`
`RESEARCH
`
`APPLICATION NUMBER:
`
`21-023
`
`MEDICAL REVIEWS)
`
`1
`
`ALL 2073
`MYLAN PHARMACEUTICALS v. ALLERGAN
`|PR2016-01131
`
`1
`
`ALL 2078
`MYLAN PHARMACEUTICALS V. ALLERGAN
`IPR2016-01131
`
`
`
`
`
`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
`P.0. Box 19534
`
`Irvine, CA 926233534
`
`Pharmacologic Category:
`
`immunomoduiator
`
`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, discussiorr
`between ODE V and the Division, and a correctedpackage insert transmitted by the
`applicant on December 20, 2002.
`
`The applicant proposes inserting the word “(apical " before "anti-inflammation) " in the
`Clinical Evaluations and Indications and Usage sections ofIbe {abet
`
`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 sicca.
`
`There are no recommendations for additional postmarketing studies.
`
`William M. Boyd, MD.
`Medical Officer
`
`NDA 21-023
`HFD-SSOfDiv Files
`
`HFD-SSO/MO/Boyd
`HFD—SSOIDep Director/Chambers
`HFD-725/Stat/LuHo
`
`HFD-SOS/MicrofRiley
`HFD—S SOIChemeso
`
`HFD—SSO/Chem TUNg
`HFD-SSO/PlWGorski
`
`HFD-SSO/PharmTofoukherjee
`HFD-SSO/Pharm Tox TIJYang
`RFD-880! Biopharm TUBashaw
`
`Medical Officer's Review of NBA 2l-023 Amendment: cyclosporine ophthalmic emulsion 0.05%
`Review #9
`
`4
`
`
`
` -—-——-—.-----—------------a-—-------_ ---—--—------------_—_-.—.n--------------—----------——-.. .-----m._....---_--- --
`
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`mun-- -__--_--—-------—- --- ---------a-___-_-___--__-_....----u----———---—-.... ------_-...--_____--_—-—-.--.--- ----.-- n--
`
`/s/
`
`William Boyd
`12/23/02 10:27:00 AM
`MEDICAL OFFICER
`
`Wiley Chambers
`12/23/02 03:29:14 PM
`MEDICAL OFFICER
`
`
`
`5
`
`
`
`Medical Officer's Review of NBA 21-023
`Amendment
`
`NDA 21-023
`
`Submissions:
`
`Sefitember 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:
`
`Sponsor:
`
`CycIoSporine ophthalmic emulsion, 005%
`
`Allergen, Inc.
`2525 Dupom 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
`administratiorl
`
`Revised labeling is based onfim’her discussion within the Division on December I 9,
`2002, regarding the Ciinical Pharmacology, Clinicai Evaluations, and Indication and
`Usage sections and subsactfons ofthe Iabeling.
`
`
`
`6
`
`
`
`/@
`
`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 Reslasis (cyclosporinc
`ophthalmic emulsion) 0.05%
`_ MW“
`Mmwmmwyh—cmm 1......»
`
`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/StathuHo
`
`HFD-SOS/Micro/Riley
`HFD-SSO/Chem/Tso
`
`HFD-SSO/Chem TUNg
`HFD-SSO/PM/Gorski
`
`HFD—SSO/PhamiTox/Mukherjee
`HFD-SSO/Pharm Tox TL/Yang
`HFD—SSO/ Biopharm TL/Bashaw
`
`Medical Officer‘s Review ofNDA 3 [-023 Amendment: cyclosporine ophthalmic emulsion 0.05%
`Review #8
`
`8
`
`
`
` _-----.--------—.—..---—-—--__-—-__—-- InuthCOIl-II---------“—--..--'-------—----- ..--------—-—-----—-- --- .-_------
`
`.=r.-r
`
`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«-—------—----------—-—‘-h“ ..--------------- -----_.... ..-__-__
`
`/5/
`
`William Boyd
`12/20/02 02:42:36 PM
`MEDICAL OFFICER
`
`Wiley Chambers
`12/20/02 03:26:37 PM
`MEDICAL OFFICER
`
`9
`
`
`
`
`
`Medical Officer’s Review of NDA 21-023
`Amendment
`
`N DA 21-023
`Medical Officer’s Review #7
`
`Submissions:
`
`December 16, 2002
`Review Completed: December 16,2002
`
`Proposed Tradenam e:
`
`Restasis
`
`Generic Name:
`
`Cyclosporine ophthalmic emulsion, 0.05%
`
`Sponsor:
`
`Allergen, Inc.
`2525 Dupont Drive
`P.0. Box 19534
`
`Irvine, CA 92623-9534
`
`Pharmacologie 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 l2ll6i02.
`
`Reviewer’s Comments:
`
`Two labeling comments appearing in the Chemist ’5 reviBW, dated 12/} 3/02 12:12:56 PM
`in DFS, were not included in thefinal drugproduct labeling.
`
`1) Under Description, “The amount as "" J should replace 0.05% for cyclosporine."
`
`The proportion ofthe active ingredient, cycfosporfne, is acceptable per CFR 201.100
`(15%4)-
`
`2) Under How Supplied, “The word vial should be replaced by ‘7- 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
`
`
`
`_{— Draft Labeling Page(s) Withheld
`
`11
`
`11
`
`
`
`Recommendations:
`
`(1‘
`
`1: .013
`
`It is recommended that NDA "- be afiproved with the labeling revisions listed in this
`review.
`
`The application supports the safeg and effectiveness of Restasis (cyclosporine
`ophthalmic emulsion) 0.05%
`
`_
`
`There are no recommendations for additional postmarkcting studies.
`
`William M. Boyd, MD.
`Medical Officer
`
`NDA 21-023
`HFD—SSO/Div Files
`
`HPD—SSO/MO/Boyd
`HFD-SSO/Dep Director/Chambers
`HFD-‘IZS/Stat/LuHo
`
`HFD-SOS/Micro/Riley
`HFD—SSO/Chemfl‘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 NBA 21-023 Amendment: cyclosporine ophthalmic emulsion 0.03%
`Review #7
`
`12
`
`
`
`
`
`12
`
`
`
`----_-..----_--—-----———_-- - --------..-.-----------------noon-u-----—--_-_.----------------—.._--.--____._—-—ma-..
`
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`----- ——-—-.--------- -----------_-_-___--———————-.-I-u-u-m-uu-u.-----------—-----_ ---—----..... “up-nunnnnnun.----- ---
`
`/8/
`
`William Boyd
`12/16/02 02:33:44 PM
`MEDICAL OFFICER
`
`Wiley Chambers
`12/16/02 02:54:09 PM
`MEDICAL OFFICER
`
`13
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`13
`
`
`
`I
`
`m
`
`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:
`
`Allergen, Inc.
`2525 Dupont Drive
`P.O. Box 19534
`
`Irvine, CA 92623-9534
`
`Pharmacologic Category:
`
`immunornodulator
`
`Proposed Indication:
`
`Dosage Form and
`Route of Administration:
`
`Submitted:
`
`ophthalmic emulsion for topical ocular
`administration
`
`Submitted is 3 Office of Drug Safety memorandum in response to a November 19, 200?.
`request from the Division of Anti-inflammatory, Analgesic, and Ophthalmologic Drug
`Products for a re-rcview 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, DME’I‘S acknowledges that
`packaging the product in single-use containers and labeling them as single-use addresses
`the concern surrounding the % 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 drops per milliiiter
`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 eiearly communicated to practitioners, patients and caregivers
`
`14
`
`14
`
`
`
`
`
`it?
`
`
`
`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
`--—-—-—
`-—.. he added to the labels and labeling.
`
`Medical Officer’s Comments:
`
`Single-use, unpreserved topical ophthalmic drug products uniformbt contain a volume I
`exceeding the amount neededfor a single date (including ovetjill).
`
`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 single’use, unpreserved product there is the risk th at 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 inithediately after administration.
`
`Do not allow the tip of the vial to touch the eye or any surface, as this may
`contaminate the emulsion.
`
`. .WW
`The Restasis tray label is marked "
`The W is marked ‘
`..._-
`“WW 'Both tray label and _ MW...-
`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 ofNDA 21-023: cyclosporine ophthalmic emulsion 0.05%
`Review #6
`
`15
`
`15
`
`
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`----.----.................................................a...---------.n...........................................-
`
`This is a representation of an electronic record that was signed electronically and
`---------—- -- —-—-——-—-—-—-— -————--- — -——---_-.—.--_-----.---- ------.-n—-— -—..__-----.. -_--- -..-------- --- —-_ -_ ----_-----
`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, and'ipratropium 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 b?
`
`‘
`
`with, "
`
`I
`
`_ _
`
`The proposed labeling on the Resrosis 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, Restosis is
`a white, opaque emulsion. There is no perceived additional risk to the indicated
`populationfrom the use of a nonprescription ophthalmic lubricant. Based on the safety
`profile ofRestosis, there is no perceived safety riskfi‘om the inadvertent use ofResiosis in
`the population utilizing nonprescription ophthalmic lubricants.
`
`The volume and packaging ofnon-ophthalmic products on the marker in the US. is unlike
`the proposed packaging of the Restasis vial, carton. or tray. Again, the proposed
`labeling on the Resrasis vial is clear and distinctive; the proposed packaging of the tray
`andphysician sample carton is clear and distinctive.
`
`Medical Officer‘s Review of NBA 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
`t.._._—-/
` «we.
`_~'_WH__IF”H_MW I
`we“:
`_ according to the statement above, if strictly adhered to by the
`“SET.
`
`W I
`
`Medical Officer’s Comments:
`
`
`
`is no longerfound in the package insert, Restasis vial,
`The phrase ‘
`tray or;
`_ma It has been replaced, where appropriate with ‘ "‘-
`'
`, or “ m These phases are
`intentionally more restrictive than "
`--———-..
`
`1n 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:
`
`.
`‘
`.
`S‘ee prevtous Comment 3 egardlng
`
`u- w .-
`_
`
`Again, with every single—use, ttnpreservedprodact there is the risk that patients may save
`the vial and use the remaining drug at a later time. The risks affixing the cyclosparine
`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 afier
`opening for administration to one or both eyes, and the remaining contents should
`be discarded immediately afier administration.
`
`Do not allow the tip of the vial to touch the eye or any surface, as this may
`contaminate the emulsion.
`
`
`-—--*”""'
`-” and “
`The Restasis tray label is marked " -««-—-s-""""""'
`’
`” The‘
`is marked '
` q.
`'Both travlabeiana
`—
`__ indicate the drug product is
`.-———-----':""‘
`
`..————-_s '
`
`Medical Officer's Review of NBA 21-023: cyclosporine ophthalmic emulsion 095%
`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 singie to drop to each eye.
`
`On the my label, revise —-—-——--"'L'statement to read: “ ""'"—"-'-——'-
`W
`
`Medical Officer’s Comments:
`
`In the ctinicoi trials performed by the applicant in support ofthe eflicacy and safety of
`the drug product, dosing took place approximately 12 hours apart.
`t;
`,
`'
`
`This reviewer does not-agree that the suggested revision to the M is
`appropriate.
`
`We suggest substitution of the word “-- ’ for the Greek “1.11.”. as p[L} is frequently
`mistaken for m[L], particularly with scripted instructions.
`
`Medical Officer’s Comments:
`
`" "—- ‘ for the
`This reviewer does not agree that the suggested substitution of the war
`Greek "FL " is appropriate. There could be no substitution ofRestasis with a -—
`concentration since none exits.
`
`Topicaf ophthaimic prostogtondins 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 of NBA 21-023: cyclosporine ophthalmic emulsion 0.05%
`Review #6
`
`19
`
`19
`
`
`
`
`
`RESTASISm 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 confilsfon 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
`W
`ophthalmic emulsion) 0.05%
`. ‘mwwW‘Nfi
`" u" I.
`
`There are no recommendations for additional postmarketing studies.
`
`William M. Boyd, MD.
`Medical Officer
`
`
`
`N DA 21-023
`HFD-SSOIDiv Files
`
`HFD-SSO/MO/Boyd
`HPD-SSO/Dep Director/Chambers
`HFD-"lZSfStat/LuHo
`
`HFD—BOS/Microijley
`HFD-SSO/Chemfl‘so
`
`HFD-SSO/Chem TUNg
`HFD-SSO/PMlGorski
`
`HFD-SSO/PharmTox/Mukherjee
`HFD—SSO/Pharm Tox TL’Yang
`HFD-SSOI Biopharm TUBashaw
`
`Medical Officer’s Review ofNDA 21—023: cyclosporine ophthalmic emulsion 005%
`Review #6
`
`20
`
`20
`
`
`
` --- ---_-___-_--—.~—--__--—.—-_----__-.--—---—-----—-—___-------—---.n--.ou--nun--.Qah----_-.———----------------
`
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`------..—--------.—---—---—-.—------_—-m.———————---..-.._.——----o--------___...po¢-¢-———-—-—----.-.--.-- ----nu ... n-n —--—-
`
`/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
`
`
`
`
`
`
`
`‘
`
`‘
`
`4;:-
`
`Medical Officer’s Review of NBA 21-023
`Amendment and
`
`NDA 21-023
`
`Safety Update
`
`Submissions:
`
`September 7, 2001
`April 23, 2002
`June 17, 2002
`July 1], 2002
`September 6, 2002
`November 15, 2002
`
`Medical Officer’s Review #5
`
`Review Completed: December 13, 2002
`
`Proposed Tradename:
`
`Restasis
`
`Generic Name:
`
`Sponsor:
`
`Cyc108porine ophthalmic emulsion, 0.05%
`
`Allergen, Inc.
`2525 Dupont Drive
`._ Po. Box 19534
`Irvine, CA 92623-9534
`
`Pharmacologic Category:
`
`immunomodnlator
`
`Proposed Indication:
`
`Dosage Form and
`Route of Administration:
`
`Submitted:
`
`AW
`
`W.
`
`ophthalmic emulsion for topical ocular
`administration
`
`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 (cycloSporinc 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.
`
`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
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`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 Schimier 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 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.
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`Medical Officer’s Review ofNDA 2 LOB Amendment: cyclesporine ophthalmic emulsion 0.05%
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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—5 01 (Europe), and Allergen study
`192371-503 (Europe).
`
`Table 1: Validation — Schirmer Score as Clinically Relevant Endpoint
`r—r..__.___.._
`
`192371-5032
`HFHS (OSDI)
`
`
`
`Group 2 Group 3
`p—value
`
`N=36 N=43 N=53
`
`
`
`
`m 9°“
`
`0.24
`0.24
`0.013
`
`
`
`
`
`E 051)] symptom——
`i subscale
`‘ OSDI overall
`score
`
`
`
`analyses performed on data obtained at single visit
`analyses performed on data obtained at week 24
`
`1 '
`
`Reviewer’s Comments:
`
`Both the 0313! symptom subscaie and the 05.91 overait‘ score are statistically
`significantly tower in subjects with Schirmer wetting scores qfa H mm. There are also
`statistically significantiy lower corneal staining scores in Sitiiiects with Schirmer wetting
`scores of-E H mm.
`
`
`
`Table 2: Correlation coefficient: with confidence intervals for validation analyses on
`HFHS and 192371—503
`
`HFHS (OSDI)
`
`
`
`6-10
`N=28
`
`N=20
`
`211
`N 89
`
`
`
`
`
`Group 2
`610
`N=69
`
`192371-503
`
`Group 3
`
`
`211
`N=47
`
`
`
`
`
`
`subscale
`05]): overall
`
`—O.54, 0.33
`-0.66, 0.16)
`
`4156, 0.15
`-o.42, 0.32
`0.060
`
`-0.25, 0.16
`—o.21, 0.21
`
`-0.68. 0.13
`
`41.38 0.37
`
`41.28 0.13
`
`
`
`
`.
`
`.
`
`-0.32, 0.15
`
`-0.26, -0.03}
`
`
`
`
`
`(-0.13, 0.25
`
`(—0.33, 0.14)
`
`(-0.27. -0.02)
`
`-0.30 0.07
`
`-0.24, 0.23
`
`43.43 0.13
`
`
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`Medical Officer‘s Review ofNDA 21-023 Amendment: cyclosporinc ophthalmic emulsion 0.05%
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`Reviewer’s Comments:
`
`None of the submitted correlation coefiicients approach 1' (or ml), and based on the
`confidence intervals pmvided, veryfew of(he coeflicienis 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
`HT population excluding ocular anti-inflammatory drugs and punctal plugs for 192371 —
`002, -003, -501, -503.
`
`if an increase in Schirmer score above It mm were clinically relevant, these groups
`should show less ocular surface staining in 192371—002, -003, -50 l, -SO3.
`
`[Note: responders here are patients who achieved an increase in Schirrner wetting scores
`2 10 mm at the six-month timepoint.]
`
`Table 3: Corneal Staining at Month I5
`Percent of Patients with a Corneal Staining Score of Zero
`
`
`
`i92371-002
`i92371-003
`
`Corneal Staining
`Group 1 Group 2 Group 3
`p-value
`Group 1 Group 2 Group 3
`
`-
`5 5mm
`6-10
`
`S 5mm;
`6—10
`
`234
`93
`
`
`
`Ill-
`2‘1
`14
`
`ll
`34
`22
`
`(8%)
`(12%)
`(15%)
`(24%)
`_
`1__.._______
`
`responder analysis is the number (percent) of patients with a corneal staining score ofO at month 6
`
`
`
`
`
`:131377.50 1
`
`_ 192371-503
`
`Group I Group 2 Group3 I p-value
`
`
`S 5mg
`6-10
`
`103
`53
`
`2.0
`1.2
`
`
`V
`16
`17
`
`{41%
`32%)
`16‘1’1
`(38%)
`(16%)
`(7%)
`m
`responder analysis is the number (percent) of paticnls with a comeal 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 scare oft}I 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” mm at month 6.
`
`(Note: responders here are patients who achieved a corneal staining score of 0 at month
`6.]
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`Medical Officer‘s Review of NDA 21-023 Amendment: cyclosporine ophthalmic emulsion 0.05%
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`Responder Analysis:
`
`Table 4: Responder Analysis - Month 6 — 192371—0021 4103
`
`192371-002
`
`
`
`(0%)
`
`111113
`
`(10%)
`10/106
`(9%)
`
`20/117
`
`(11%)
`10/109
`(18%)
`
`8/37
`(22%)
`8/34
`(24%)
`
`Inflammatory Rx
`and Plggs
`Sjiigrens
`
`Sjégrens - Anli-
`Inflammatory Rx
`and Plugs
`
`161137 mm
`
`(12%)
`15/129
`(l2%)
`
`(8%)
`11/125
`(9%)
`
`2’43
`(5%)
`
`0.52
`
`0.04907
`
`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).
`Table 1, all of the populations trend towards higlier responder ratesfor the 0. 05%
`ci'closporine treatment group.
`
`in
`
`In two ofthe groups (ITT— anti—inflammatory Rx andpunctal plugs and Sjligrens - anti-
`irtflammatory Rx and punctal plugs), the responder rates are statistically significant
`fm'oring 0.05% cyclosporine in both trials.
`
`Table 5: Responder Analysis - Month 6 —1923'll»5l}l, 603
`
`and Flu s
`
`Inflammatory Rx
`
`Reviewer’s Comments:
`
`The responder analyses of} 923 71401 and W23 71 w5 03 (Table 2) do not achieve
`statistical significance for the specyic dry eye population H75 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 ~50} and H503 analyses did not achieve statistical significance, the responder
`analyses are supportive of thefindings in -002 and -003.
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`Medical Officer‘s Review of NBA 21-023 Amendment: cyclosporine ophthalmic emulsion 0.05%
`Review #5
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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% cyclosporine ophthalmic emulsion in
`the W .lre not
`
`APPEARS Tl‘llfi 3-?“
`0ii0§ifiifi§al
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`Medical Officer's Review of NBA 21-023 Amendment: cyclosponne ophthalmic emulsion 0.05%
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`4,
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`Draft Labeling Page(s) Withheld
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`Conclusions:
`
`i)
`
`A clinically relevant, dry eye population (ITT — ocular anti-inflammatory Rx and
`punetal 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 ~SO3 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 OSDl overall score are statistically
`significantly lower in subjects with Schirmer wetting scores of 2 l 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.
`
`Allergen 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.
`»
`r
`
`‘4)
`
`Original conclusions regarding the safety of 0.05% cyclosporine ophthalmic emulsion
`in
`are not altered,
`
`APPEEFS‘ TEL“: WAY
`CPI ORlGl’ifill
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`Medical Officer’s Review ofNDA 21-023 Amendment: cyeIOSporine ophthalmic emulsion 0.05%
`Review #5
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`16
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`Recommendations:
`
`It is recommended that NDA 21-496 be approved with the labeling revisions iisted in this
`review.
`
`The application supports the safety and effectiveness of Restasis (cyclosporine
`ophthalmic emulsion) 0.05%W
`Wf... .
`
`
`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
`liFD—725/Stat/LuHo
`
`HFD-SOSlMicro/Riley
`HFD-SSO/Chenm’l‘so
`HFD-SSO/Chem TL/Ng
`HFD—SSO/PM/Gorski
`
`HFD-SSO/PhaImTox/Mukherjee
`HFD-SSO/Pharm Tox TLlYang
`RFD-8801 Biopharm TUBashaw
`
`1-».
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`Medical Officer's Review ofNDA 21-023 Amendment: cyclosporine ophthalmic emulsion 0.05%
`Review #5
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`______._-___--_____---———-————-.--------..---------------..----____—---- --___---—-_---__-_-..——.-_c----------—------- ---
`
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`honntu-ofln—--—---—----------- _------—--—-------------------_-- ---..-- -___-_-__-_--__--_--_--_--___-_- --_--_--_--—---
`
`/s/
`
`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 NBA 21-023
`Amendment
`
`NDA 21-023
`Medical Officer’s Review #4
`
`Submission:
`
`1083'00
`
`Review Completed:
`
`10f5l00
`
`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:
`
`I‘Imnunomodulalor
`
`Proposed Indication:
`
`Dosage Form and
`Route of Administration:
`
`Submitted:
`
`Ophthalmic emulsion for topical ocular
`administration
`
`Response dated October 3, 2000, to items identified in the approvable letter dated March
`25, 2000, for NBA 21-023 Restasis(cy0105porine 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
`ITT analyses originally submitted in NDA 21-023.
`
`32
`
`
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`32
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`
`
`
`
`A clinically relevant keratoconjunctivitis sioca subpopnlation 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 Vic-ant protocol violations included:
`
`1) prohibited diseases (severe acne rosacea, severe migraine, Grave ’3 disease)
`2) prohibited surgeries during study
`3) use ofprohibited medicationsfor surgeries
`4) use ofpmhibfled ocular “immemS. Pilocarpine, ocular NSAIDg beta-blocker, 0r
`ocularsteroids.
`' “
`v
`v
`.
`
`Analyses were limited to presenting the proportions ofpatients with zero severity score
`for one sign (temporal corneal staining) and one symptom (bluu‘ed vision) at Month 6.
`
`Description of Patients in the High-Risk Patient Subpopulation:
`
`There are no statistically significant differences in the subpopulation demogiaphic
`variables between treatment groups for age, age-by—group, sex, race, or iris color in
`studies 192371—