`1__.______
`
`i
`(28%)
`_
`(8%)
`(12%)
`(15%)
`(24%)
`responder analysis is the number (percent) of patients with a corneal staining score of0 at month 6
`
`
`
`
`
`
`
`
`
`
`_ 192371-503”
`
`Group I Group 2 Group 3 l p-value
`
`S 5mm
`6-10 will
`
`
`103
`53
`29
`1.22.0 0.7
`
`
`
`12
`16
`17
`v
`l
`432%)
`([696)
`(38%)
`(16%)
`m
`{41%)
`
`responder analysis is the number (percent) ofpaticnls wilh a corneal staining score oft} at month 6
`
`Reviewer’s Comments:
`
`Three of the clinical trials demonstrated statisticot significance in the number
`(percentage) ofpatients with a corneal staining score ofO or month 6 when subjects are
`grouped by absolute values ofSchirmer. The remaining trio! demonstrates a trend
`favoring less corneal staining when Schirmer '3 is .2” mm at month 6.
`
`[Note: responders here are patients who achieved a corneal staining score ofO or month
`6.]
`
`Medical Officer's Review oleM 21—023 Amendment: cyclosporine ophthalmic emulsion 0.05%
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`=39
`
`Responder Analysis:
`
`Table 4: Responder Analysis - Month 6 — 192371—002, —003
` 192371—002
`
`
`
`
`
`
`11/113
`(10%)
`10/106
`(9%)
`
`20/117
`(17%)
`10/109
`(18%)
`
`8/37
`(22%)
`8/34
`{24%)
`
`Inflammatory Rx
`and Flags
`Sjbgrens
`
`Sjégrens — Ami-
`Inflammatory Rx
`and Plugs
`
`'
`
`16/137
`(12%)
`15/129
`02%)
`
`11/131
`(8%)
`11/125
`(9%)
`
`0.14735
`
`0.04025
`
`0.01920
`_
`000823
`
`0.06704
`
`_
`
`1 0.04907
`
`Reviewer’s Comments:
`
`Specific dry eye populations are identified and anaivzedfar patients who achieved an
`increase in Schirmer wetting scores 2 10 mm at the six-month timepaint (responders).
`Table 1, all of the papalations trend towards higiier responder ratesfor the 0.05%
`qx'closporine treatment group.
`
`in
`
`In two of the groups (117— anti—inflammatory Rx and pitactai plugs and .degrens - anti-
`inflammatory Rx andpunctal plugs), the responder rates are statistically sigmficant
`fm'oritig 0.05% cyciosporine in both trials.
`
`Table 5: Responder Analysis - Month 6 — 1923'} [~50]. ~503
`
` 192371-50]
`
` TIT — Ami-
`and Flu s
`
`Iuflammaton‘ Rx
`
`
`
`Reviewer's Comments:
`
`The responder analyses ofi923717501 and19237}7503 (Table 2) do riot achieve
`statistical significance for the specific dry eye population ITI‘ — anti-inflammatory R): and
`ptmctai pings. The sample sizes are smafi.
`
`There is a trend towards higher responder rates for the 0. 05 “/6 cyct'osparine treatment
`groups.
`
`Although —50} and —5 03 analyses did not achieve statistical significance. the responder
`attaivses are supportive of the findings in —002 and —003.
`
`Medical DmCEr's Review of NBA 21—023 Amendment: cyclosporine ophlhalmic emulsion 0.05%
`Review #5
`
`26
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`26
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`

`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% cyclosponne ophthalmic emulsion in
`the Wm' .tl'c nol altered
`
`APPEARS was: rm
`ottoman
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`Medical Officer's Review ofNDA 21~023 Amendment: cyclospmine ophthalmic emulsion 0.05%
`Review #5
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`.5;
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`_____(:7_'_______ Draft Labeling Page(s) Withheld
`
`28
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`
`
`Conclusions:
`
`l) 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 Schirmer wetting scores 2 10 mm
`at the six~month timepoint in 192371-002 and —003.
`
`Although 7501 and ~503 analyses did not achieve statistical significance, the
`responder analyses are supportive of the findings in —002 and 77003,
`
`Regarding validation of this clinical sign:
`
`Both the OSDI symptom subscale and the OSDI overall score are statistically
`significantly lower in subjects with Schirmer wetting scores of 2 1 1 mm in the
`validation studies. There are also statistically significantly lower corneal staining
`scores in subjects with Schirrner wetting scores of> l 1 mm in the validation studies.
`
`Allergan has successfully demonstrated that the clinical sign (increase in Schirmer
`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
`r
`staining.
`»
`1
`
`‘4)
`
`Original conclusions regarding the safety of 0.05% cyclosporinc ophthalmic emulsion
`in
`
`
`
`APPE’TS‘ T333 WAY
`ca cinema
`
`Medical Officer‘s Review ofNDA 21—023 Amendment: cyclosporine Ophthalmic emulsion 0.05%
`Review #5
`
`29
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`

`
`
`[6
`
`Recommendations:
`
`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) 0.05% MM
`WK .
`
`
`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
`HPD-SSO/Dep Director/Chambers
`HFD—725/Stat/LuHo
`
`HFD-SOS/Micro/Riley
`HFD-SSO/Chemfl‘so
`HFD-SSO/Chem TL/Ng
`HFD—SSO/PM/Gorski
`
`HFD-SSO/PharmTox/Mukherjee
`HFD-SSO/Pharm Tox TL/Yang
`HEB-880] Biopharm TUBashaw
`
`Medical Officer's Review ofNDA 21-023 Amendment: cyclosporine ophthalmic emulsion 0.05%
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`

`---_-_..-___--_____---———--——--.--—---.-..-----------------_--____—---- _________.______.____-__.._..-_-..--__--_-___-_ -_-
`
`at;
`
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`so-..--.ohn—--Iu---—----------- _------—--—---—-----------_-----. ------ -___-_-__-_--__--_--_--_--___-_- --_--_--__-—---
`
`ls/
`
`William Boyd
`12/13/02 04:24:16 PM
`MEDICAL OFFICER
`
`Wiley Chambers
`12/16/02 02:18:24 PM
`MEDICAL OFFICER
`
`m
`
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`
`
`Medical Officer’s Review of NDA 21-023
`Amendment
`
`NDA 21-023
`Medical Officer’s Review #4
`
`Submission:
`
`10f3!00
`
`Review Completed:
`
`105100
`
`Proposed Tradename:
`
`Restasis
`
`Generic Name:
`
`Sponsor:
`
`Cyclosporine Ophthalmic emuision, 0.05%
`
`Allergan, Inc.
`2525 Dupont Drive
`PO. Box 19534
`
`Irvine, CA 92623-9534
`
`Pharmacologic Category:
`
`I‘Imnunomodulator
`
`Proposed Indication:
`
`Dosage Form and
`Route of Administration:
`
`Submitted:
`
`Ophthalmic emulsion for topical ocuiar
`administration
`
`Response dated October 3, 2000, to items identified in the approvable letter dated March
`25, 2000, for NDA 21-023 Restasis (cycltiSporine ophthalmic emulsion) 0.05%.
`
`Sponsor’s Clinical Response Overview:
`
`This response presents study data fi'om a keratoconjunctivitis sicca subpopulation 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
`I'IT analyse; originally submitted in NDA 21-023.
`
`32
`
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`32
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`

`
`
`A clinically relevant keratoconjunctivitis sioca 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:
`
`Sign meant protocol violations included:
`
`I) prohibited diseases (severe acne rosacea, severe migraine, Grove '5 disease)
`2) prohibited surgeries during study
`3) use ofprohibited medicationsfor surgeries
`4) use ofprohibited ocular ointments, pilocnrpine, ocular NSAIDi beta-blocker, or
`ocular steroids.
`7 H
`V
`V
`I
`
`Analyses were limited to presenting the proportions of p