CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICATION NUMBER.-
`
`21-023
`
`MEDICAL REVIEW(S)
`
`
`
`
`
`1
`
`ALL 2078
`MYLAN PHARMACEUTICALS V. ALLERGAN
`|PR2016-01127
`
`1
`
`ALL 2078
`MYLAN PHARMACEUTICALS V. ALLERGAN
`IPR2016-01127
`
`

`

`Elf-
`
`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’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
`apph'cant on December 20, 2002.
`
`The applicant proposes inserting the word “topical " before "anti—inflammatory" in the
`Clinical Evaiuations and Indications and Usage sections of[he label.
`
`This is acceptable.
`
`
`
`
`
`2
`
`

`

`L 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% 10 increase tear production in patients whose tear production
`is presumed to be suppressed due to ocular inflammation associated with
`keratoconjunctivitis siccai
`
`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 Director/Chambers
`HFD-725/Stat/Lul—lo
`
`HFD-SOS/MicrofRiley
`HFD—S SOIChemeso
`
`HFD—SSO/Chem TUNg
`HFD-SSO/PM/Gorski
`
`HFD-SSO/PharrnTofoukherjee
`HFD-SSO/Pharm Tox TLlYang
`HFD~88OI Biopharm TUBashaw
`
`Medical Officer’s Review ofNDA 21-023 Amendment; cyclosporinc ophthalmic emulsion 0.05%
`Review #9
`
`
`
`4
`
`

`

`-—-——-..------------------a-—m------_ -------p------n------_-.—-—--------------—----------——-.. ..---.m.---o------- --
`
`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----—-—----».... -----.-..................................
`
`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 11, 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.
`
`
`
`6
`
`

`

`m 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.
`
` “M~...~,_..__._.—--
`The application supports the safety and effectiveness of Restasis (cyclosporinc
`ophthalmic emulsion) 0.05%
`m... m.“
`m _,_.,_ .,._..,... m ”ymwe—mem-
`.M
`
`“me ~ :.
`
`There are no recommendations for additional postmarketing studies.
`
`William M. Boyd, MD.
`Medical Officer
`
`NBA 2 1 -023
`HFD—S 50/Div Files
`
`HFD-SSO/MO/Boyd
`HFD-SSO/Dep Director/Chambers
`HFD-725/Stat/LuHo
`
`HFD-805/Micro/Riley
`HFD-SSO/Chem/Tso
`
`HFD-SSO/Chem TUN g
`HFD—S 50/PMfGorski
`
`HFD—SSO/PhamiTox/Mukherjee
`HFD-SSO/Pharm Tox TL/Yang
`HFD—880/ Biopharm TL/Bashaw
`
`Medical Offic er‘s Review of NDA 2|~023 Amendment: cyclosporinc ophthalmic emulsion 0.05%
`Review #8
`
`
`
`8
`
`

`

` _-----.--------—.—..---—-—--__-—-__--- mun-m----.-------.---n—-...--p-------—----- ..--------—---- -----_ -- - - ----- ---
`
`1:7;
`
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`n-.-m.——---—-------u.-—.—--—--—-.----------------—-p—u-—-—-—--___--_____--.._--nu ..--------------. ----..-.... ..___-__
`
`/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 Completed: December 16, 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:
`
`immunomoduiator
`
`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 thefinal drug product labeling.
`
`1) Under Description, “The amount as “" Q Should replace 0.05% for cyclosporine.”
`
`The proportion ofthe active ingredient, cyclosporine, is acceptable per CFR 201100
`(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
`container is a vial (“A container designedfor use with parenteral drug products ").
`
`10
`
`
`
`10
`
`

`

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

`

`
`
`a;
`
`Recommendations:
`
`(f‘
`
`-u -013
`
`It is recommended that NDA ““ be afiproved with the labeling revisions listed in this
`review.
`
`The application supports the safegy and effectiveness of Restasis (cyclosporine
`ophthalmic emulsion) 0.05%
`,
`
`_W
`
`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/Fso
`
`HFD—SSO/Chem TUN g
`HFD-SSO/PM/Gorski
`
`HFD-SSO/PharmTox/Mukheljee
`HFD-SSO/Pharm Tox TL/Yang
`HFD-880/ Biopharm TUBashaw
`
`Medical Officer's Review of NDA 21-023 Amendment: cyclosporine ophthalmic emulsion 0.05%
`Review #7
`
`12
`
`
`
`12
`
`

`

`_-_-_-.._____-_--_--_-_____ - --------~.--..-----n.pun-nu...up..—----------_-------------—-------- ._-___.._--—-—--..
`
`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.------------------ ---—---..... .n-p-n-n-n-n-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
`
`fl
`
`13
`
`

`

`‘
`
`
`
`we
`
`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 11, 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:
`
`immunomodulator
`
`Proposed Indication:
`
`Dosage Form and
`Route of Administration:
`
`Submitted:
`
`w was-wwwvmmwm
`
`ophthalmic emulsion for 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 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 milliiiter
`is 0.1 — 0.13 mL. Therefore, there is a risk that patients may save the via! 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
`
`

`

`
`
`ill "'l
`
`
`
`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 of the vial to touch the eye or any surface, as this may
`contaminate the emulsion.
`
`The Restasis tray label is marked "
`
`. .Mwwmw“
`
`‘
`,
`- WW” '
`“arranger-sweat" The .W is marked '
`WWWWWW 'Both tray label and.
`_
`'W‘flkflwwn-N‘
`indicate the drug product is W
`
`—’
`
`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 of NDA 21-023: cyclosporine ophthalmic emulsion 005%
`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 ophthalr'nic 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
`3——
`
`“
`
`with, "
`
`,
`
`4 f'
`
`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, Resrasis is
`a while, opaque emulsion. There is no perceived additional risk to the indicated
`populationfiom the use of a nonprescription ophthalmic lubricant. Based on the safety
`profile ofReslasis, there is no perceived safely riskfiom the inadvertent use ofRestasis in
`1112 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 ofthe tray
`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
`,___..—-—’
`
`
`4...?
`user.
`
`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 ‘
`It has been replaced, where appropriate with ‘ N‘-
`tray or‘
`, ..__...———-—.____,
`' /W , or “ M These phases are
`intentionally more restrictive than "
`.,___—.—t‘
`
`in 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 prevrous comment regardzng
`
`.r 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 ofusing 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 afler 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
`53 marked ‘
`“‘"'—'""""'—"
`
`..._
`‘Both tray label aria
`——-—-'—‘-~ -
`__ indicate the drug product is M
`
`Medical Officer’s Review ofNDA 2l—023: cyclosporine 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 LDPE 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.
`
`-————--'"':‘statemcnt to read: “ I --—-—-—-——~——.~.
`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
`the drug product, dosing took place approximately 12 hours apart.
`/.'
`_
`.
`
`This reviewer does not’agree that the suggested revision to the MM. is
`appropriate.
`
`We suggest 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 "yL " is appropriate. There could be no substitution ofRestasis with a F
`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 via]”,'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 of the
`product:
`
`Medical Officer’s Review of NDA 21-023: cyclospon'ne 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 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%
`. ‘mwmW‘g“ " u" 'i
`
`-
`
`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
`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/Mukhcrjee
`HFD-SSO/Pharm Tox TUYang
`HFD-880/ Biopharm TUBashaw
`
`Medical Officer's Review of NDA 21—023: cyclospoxine ophthalmic emulsion (105%
`Review #6
`
`20
`
`
`
`
`
`20
`
`

`

`
`
`.-----_-___----—.-—-__---.—._-------.--------------------------_---.-a-.-..—-------ou-------.—-----------------.
`
`\ll
`
`
`
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`------..—--------9----------.—_--__-_-nn-—————-------..--—---------------___..o—--——-—-——-—--.p-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 NDA 21-023
`Amendment and
`
`Safety Update
`
`Submissions:
`
`NDA 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:
`
`Cyclosporine ophthalmic emulsion, 0.05%
`
`Allergan, Inc.
`2525 Dupont Drive
`. PO. Box 19534
`h’vine, CA 92623—9534
`
`Pharmacologic Category:
`
`immunomodulator
`
`Wm
`
`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 1 l, 2002,
`September 6, 2002, and November 15, 2002, to items identified in the approvable letter
`dated March 25, 2000, for NDA 21-023 Restasis (oyclosporine 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, 192371-50} , and 192371-
`503.
`
`
`
`22
`
`22
`
`

`

`
`
`
`
`TABLE OF CONTENTS
`
`Overview of the Sponsor’s Clinical Response
`
`Validation of the Clinical Relevance of the Clinical Sign
`
`Responder Analyses
`
`Safety Update
`
`Labeling
`
`Conclusions
`
`Recommendations
`
`Page 2
`
`Page 3
`
`Page 5
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`Page 6»
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`Page 7
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`Page 15
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`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 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 Sehinner wetting
`scores of 2 10 mm at the six-month timepoint) is provided.
`
`E
`5.25::
`is:
`53:»"" ”4
`'3'
`93 ”I.H..-
`3":
`r”?!
`
`f2
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`Medical Officer’s Review ofNDA 2102} Amendment: cyclosporine ophthalmic emulsion 005%
`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
`,._.,_______
`
`192371-5032 .1
`HFHS (OSDI)
`
`
`E‘1l,
`Group 2 Group 3
`p-value
`
`N=36 N=43 N=58
`
`
`
`0.30
`0.025
`
`
`0.35
`
`
`
`analyses performed on data obtained at single visit
`analyses performed on data obtained at week 24
`
`1 ‘
`
`0.31
`
`0.27
`
`0.004
`
`0.24 -m 0.013
`
`0.044
`
`
`
`l 031)] symptom——
`
`E subscale
`’OSDI overall
`score
`
`
`
`Reviewer’s Comments:
`
`Both the OSD] symptom subscale and the OSDI overall score are statistically
`significantly lower in subjects with Schfrmer wetting scores of2 l 1 mm. There are also
`statistically significantly lower corneal staining scores in subjects with Schirmer wetting
`scores 0f2 l 1 mm.
`
`Table 2: Correlation coefficients with confidence intervals for validation analyses on
`HFHS and 192371—503
`
`
`
`Group 3
`Group 2
`
`
`
`6-10
`211
`N=20
`N=28
`N=89
`
`
`
`
`-024, 0.23
`
`
`HFHS (OSDI)
`
`-0.56, 0.15
`0.060
`-042, 0.32
`
`025, 0.16
`
`021, 0.21
`
`Group 2
`6‘10
`N=69
`
`192371-503
`
`Group 3
`
`211
`N=47
`
`
`
`-0.32, 0.15
`—0.104
`(—0.33, 0.14)
`
`-0.26, -0.03)
`0.008
`(-0.27. -0,02}
`
`-0.43, 0.13
`
`
`
`subscale
`05])! overall
`score
`
`—O.S4, 0.33
`-0303
`-0.66, 0.16)
`
`
`
`
`
`
`-0.68, 0.13
`
`
`-0.38, 0.37
`
`0.23, 0.13
`
`
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`Medical Officer‘s Review of NDA Zlv023 Amendment: cyclosporinc ophthalmic emulsion 0.05%
`Review #5
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`Reviewer’s Comments:
`
`None of the submitted correlation coefficients approach 1 (or --l), 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 0, grouped by absolute values of Schirmer, in the
`HT population excluding ocular anti-inflammatory drugs and pnnctal plugs for l92371—
`002, -003, 601, -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.
`
`[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
`
`
`
`
`i92371-002
`i92371-003
`
`p-value
`Corneal Staining
`Group 1 Group 2 Group 3
`Group 1 Group 2 Group 3
`
`
`
`-
`5 5mm
`6-10
`5 5mm;
`6—10
`
`
`234
`93
`
`
`_-I-
`241
`1.4
`|
`11
`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”
`
`p-value Group I Group 2 Group 3 l p-value
`
`S 5mm
`6-10
`_._>__ll
`
`
`(0.001
`103
`53
`29
`
`
`2.0
`1.2
`0']
`
`
`0.005
`<0.001
`16
`l7
`l2
`
`
`
`m
`(16%)
`(38%)
`(4 1%)_L
`(16%)
`(32%)
`responder analysis is the number (percent) of patients with a corneal staining score of 0 at month 6
`
`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 211 mm at month 6.
`
`[Note: responders here are patients who achieved a corneal staining score of0 at month
`6-]
`
`Medical Officer‘s Review ofNDA 21-023 Amendment: cyclosporine ophthalmic emulsion 0.05%
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`32-:
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`Responder Analysis:
`
`Table 4: Responder Analysis - Month 6 — 192371—002, —003
` 192371—002
`
`
`and Plugs
`
`11/113
`
`(10%)
`10/106
`(9%)
`
`20/117
`
`(17%)
`10/109
`(18%)
`
`8/37
`(22%)
`8/34
`(24%)
`
`Inflammatory Rx
`and Plt._1gs
`Sjbgrens
`
`Sjégrens — Anti-
`Inflammatory Rx
`
`16/137
`
`(12%)
`15/129
`(12%)
`
`11/131
`
`(8%)
`11/125
`(9%)
`
`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 papalations trend towards higher responder ratesfor the 0.05%
`cyclosporine treatment group.
`
`In two of the groups (117— 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 — 192371-5111, 6031
`
`192371-5—03
`
`
`
`ITI‘ — Anti-
`Iut‘lammatory Rx
`and Flu s
`
`
`
`Reviewer’s Comments:
`
`The responder analyses of1923 71-501 and 1923 71 -503 (Table 2) do not achieve
`statistical significancefor the specific dry eye population ITTT— 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 ofthe findings in —002 and —003.
`
`Medical Officer’s Review ofNDA 21—023 Amendment cyclosporine ophthalmic emulsion 0.05%
`Review #5
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`:13":
`
`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, prurirus, stinging, and visual
`disturbance (most often blurring).
`
`Original conclusions regarding the safety of 0.05% cyclosporine ophthalmic emulsion in
`the W- .11'6 not altered
`
`
`
`APPEA?STHL‘R ‘EfAY
`
`Oil Gfilfiil‘i‘9.1.
`
`
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`Medical Officer’s Review of NDA 21-023 Amendment: cyclosporlne ophthalmic emulsion 0.05%
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`Draft Labeling Page(s) Withheld
`
`28
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`
`
`
`
`[5
`
`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 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 -—003.
`
`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% cyclosporine ophthalmic emulsion
`in
`
`
`
`APPef-EP‘E Tfa’lS WA
`0?! iliiltilml.
`Iflh
`
`Medical Officer’s Review ofNDA 21-023 Amendment: cycIosporine ophthalmic emulsion 0.05%
`Review #5
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`
`'~.,
`
`16
`
`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% Wm
`MK .
`
`
`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
`l1FD—725/Stat/LuHo
`
`HFD-SOS/Micro/Riley
`HFD-SSO/Chemfl‘so
`HFD-SSO/Chem TL/Ng
`HFD—SSO/PM/Gorski
`
`HFD-SSO/PhaImTox/Mukherjee
`HFD-SSO/Pharm Tox TL/Yang
`HEB-880] Biopharm TUBashaw
`
`Medical Officer's Review ofNDA 21—023 Amendment: eyclosporine ophthalmic emulsion 0.05%
`Review #5
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`---_-_..-___--_____---———--——--.--—---.-..------------------.-____—---- --_-----..-_---..-------------------------------
`
`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
`
`31
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`

`,
`.
`_
`:93;
`
`'
`
`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:
`
`Cyclosporine ophthalmic emulsion, 0.05%
`
`Sponsor:
`
`Allergan, Inc.
`2525 Dupont Drive
`PO. Box 19534
`
`lrvine, CA 92623—9534
`
`Pharmacologic Category:
`
`I‘rmnunomodulator
`
`Proposed Indication:
`
`(”mm-WWW
`flax-u. «pm-«av
`thmwm. .
`
`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 NDA 21-023 Restasis(cyc105porine 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 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% cyclosporine emulsion, Allergan has performed new analyses beyond the 6-month
`I'IT analyses originally submitted in NDA 21-023.
`
`
`
`
`
`32
`
`32
`
`

`

`A clinically relevant keratoconjunctivitis sioca subpopulation consisting of two
`subgroups has been defined:
`
`1) degren’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, Grave ’3 disease)
`2) prohibited surgeries during study
`3) use ofprohibited medicationsfor surgeries
`4) use ofprohibited ocular ointments, pilocqrpine, ocular NSAID, beta—blocker, 0r
`ocular steroids.
`' H
`'
`'
`
`Analyses were limited to presenting the proportions of patients with zero