`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`APPLICA TION NUMBER.-
`
`21-023
`
`Trade Name:
`
`Restasis
`
`Generic Name:
`
`Cyclosporine ophthalmic emulsion, 0.05%
`
`Sponsor:
`
`Allergan, Inc.
`
`Approval Date:
`
`October 10, 2003
`
`Indications:
`
`Provides for the use of R_estasis (cyclosporine
`ophthalmic emulsion) Opthalmic Emulsion, 0.05%
`for the following indication:
`to increase tear
`production in patients whose tear production is
`presumed to be suppressed due to ocular
`inflammation associated with keratoconjunctivitis
`sicca. Increased tear production was not seen in
`patients currently taking topical anti—inflamrnatory
`drugs or using punctal plugs.
`
`1
`
`ALL 2033
`MYLAN PHARMACEUTICALS v. ALLERGAN
`|PR2016-01128
`
`1
`
`ALL 2033
`MYLAN PHARMACEUTICALS V. ALLERGAN
`IPR2016-01128
`
`

`

`
`
`CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`21-023
`
`CONTENTS
`
`
`A Rs /
`
`ded in this ND Review.
`
`
`
`A roval Letter
`
`A rovable Letter(s)
`
`Final Printed Labelin
`
`Medical Review(s)
`
`Chemistry Review(s)
`EA/FONSI
`
`Pharmacolo Review(s)
`
`Statistical Review(s)
`
`Microbiolo Review(s)
`Clinical Pharm_ac0logy/ Biogharmaceutics Review(s)
`Administrative D0cument(s)
`
`
`
`Correspondence
`
`2
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`21-023
`
`APPROVAL LETTER! S!
`
`3
`
`

`

`_€
`
`DEPARTMENT OFHEALTH & HUMAN SERVICES
`
`PubficHeathSewice
`
`Food and Drug Administration
`Rockville, MD 20857
`
`NDA 21-O23
`
`Allergan, Inc.
`Attention: Elizabeth Bancroft
`
`Senior Director, Regulatory Affairs
`2525 Dupont Drive
`P.O. Box 19534
`
`Irvine, California 92623-9534
`
`Dear Ms. Bancroft:
`
`Please refer to your new drug application (NDA) dated February 24, 1999, received February 25, 1999,
`submitted under section 505(b) ofthe Federal Food, Drug, and Cosmetic Act for Restasis
`Lcyclosporine ophthalmic emulsion) Ophthalmic Emulsion, 0.05%.
`/_.
`_
`'
`We acknowledge receipt of your submissions dated September 7, 2001, and April 23, May 22,
`June 17, July 11, September 6, October 28, November 15, and December 4, 6, 16 and 20, 2002.
`
`We also refer to our approvable letters of August 3, 1999, and March 25, and October l9, 2000.
`The September 6, 2002, submission constituted a complete response to our October 19, 2000, action
`letter.
`
`This new drug application provides for the use of Restasis {cyclosporine ophthalmic emulsion)
`Ophthalmic Emulsion, 0.05% for the following indication: to increase tear production in patients
`whose tear production is presumed to be suppressed due to ocular inflammation associated with
`keratoconjunetivitis sicca. Increased tear production was not seen in patients currently taking topical
`anti—inflammatory drugs or using punctal plugs.
`
`It is approved, effective on the date of this
`We completed our review of this application, as amended.
`letter, for use as recommended in the enclosed labeling text.
`
`The final printed labeling (FPL) must be identical to the enclosed labeling text for the package insert,
`immediate container and carton labels. Marketing the product with FPL that is not identical to the
`approved labeling text may render the product misbranded and an unapproved new drug.
`
`Please submit an electronic version of the FPL according to the guidance for industry titled Providing
`Regulatory Submissions in Electronic Format - NDA. Alternatively, you may submit 20 paper copies
`of the FPL as soon as it is available but no more than 30 days after it is printed. Individually mount ten
`of the copies on heavy-weight paper or similar material. For administrative purposes, designate this
`submission "FPL for approved NDA 21-023." Approval of this submission by FDA is not required
`before the labeling is used.
`
`4
`
`

`

`NDA 21-023
`
`Page 2
`
`In addition, submit three copies of the introductory promotional materials that you propose to use for
`this product. Submit all proposed materials in draft or mock-up form, not final print. Send one copy to
`this Division and two copies of both the promotional materials and the package insert directly to:
`
`Division of Drug Marketing, Advertising, and Communications, HFD-42
`Food and Drug Administration
`5600 Fishers Lane
`
`Rockville, MD 20857
`
`Please submit one market package of the drug product when it is available.
`
`We have not completed validation of the regulatory methods. However, we expect your continued
`cooperation to resolve any problems that may be identified.
`
`We remind you that you must comply with reporting requirements for an approved NBA (21 CFR
`3 £4.80 and 314.81).
`
`It‘_\‘ou have any questions, call Lori M. Gorski, Project Manager, at (301) 827-2090.
`
`Sincerely,
`
`{See appended eIec:Ir(mic' .\'igrmtin'c gmgc,‘
`
`Wiley A. Chambers, MD.
`Deputy Director
`Division ofAnti-Inflammatory, Analgesic
`and Ophthalmic Drug Products, HFD-550
`Office of Drug Evaluation V
`Center for Drug Evaluation and Research
`
`Enclosure
`
`5
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`21-023
`
`APPROVABLE LETTERQ SQ
`
`6
`
`

`

`
`DEPARTIVLENT OF HEALTH & HUIVIAN SERVICES
`Public Health Service
`
`NBA 21-023
`
`OCT I 9 2000
`
`Food and Drug Administration
`Rockville MD 20857
`
`Allergan, Inc.
`Attention: Elizabeth Bancroft
`
`Director, Regulatory Affairs
`2525 Dupont Drive
`P.0. Box 19534
`
`Irvine, California 92623-9534
`
`Dear Ms. Bancroft:
`
`Please refer to your new drug application (NDA) dated February 24, 1999, received
`February 25, 1999, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic
`Act for Restasis (cyclosporine ophthalmic emulsion) Ophthalmic Emulsion, 0.05%.
`
`We acknowledge receipt of your submissions dated-April 24, August 9, 22, 23, and 31,
`September 7, and October:..2 and 3, 2000.
`tWe also refer to our approvable letters of
`August 3, 1999, and March 25, 2000. Your submission of August 9, 2000, constituted a
`complete response to our March 25, 2000, action letter.
`
`We have completed the review of this application, as amended, and it is approvable. Before
`this application may be approved, however, it will be necessary for you to address the lack of
`substantial evidence of efficacy. Substantial evidence should consist of adequate and well-
`controlled investigations, as defined in 21 CFR 314.126, that the drug product will have the
`effect it purports or is represented to have under the conditions of use prescribed,
`recommended or suggested in the proposed labeling. Specifically, the submitted studies are
`not replicative and are insufficient to establish efficacy —--..........__..._......-—...______
`'
`.4: : 4.
`a
`
`Under 21 CFR 314.50(d)(5)(vi)(b), we request that you update your NDA by submitting all
`safety information you now have regarding your new drug.
`
`We will continue to work with you on the proposed labeling for this product.
`
`In addition, please submit three copies of the introductory promotional materials that you
`propose to use for this product. All proposed materials should be submitted in draft or mock-
`up form, not final print. Please submit one copy to this Division and two copies ofboth the
`promotional materials and the package insert directly to:
`
`7
`
`

`

`Page 2
`NDA 21-023
`
`Division of Drug Marketing, Advertising, and Communications, HFD-40
`Food and Drug Administration
`5600 Fishers Lane
`
`Rockville, Maryland 20857
`
`Within 10 days after the date of this letter, you are required to amend the application, notify us
`of your intent to file an amendment, or follow one of your other options under 21 CFR
`314.} 10. In the absence of any such action FDA may proceed to withdraw the application.
`
`Under 21 CFR 314.102(d) of the new drug regulations, you may request an informal meeting
`or telephone conference with this Division to discuss what further steps need to be taken before
`the application may be approved.
`
`The drug product may not be legally marketed until you have been notified in writing that the
`application is approved.
`
`If you have any questions, call Lori M. Gorski, Project Manager, at (301) 827-2020.
`
`Sincerely,
`
`(ff
`Wi1e)7A. Chambers, MD.
`Deputy Director
`Division of Anti—lnflammatory, Analgesic and
`Ophthalmic Drug Products, HFD—550
`Office of Drug Evaluation V
`Center for Drug Evaluation and Research
`
`8
`
`

`

`
`
`NDA 21-023
`
`Page 3
`
`cc:
`
`NDA 21-Q23
`HFD-550/Div. Files
`[nitialed by:
`HFD-‘S50/CSO/Gorsk
`HFD-550/MO/Boyd‘
`I-[FD-550/Chem/'I‘so
`I-[FD~S50/Phar/Mukheriee
`HFD-725/Stat/Lu
`HFD-880/PK/Tandon
`
`Z; I
`
`5.6’!
`. L; (
`‘
`I/_§(
`
`(5 I
`
`HFD-805/Micro/Riley
`I-IFD-550/DepDir/Cham m
`HFD-550/ADD/Bull
`‘
`HFD-5S0/SCSONacoc'11.
`I-[FD-550/ChemTL/Ng
`HFD-725/Stat TL/Lin
`HFD-880/PK TL/Bashaw
`HFD-805/Micro TL/Cooney
`HFD-002/ORM
`
`}
`£5:
`
`55-.‘
`;’
`
`HFD-105/ADRA
`
`HFD-95/DDMS
`
`HFD-830/DNDC Division Director
`DISTRICT OFFICE
`
`Drafted by: /October 12. 2000. revised 10/16/00
`Inif 1 db :
`7
`fin? ’
`25/
`filenamez
`
`APPROVABLE (AE)
`
`9
`
`

`

`
`
`DEPARTMENT OF HEALTH & HUMAN SERVICES
`
`Public Health Service
`
`
`NDA21-O23
`
`MAR 2 5 2000
`
`Food and Drug Administration
`Rockville MD 20857
`
`Allergan, Inc.
`Attention: Elizabeth Bancroft
`
`Director, Regulatory Affairs
`2525 Dupont Drive
`P.0. Box 19534
`
`Irvine, California 92623-9534
`
`Dear Ms. Bancrofi:
`
`Please refer to your new drug application (NDA) dated February 24, 1999, received
`February 25, 1999, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic
`Act for Restasis (eyclosporine ophthalmic emulsion) Ophthalmic Emulsion, 0.05%.
`
`We acknowledge receipt of your submissions dated August 4 (two), September 3 and 20, and
`December 8, 1999. Your submission of December 8, 1999, constituted a complete response to
`our August 3, 1999, action letter.
`
`We have completed the review of this application, as amended, and it is approvable. Before
`this application may be approved, however, it will be necessary for you to address the
`following:
`
`1. There is a lack of substantial evidence consisting of adequate and well-controlled
`investigations, as defined in 21 CFR 314.126, that the drug product will have the effect it
`purports or is represented to have under the conditions of use prescribed, recommended or
`suggested in the proposed labeling. Specifically, the submitted studies are not replicative
`and are insufficient to establish efficacy
`
`
` __.. ___._,,__;u—-H|“""‘!'“"=" "" ' ' "'5 "”‘***I=0hu=aetrsnnafiu.s-ys;g‘,,;,_$._"_“_“‘_.'§i‘-mi”
`
`2. Under 21 CFR 3 14.50(d)(5)(vi)(b), .we request thatyou update your NDA by-submitting all--
`safety information you now have regarding your new drug.
`
`We will continue to work with you on the proposed labeling for this product.
`
`In addition, please submit three copies of the introductory promotional materials that you
`propose to use for this product. All proposed materials should be submitted in draft or mock-
`up form, not final print. Please submit one copy to this Division and two copies of both the
`promotional materials and the package insert directly to:
`
`10
`
`10
`
`

`

`NDA 21 -023
`
`Page 2
`
`Division of Drug Marketing, Advertising, and Communications, HFD-40
`Food and Drug Administration
`5600 Fishers Lane
`
`Rockville, Maryland 2085?
`
`Within 10 days after the date ofthis letter, you are required to amend the application, notify us
`of your intent to file an amendment, or follow one of your other options under 21 CFR
`314.110. In the absence of any such action FDA may proceed to withdraw the application.
`Any amendment should respond to all the deficiencies listed. We will not process a partial
`reply as a major amendment nor will the review clock be reactivated until all deficiencies have
`been addressed.
`
`Under 21 CFR 31 4.l02(d) of the new drug regulations, you may request an informal meeting
`or telephone conference with this Division to discuss what fiirther steps need to be taken before
`the application may be approved.
`
`The drug product may not be legally marketed until you have been notified in writing that the
`application is approved.
`
`If you have any questions, call Lori M. Gorski, Project Manager, at (301) 827-2090.
`
`Sincerely,
`
`#4
`Wiley A. Chambers, MD.
`Deputy Director
`Division of Anti-Inflammatory, Analgesic
`Ophthalmic Drug Products, I-IFD—550
`Office of Drug Evaluation V
`Center for Drug Evaluation and Research
`
`11
`
`11
`
`

`

`Page 3
`NDA 21-023
`
`cc:
`
`NDA 21-O23
`HIFD—550/Div. Files
`HFD-550/CSO/Gorsk‘
`
`HFD-SSOIMO/Boyd,
`HZFD~550/Chem/Fensélau
`
`L5,:
`
`'
`
`0.51‘
`
`;
`
`I-IFD-550/Phar/Mukhelfiee
`HFD-725/Stat/Lu
`’
`HFD-880/PK/Tandon {5}
`I-II-‘D-805/Micro/Ri1e_v -
`‘
`Ifi'~'D—550/DepDir/Chambers‘
`HFD-550/DD/Midthun . £5
`HFD-550/SCSONaccari
`13!
`
`HFD-550/ChemTL/Ng
`HFD-725/Stat TL/Lin
`
`12
`
`/52
`
`M £
`
`5!
`
`- 4
`
`HFD-880fPK TL/Bashaw
`
`I-[FD-805/Micro TL/Cooncy
`I-[FD-O02/ORM
`
`HFD-105/ADRA
`HIFD-95/DDMS
`
`-
`
`HZFD-83 0/DNDC Division Director
`
`DISTRICT OFFICE
`
`[ff
`
`Drafted by: /March 15, 2000
`Initialed by: __
`
`APPROVABLE (AB)
`
`12
`
`

`

`( DEPARTMENTOFHEALTH &HUMANSERVICES
`
`Public Health Service
`
`Food and Drug Administration
`Rocicville MD 20857
`
`NDA21-023
`
`AUG
`
`-3 ’999
`
`Allergan, Inc.
`Attention: Elizabeth Bancroft
`
`Director, Regulatory Affairs
`2525 Dupont Drive
`P.O. Box 19534
`
`Irvine, California 92623-9534
`
`"Dear Ms. Bancroft:
`
`Please refer to your new drug application (NDA) dated February 24, 1999, received
`February 25, 1999, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic
`Act for Restasis (cyclosporine ophthalmic emulsion) Ophthalmic Emulsion, 0.05%.
`
`We acknowledge receipt of your submissions dated February 24, March 2, 3, 18, and 30,
`April 7, 20, 22, and 23, May 5, 10 (three), and 28, June 17, and July 8, 12, 13, 16 and 26, 1999.
`
`We have completed the review of this application, as amended, and it is approvable. Before this
`application may be approved, however, it will be necessary for you to address the following:
`
`1. There is a lack of substantial evidence consisting of adequate and well-controlled
`investigations, as defined in 21 CFR 314.126, that the drug product will have the effect it
`purports or is represented to have under the conditions of use prescribed, recommended
`or suggested in the proposed labeling. Specifically, the submitted studies are not
`replicative and are insufficient to establish efficacy in the re"-“""“*—-—--—v
`r‘-""-——-—.__.._.....—---"-.
`
`2. The methods to be used in, and the facilities and controls used for, the manufacture,
`processing, packing or holding of the drug substance or the drug product are inadequate
`to preserve its identity, strength, quality, purity, stability and bioavailablity. Specifically, -
`the following issues will need to be addressed:
`
`
`- appears high for a sterile product. Please
`for
`a. The limit of -
`provide justification for using this limit.
`
`
`
`__,....__—g-- . test data was not included. Please provide the data for the
`b. The
`
`containerlclosure
`.. {ESL
`
`13
`
`13
`
`

`

`NDA 21-023
`
`Page 2
`
`‘c. With regard to the performance qualification of the '_' machine and the verification
`
`ofthe
`_
`_
`please provide the data from the original qualification
`performed using _‘—-—--'——---
`
`d.
`
`‘
`
`
`Jvere not included in the
`_
`.
`‘
`.e~.....a....nn--_c:-....¢
`s validation. Therefore, the effect of the‘
`
`_
`has not been established. Please provide information to
`demonstrate that a
`‘~--~--—----—-—--''*''''''‘''''''‘'‘'''''''''''‘''‘''''‘'‘''-'' _ will be
`sufficient to '
`
`during the --
`
`on the
`
`e. The study perfonned to validate a
`
`*-""*---"j""""": for the drug product does not
`
`.
`
`support --v--*“:""‘“"“""‘
`
`We will continue to work with you on the proposed labeling for this product.
`
`Within 10 days after the date of this letter, you are required to arnend the application, notify us of
`your intent to file an amendment, or follow one of the other options under 21 CFR 314.110. In
`the absence of any such action FDA may proceed to withdraw the application. Any amendment
`should respond to all the deficiencies listed. We will not process a partial reply as a major
`amendment nor will the review clock be reactivated until all deficiencies have been addressed.
`
`Under 21 CFR 314.50(d)(5)(vi)(b), we request that you update your NDA by submitting all
`safety information you now have regarding your new drug.
`
`In addition, please submit three copies of the introductory promotional materials that you
`propose to use for this product. All proposed materials should be submitted in draft or mock-up
`form, not final print. Please submit one copy to this Division and two copies of both the
`promotional materials and the package insert directly to:
`
`Division of Drug Marketing, Advertising, and Communications, I-IFD-40
`Food and Drug Administration
`5600 Fishers Lane
`
`Rockville, Maryland 20857
`
`Under 21 CFR 3l4.l02(d) of the new drug regulations, you may request an informal meeting or
`telephone conference with this Division to discuss what further steps need to be taken before the
`application may be approved.
`
`The drug product may not be legally marketed until you have been notified in writing that the
`application is approved.
`
`14
`
`14
`
`

`

`
`
`NDA 21-023
`
`Page 3
`
`If you have any questions, contact Lori M. Gorski, Project Manager, at (301) 827-2090.
`
`Sincerely,
`
`Wileyéflhaanbers, M.D.
`
`J
`
`Deputy Director
`Division of Anti-Inflammatory, Analgesic and
`Ophthalmic Drug Products, HFD-550
`Office of Drug Evaluation V
`Center for Drug Evaluation and Research
`
`15
`
`

`

`
`
`NDA 21-023
`
`Page 4
`
`cc:
`
`£5}
`
`NDA 21-023
`HFD-550/Div. Files
`HFD-550/CSO/Gorski
`HFD-550/MO/Boyd
`HFD-550/Chem/Bhnanwu -
`HFD-550/Phar/Mukheriee
`HFD-725/Stat/Lu
`1!!
`PIFD—880/PK/'I‘anaon
`HFD-805/Micro/Riley
`HFD-550/DepDir/Chambers
`HZFD-5 5 0/ChemTL/Ng
`HFD-550/Pharm TL/Weir
`HFD-550lC1in Rev/Holmes
`
`HFD-725/Stat TL/Lin
`
`1-;I
`
`_
`
`‘.
`
`Lg
`
`15 S
`
`HFD-880/PK TL/Bashaw
`
`HFD-805/Micro TL/Cooncy
`HFD-002/ORM
`
`I-IFD-105/ADRA
`
`J,
`
`.
`
`4
`HFD-95/DDMS
`HFD-830/DNDC Division Director
`
`DISTRICT OFFICE
`
`Drafted by: /July 28, 1999
`
`filename: 21023A.E.WPD
`
`APPROVABLE (AB)
`
`16
`
`16
`
`