`
`CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`21-023
`
`ADMINISTRATIVE DOCUMENTS
`
`

`

`
`
`EXCLUSIVITY SUMMARY for NDA #
`
`21—023
`
`Trade Name Restasis Ophthalmic Emulsion, 0.05%
`Generic Name cyclosporine ophthalmic emulsion
`Applicant Name Allergan Inc.
`Approval Date
`December 23, 2002
`
`HFD—SSO
`
`PART I:
`
`IS AN EXCLUSIVITY DETERMINATION NEEDED?
`
`1. An exclusivity determination will be made for all original
`applications, but only for certain supplements. Complete
`Parts II and III of this Exclusivity Summary only if you
`answer ”YES"
`to one or more of the following questions about
`the submission.
`
`a) Is it an original NDA?
`
`YES/_§_/
`
`NO /
`
`/
`
`b) Is it an effectiveness supplement? YES /
`
`/
`
`NO /#X_/
`
`c) Did it require the review of clinical data other than to
`
`support a safety claim or change in labeling related to
`safety?
`(It it required review only of bioavailability
`or bioequivalence data, answer ”NO.”)
`
`YES / L/
`
`NO /_/
`
`If your answer is "no” because you believe the study is a
`bioavailability study and,
`therefore, not eligible for
`exclusivity, EXPLAIN why it is a bioavailability study,
`including your reasons for disagreeing with any arguments
`made by the applicant that the study was not simply a
`bioavailability study.
`
`If it is a supplement requiring the review of clinical
`data but it is not an effectiveness supplement, describe
`the change or claim that is supported by the clinical
`data:
`
`d) Did the applicant request exclusivity?
`
`is "yes," how many years of
`If the answer to (d)
`exclusivity did the applicant request?
`
`YES /_;g_/ NO /_/
`
`5 years
`
`Page 1
`
`
`
`

`

`e} Has pediatric exclusivity been granted for this Active
`Moiety?
`
`YEs
`
`/+7 /
`
`NO /_§_/
`
`IF YOU HAVE ANSWERED “NO“ TO ALL OF THE ABOVE QUESTIONS, GO
`
`DIRECTLY TO THE SIGNATURE BLOCKS ON Page 9.
`
`2. Has a product with the same active ingredient(s), dosage form,
`strength,
`route of administration, and dosing schedule
`previously been approved by FDA for the same use? (RX to OTC)
`Swi:ches should be answered No w Please indicate as such).
`
`If yes, NDA #
`
`Drug Name
`
`
`
`YEs /4if
`
`NO / X /
`
`IF THE ANSWER TO QUESTION 2
`
`IS "YES," GO DIRECTLY TO THE
`
`SIGNATURE BLOCKS ON Page 9.
`
`3. Is this drug product or indication a DESI upgrade?
`
`YES /___/
`
`NO /_§_/
`
`IF THE ANSWER TO QUESTION 3
`
`IS "YES,“ GO DIRECTLY TO THE
`
`SIGNATURE BLOCKS ON Page 9
`upgrade).
`
`(even if a study was required for the
`
`
`PART II: FIVE—YEAR EXCLUSIVITY FOR NEW CHEMICAL ENTITIES
`
`(Answer either #1 or #2, as appropriate)
`
`l.Single active ingredient product.
`
`Has FDA previously approved under section 505 of the Act any
`drug product containing the same active moiety as the drug
`under consideration? Answer "yes" if the active moiety
`(including other esterified forms, salts, complexes, chelates
`or clathrates) has been previously approved, but this
`particular form of the active moiety, e.g.,
`this particular
`ester or salt
`(including salts with hydrogen or coordination
`bonding) or other non~covalent derivative (such as a complex,
`chelate, or clathrate) has not been approved. Answer "no“ if
`the compound requires metabolic conversion (other than
`deesterification of an esterified form of the drug)
`to produce
`an already approved active moiety.
`
`YES /__§_/
`
`N0 /___/
`
`Page 2
`
`
`
`

`

`If "yes," identify the approved drug product(s} containing the
`active moiety, and,
`if known,
`the NDA #(s).
`
`NDA #
`
`50—563
`
`Sandimmune
`
`NDA #
`
`50-715
`
`Neoral
`
`NDA #
`
`2. Combination product-
`
`If the product contains more than one active moiety (as
`defined in Part II, #1), has FDA previously approved an
`application under section 505 containing apy 92E of the active
`moieties in the drug product?
`If,
`for example,
`the
`combination contains one never—before—approved active moiety
`and one previously approved active moiety, answer "yes."
`(An
`active moiety that is marketed under an OTC monograph, but
`that was never approved under an NBA,
`is considered not
`previously approved.)
`
`YES /___/
`
`NO /
`
`/
`
`If "yes,“ identify the approved drug product(s) containing the
`active moiety, and,
`if known,
`the NDA #(s).
`
`NDA #
`
`NDA #
`
`NDA #
`
`IF THE ANSWER TO QUESTION 1 OR 2 UNDER PART II IS "NO,“ GO
`
`DIRECTLY TO THE SIGNATURE BLOCKS ON Page 9.
`III.
`
`IF "YES,F GO TO PART
`
`PART III: THREE-YEAR EXCLUSIVITY FOR NDA'S AND SUPPLEMENTS
`
`To qualify for three years of exclusivity, an application or
`supplement must contain "reports of new clinical investigations
`(other than bioavailability studies) essential to the approval of
`the application and conducted or sponsored by the applicant."
`This section should be completed only if the answer to PART II,
`Question 1 or 2, was "yes."
`
`1. Does the application contain reports of clinical
`investigations?
`(The Agency interprets "clinical
`investigations” to mean investigations conducted on humans
`other than bioavailability studies.)
`If the application
`
`Page 3
`
`
`
`

`

`
`
`investigations only by virtue of a right of
`contains clinical
`reference to clinical investigations in another application,
`answer "yes," then skip to question 3(a).
`If the answer to
`3(a)
`is "yes" for any investigation referred to in another
`application, do not complete remainder of summary for that
`investigation.
`
`IF “NO," GO DIRECTLY TO THE SIGNATURE BLOCKS ON Page 9.
`
`YES
`
`/_§__/
`
`NO /
`
`/
`
`2.
`
`to the approval” if the
`A clinical investigation is "essential
`Agency could not have approved the application or supplement
`without relying on that investigation.
`Thus,
`the
`investigation is not essential to the approval if 1) no
`clinical investigation is necessary to support
`the supplement
`or application in light of previously approved applications
`(i.e.,
`information other than clinical trials, such as
`bioavailability data, would be sufficient to provide a basis
`for approval as an ANDA or 505(b)(2) application because of
`what is already known about a previously approved product), or
`2)
`there are published reports of studies (other than those
`conducted or sponsored by the applicant) or other publicly
`available data that independently would have been sufficient
`to support approval of the application, without reference to
`the clinical investigation submitted in the application.
`
`For the purposes of this section, studies comparing two
`products with the same ingredient(s) are considered to be
`bioavailability studies.
`
`(a)
`
`is-a
`In light of previously approved applications,
`clinical investigation (either conducted by the
`applicant or available from some other source,
`including the published literature) necessary to
`support approval of the application or supplement?
`
`YES /
`
`
`x /
`
`NO /
`
`/
`
`If "no," state the basis for your conclusion that a
`clinical trial is not necessary for approval AND GO
`DIRECTLY TO SIGNATURE BLOCK ON Page 9:
`
`
`
`
`Page 4
`
`
`
`

`

`(b) Did the applicant submit a list of published studies
`relevant to the safety and effectiveness of this drug
`product and a statement that
`the publicly available
`data would not
`independently support approval of the
`application?
`
`YES/i/
`
`NO/_§_/
`
`(I)
`
`is "yes,” do you personally
`If the answer to 2(b)
`know of any reason to disagree with the applicant's
`conclusion?
`If not applicable, answer NO.
`
`YES /_‘_/ NO/
`
`
`x /
`
`(2)
`
`
`_
`If yes, explain:
`is "no,” are you aware of
`If the answer to 2(b)
`published studies not conducted or sponsored by the
`applicant or other publicly available data that could
`independently demonstrate the safety and effectiveness
`of this drug product?
`
`If yes, explain:.r
`
`
`
`res/_/
`
`
`NO/X/
`
`(c)
`
`If the answers to (b)(1) and (b)(2) were both "no,"
`identify the clinical investigations submitted in the
`application that are essential to the approval:
`
`Investigation #1, Study # 192371—002
`
`Investigation #2, Study # 192371—003
`
`Investigation #3, Study # 1923717501
`
`Investigation #4, Study # 192371—503
`
`investigations must be "new“
`3. In addition to being essential,
`to support exclusivity.
`The agency interprets "new clinical
`investigation" to mean an investigation that I) has not been
`relied on by the agency to demonstrate the effectiveness of a
`previously approved drug for any indication and 2) does not
`duplicate the results of another investigation that was relied
`on by the agency to demonstrate the effectiveness of a
`previously approved drug product, i.e., does not redemonstrate
`something the agency considers to have been demonstrated in an
`already approved application.
`
`Page 5
`
`
`
`

`

`For each investigation identified as "essential to the
`approval," has the investigation been relied on by the
`agency to demonstrate the effectiveness of a previously
`approved drug product?
`(If the investigation was relied
`on only to support
`the safety of a previously approved
`drug, answer ”no.")
`
`Investigation #1
`
`YES /___/
`
`NO /4§#/
`
`Investigation #2
`
`YES /___/
`
`NO /_§_/
`
`Investigation #3
`
`YES /44i/
`
`NO /_§_/
`
`Investigation #4
`
`YES /
`
`/
`
`NO /_§_/
`
`If you have answered "yes" for one or more
`investigations,
`identify each such investigation and the
`NBA in which each was relied upon:
`
`NDA #
`NDA #
`NDA # _
`
`r
`
`‘
`
`__
`Study #
`. ______________
`Study # mi_
`
`Study #
`
`(b)
`
`For each investigation identified as "essential to the
`approval," does the investigation duplicate the results
`of another investigation that was relied on by the agency
`to support
`the effectiveness of a previously approved
`drug product?
`
`Investigation #1
`
`YES /___/
`
`NO /H§*/
`
`Investigation #2
`
`YES /___/
`
`NO /_§fl/
`
`Investigation #3
`
`YES /_“_/
`
`NO,/_§_/
`
`Investigation #4
`
`YES /___/
`
`NO /_§_/
`
`If you have answered "yes" for one or more
`investigations,
`identify the NDA in which a similar
`investigation was relied on:
`
`
`
`
`
`NBA #
`
`NDA #
`
`NDA #
`
`'Study #
`
`Study #
`
`Study #
`
`Page 6
`
`

`

`
`
`w
`
`_:
`
`(c)
`
`identify each "new"
`If the answers to 3(a) and 3(b) are no,
`investigation in the application or supplement that is
`essential to the approval (i.e.,
`the investigations
`listed in #2(c),
`less any that are not "new"):
`
`Investigation #1, Study # 192371—002
`
`Investigation #g, Study # 19237l~003
`
`Investigation #g, Study # 192371—501
`
`Investigation #3, Study # 192371—503
`
`4. To be eligible for exclusivity, a new investigation that is
`essential to approval must also have been conducted or
`sponsored by the applicant-
`An investigation was "conducted
`or sponsored by” the applicant if, before or during the
`conduct of the investigation,
`1)
`the applicant was the sponsor
`of the IND named in the form FDA 1571 filed with the Agency,
`or 2)
`the applicant
`(or its predecessor in interest) provided
`substantial support for the study; Ordinarily, substantial
`support will mean providing 50 percent or more of the cost of
`the study.
`
`(a)
`
`For each investigation identified in response to
`question 3(c):
`if the investigation was carried out
`under an IND, was the applicant identified on the FDA
`1571 as the sponsor?
`
`
`
`Investigation #1
`
`IND #
`
`YES
`
`/x /
`
`NO /
`
`/ Explain:
`
`Investigation #2
`
`IND #
`
`YES / X /
`
`NO /
`
`/ Explain:
`
`Investigation #3
`
`IND #
`
`YES / X /
`
`NO /
`
`/ Explain:
`
`Investigation #4
`
`IND #
`
`YES / X /
`
`NO /
`
`/ Explain:
`
`Page 7
`
`

`

`J_“_
`"""""
`
`(b)
`
`For each investigation not carried out under an IND or
`for which the applicant was not identified as the
`sponsor, did the applicant certify that it or the
`applicant‘s predecessor in interest provided
`substantial support for the study?
`
`Investigation #1
`
`YES /
`
`/ Explain
`
`NO /
`
`/ Explain
`
`
`
`Investigation #2
`
`YES /
`
`/ Explain
`
`NO /
`
`/ Explain
`
`(b), are
`(c) Notwithstanding an answer of "yes" to (a) or
`there other reasons to believe that the applicant
`should not be credited with having ”conducted or
`sponsored” the study?
`(Purchased studies may not_be
`used as the basis for exclusivity. However, if all
`rights to the drug are purchased (not just studies on
`the drug),
`the applicant may be considered to have
`sponsored or conducted the studies sponsored or
`conducted by its predecessor in interest.)
`
`YES//
`
`NO/X/
`
`If yes, explain:
`
`See electronic signature page
`
`William.M. Boyd, M.D.
`Medical Officer
`
`Wiley A.Chambers, MxD.
`Deputy Division Director
`
`CC:
`
`HFD—OSB/Mary Ann Holovac
`HFD-lOé/PEDS/T.Crescenzi
`
`Form OGD—011347
`
`Revised 3/7/95,- edited 8/8/95; revised 8/25/98, edited 3/6/00
`
`Page 8
`
`

`

` -- -----u-.a-------u-n-o..--___-__----_—-----——-----_—_---——-—------—.........---------------------------------------
`
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`William Boyd
`12/23/02 12:22:32 PM
`
`Wiley Chambers
`12/23/02 03:42:02 PM
`
`

`

`
`
`Pediatric Page Printout for LORI GORSKI
`
`Page 1 of 1
`
`PEDIATRIC PAGE
`
`(Complete for all original application and all efficacy supplements)
`
`
`NDAIBLA
`Number:
`
`21023 Trade Name RESTASIS! CYCLOSPORINE OPHTHALMIC
`EMULSIO
`
`supplement
`Number:
`
`Supplement
`Type:
`
`Gener'c
`Name:
`
`Dosage
`Form:
`
`CYCLOSPORINE OPHTHALMIC EMULSION 0.05%
`
`
`EML
`_‘
`
`Regulatory
`Action:
`
`Proposed We ,
`AE
`— Indication:
`
`p
`
`ARE TIIERE PEDIATRIC STUDIES IN THIS SUBMISSION?
`
`NO, No waiver and no pediatric data
`
`What are the INTENDED Pediatric Age Groups for this submission?
`
`NeoNates (0-30 Days )
`
`Children (25 Months-l2 years)
`
`Infants (1-24 Months)
`
`Adolescents (13—16 Years)
`
`Does Not Apply
`
`Label Adequacy
`Formulation Status
`
`Studies Needed
`
`Study Status
`
`Are there any Pediatric Phase 4 Commitments in the Action Letter for the Original Submission? m
`
`COMIVIENTS:
`
`Keratoconjunctivitis sicca is an extremely rare occurance in the pediatric population.
`
`This Page was completed based on information from 2 PROJECT MANAGERICONSUNHQR SAFETY OFFICER,
`LORI GO§SKI
`5i
`
`_ ___— 3 26') 0?)
`
`Signature
`
`http://cdsmiwebllpeditrack/edjtdata_firm.cfin?ApN=21023&SN=0&ID=543
`
`3/20/00
`
`

`

`!
`
`I i
`
`:
`'
`
`Pediatric Page Printout
`
`Page 1 ofl
`
`PEDIATRIC PAGE
`(Complete for all original application and all efficacy supplements)
`
`NDA Number:
`
`021023
`
`Trade Name:
`
`RESTASIS(CYCLOSPORINE OPHTHALMIC EMULSIO
`
`suwlemem
`Number:
`
`Supplement
`TYPE:
`
`Regulatory
`Amion:
`
`000
`
`N
`
`AE
`
`Gene“
`Name:
`
`Dosage
`Form:
`
`COMIS
`Indicalion:
`
`Action Date:
`
`68499" {5.1 l 7 log
`
`CYCLOSPORINE OPHTHALMIC EMULSION 0.05%
`
`'
`
`.7
`
`4 lwmmwm‘m
`
`lndicafion # 1 M .
`
`Label Adequacy: Does Nul Apply
`
`meulam"
`Needed.
`
`NO NEW FORMULATION is needed
`
`gxlments (If
`
`Keraloconjunclivitis siccza is an extremely rare occurance in the pediatric population.
`
`nger Range
`0 years
`
`U93; Range
`16 years
`
`§gaggs
`Waived
`
`Date
`
`This page was last edited on lOIl'I/OO
`
`W. Kl
`
`Signalure-
`
`,
`
`_ 4AM
`
`hitp:llcdsodwscw/newpedsdevlpcdsview.asp?Source=Peds&Documcntmid=1 89 1955
`
`10/1 71‘00
`
`

`

`Pediatric Page Printout for LORI GORSKI
`
`Page 1 of 1
`
`PEDIATRIC PAGE
`(Complete for all original application and all efficacy supplements)
`
`
`IiiDA/BLA
`" ' '
`’
`'
`Number:
`21023 Trade Name.
`
`Supplement
`Number:
`
`Supplement Type:
`Regulatory Action: AB
`
`,
`.
`Generic Name.
`
`Dosage Form:
`Proposed
`Indication:
`
`' ”iiisrAsiSjCYCiosiioR'"iNE' OPHTI-I- A 1 MIC
`
`EMULSIO
`
`
`QLCLOSBQEQEE OPHTHALMIC EMULSION
`(ES/g
`
`EML
`- mm
`
`ARE THERE PEDIATRIC STUDIES IN THIS SUBMISSION?
`
`N0, N0 waiver and no pediatric data
`
`What are the INTENDED Pediatric Age Groups for this submission?
`
`_NeoNates (0-30 Days )_Chi1dren (25 Months-l2 years)
`___Infants (1-24 Months) _Adolescents (13-16 Years)
`
`I_)o_es_Not A l
`
`'
`
`Label Adequacy
`Formulation Status
`
`Studies Needed
`
`Study Status
`
`Are there any Pediatric Phase 4 Commitments in the Action Letter for the Original Submission?
`
`I_\i_Q
`
`COMJVIENTS:
`
`Keratoconjunctivitis sicca is an extremely rare occurancc in the pediatric population.
`
`
`
`This Page was completed based on information from :1 PROJECT MANAGERICONSUMER-SAFETY OFFICER,
`LORI GORSKI
`
`Signature
`
`/
`
`http://cdsmlweb llpedin'ack/editdata_firm.cfin?ApN=2 1 023 &SN=0&ID:S43
`
`7/29/99
`
`

`

`NDA: 21-023
`
`PEDIATRIC PAGE
`
`Stamp Date: February 24, 1999
`
`Action Date: December 23, 2002
`
`HFD-SSO Division of Anti—Inflammatory, Analgesic and Ophthalmic Drug Products
`
`Trade and generic names/dosage form: Restasis (cyclosporine ophthalmic emulsion) Ophthalmic
`Emulsion, 0.05%
`
`Applicant:
`
`Allergan, inc
`
`Therapeutic Class:
`
`Immunomodulator
`
`lndicatiou(s) previously approved:
`
`None
`
`There is one indication for this application: 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~infiarmnatory drugs
`or using punctal plugs.
`
`Is there a full waiver for this indication? XX Yes
`
`Please proceed to Section A.‘
`
`Section A — Fully Waived Studies
`
`Reason for full waiver:
`
`Products in this class for this indication have been studied/labeled for pediatric population
`XX Disease/condition does not exist in children
`
`Too few children with disease to study
`There are safety concerns
`
`ifstudies arefuily waived, then pediatric information is completefor this indication. ‘Ifthere is another
`indication, please see Attachment A. Otherwise, this Pediatric Page is complete and should be entered
`into DFS.
`
`This page was completed by:
`
`{See appended electronic: signature page}
`
`Lori M. Gorski
`
`Regulatory Project Manager
`
`cc: NDA 21—023
`HFD-950! Terrie Crescenzi
`HFD-960.’Grace Carrnouze
`
`(revised 9-24-02)
`FOR QUESTIONS ON COMPLETING THIS FORM CONTACT, PEDIATRIC TEAM, HFD-960
`301-594—7337
`
`
`
`

`

`.---..—-------_-----__---__-_-_-_------_---..-__nun-.-n.-u..-—_-_---an---o-—co---.-.-.---uo.puo-o---._---oonco.--oo
`
`This is a representation of an electronic record that was signed electronicaliy and
`this page is the manifestation of the electronic signature.
`—-q--—-_-no-—--.---------------------__----_-_--_—_-__—-------------------------------------------------------------
`
`Lori Gorski
`
`12/24/02 10:40:20 AM
`
`
`
`

`

`
`
`NBA/EFFICACY SUPPLEMENT ACTION PACKAGE CHECKLIST
`
`is:
`
`
`
`
`
`.
`
`
`hNDA 2_1-023 Approved December 23, 2002
`
`LDrn&___Restasis (mlgporifiofllfllflic emulsion) Ophthalmic Emulsion, 0.05% WW
`LRPM; Lori Marie Gorski
`
`__
`
`Efficac Sun lement Type SE;__ Su lenient Number
`
`licant: Allergan
`
`
`NewFormulation ' OthFtC-gt,0rphan,OTC)
`
`A-plicarion T} ue: (X) 505(b)(l) () 505(b)(2)
`
`-I- Application Classifications
`-
`Review priority
`W I Chemclass(NDASonly)“
`
`‘1' L'ser Fee Goal Dales
`-
`-
`'
`Spectal programs (1ndicatc all that apply)
`
`ii
`
`'
`
`'
`
`, ~
`
`.
`
`..
`
`l
`
`1
`
`-
`
`_ 0 Standard ( X) Priority
`
`‘N/A
`March 9, 2003
`(X) None
`Subpan H
`() 21 CFR 314.510 (accelerated
`approval)
`()21CFR314.520
`(restricted distribution)
`
`i
`
`( ) Fast Track
`( Rollin- Re 'ew
`
`
`
`
`
`, ‘
`
`.
`
`
`
`I
`
`'1' Lser Fee Information
`User Fee
`User Fee waiver
`
`0
`
`-
`
`User Fee exception
`
`—'I'
`
`
`
`( ) Small buSlTiESS
`
`() Public health
`
`
`( ) Barrierto-lnnovation
`
`
`__(_) cher
`
`
`( ) Orphan designation
`() No- fee 505(b)(2)
`
`
`
`
`
`
`I()Yes
`PEWSWWW W W - W
`
`
`
`()Yes
`.ixll‘lfl...
`
`
`..."\p§.hcatipnIntegrity Policy (AiP)
`
`__ f
`_ Applicant_15 on the Al
`J ..
`'
`___Th_l_5 applicationIS on theAIPh
`A
`0
`Exception for review(Center Director s memo)
`-
`OC clearance for approval
`‘
`
`
`Debarnienl certification: verified that qualifying language (e.g., willingly, knowingly) was
`
`not used in certification and certifications from foreign applicants are co-signed by US.
`
`
`
`agent.
`
`1!
`I
`
`
`(_X) Verified
`I
`information: Verlfy that patent information was submitted
`
`
`
`2i CFR3i4 50(i)(1)(1j(A)
`-
`Patentcertification [505(b)(2) applications]. Verifyitype of certifications
`submitted
`()1 ()II {)III
`()IV
`
`
`
` 21 CFR 314 50mm
`
`
`_{_)_(ii)
`()(iii)
`( ) Verified
`
`
`
`h .07 For paragraph IV certification, verify that the applicant notified the patent
`holder(s) of their certification that the patent(s) is invalid, unenforceable, or will
`not be infringed (certification of notification and documentation of receipt of
`notice).
`
`o
`'3' Exclusivity Summary (approvals only)
`o
`
`1
`
`-' Administrative Reviews (Project Manager, ADRA) (indicate date ofeach review)
`
`N/A
`
`
`
`December 23, 2002
`
`

`

`
`
`
`Actions
`
`(X)AP ()TA (1111-: ()NA
`”3Previous AESH
`August 3, 1999, March 25, 2000,
`October 19, 2000
`(X ) Materials requestedin AP letter
`( ) Reviewed for Sub-art H
`
`
`
`(X) Yes
`( ) Not applicable
`(X ) None
`( ) Press Release
`( ) Talk Paper
`( ) Dear Health Care Professional
`Letter
`
`1
`
`-
`
`-
`
`Proposed action
`
`Previous actions (specify type and date for each action taken)
`
`
`
`Status of advertising (approvals only)
`
`-2-
`
`Public communications
`-
`Press Office notified of action(approvalonly)
`
`0
`
`Indicate what types (ifany) of information dissemination are anticipated
`
`
`
`NBA 21-023
`
`Page 2
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Labeling (package insert patient package insert (if applicable) MedGuide (if applicable)
`Division'5proposed labeling(only if generated after latest applicant submission
`or labeling)
`
`I Mostrecent applicant-proposed labeling
`-
`Original applicantvproposed labeling
`-
`Labeling reviews (including DDMAC, Office of Drug Safety trade name review
`nomenclature reviews) and minutes oflabeling meetings (indicate dates of
`
`reviews and meetin 5)
`Other relevant labeling (e. g., most recent 3‘:1n class, class labeling)
`.- Labels (immediate container & cartonlabels)
`-
`Divisionproposed (onl).ifgenerated after latest applicant submission)
`- Applicant proposed
`0
`Reviews
`
`
`
`
`l’ost— marketing commitments
`
`-
`Agency request forpost--marketing commitments
`Documentation ofdiscussions and/or agreements relating to post——marketing
`commitments
`
`Outgoing correspondence (i.e., letters, E-mails, faxes)
`
`'2' Memoranda and Telecoms
`
`Advise? Committee Meeting
`I
`Date of Meeting
`0
`43-hour alert
`
`Federal Register Notices, DES] documents, NAS, NRC (if any are applicable)
`
`.3
`
`-
`
`.-
`.
`
`
`
`December 20 2002
`February 24, l999
`
`
`DDMAC v December 13 8.: 20, 2002
`
`
`ODS December 1 l 2002
`
`
`
`
`
`
`
`
`
`December 16 2002
`see above
`
`
`
`
`
`
`
`
`‘1' Minutes ot Meetings
`Omtober 24, 1996
`
`-
`EOP2 meeting (indicate date)
`,,, ‘ classrfiirlfi9§ .
`.
`P_re-NDA meeting (indicate date)
`N/A
`
`
`
`
` 11111
`PreApproval Safety Conference (indicate date; approvals only)
`Other
`See package
`
`
`July 2| l999
`
` NIA
`N/A
`
`

`

`
`
`NDA 21-023
`
`Page 3
`
`
`'1'
`Summary Reviews (e.g“Office Director: Division Director, Medical Team Leader)
`(indicate date [or each review)
`July 30, 1999(2), March 10, 2000,
`October 3, 2000, October 16, 2000 (2).
`November 16, and December 16, 2002 (3)
`December 20, 2002,
`December 23, 2002
`NM
`
`-1- Clinical review(s) (indicate darefor each review)
`
`1
`
`lI
`
`'1'
`
`Pediatric Page(separate page for each indication addressing status of all age groups)
`
`'3' Statistical review(s) (indicate datefor each review)
`
`
`
`4- Microbiology (efficacy) review(s) (indicate date for each review)
`
`
`See above
`'3'
`Safety Update review(s) (indicate date or location ifincorporated in another review)
`
`December 24, 2002
`1
`June 10, 1999, February 14, 2000
`1
`
`May 27, 1999 ;
`
`.- Biopharmaceutica] review(s) (indicate darefor each review)
`' a' Controlled Substance Staff rcview(s) and recommendation for scheduling (indicate
`N/A
`date for each review)
`
`1 1
`
`r j
`
`
`
`i
`1
`
`
`July 28, 1999
`N/A
`
`1
`
`-:- ( linical InspectionReview Summary(DSI)
`2-,
`0 Clinical studies
`-
`Bioequivalence studies
`
`
`June 16, 1999,July30, 19,99
`March 22 2000, December 13, 2002 (2)
`
`
` l
`
`
`.'. Emironmental Assessment
`
`Categorical Exclusion(indicate review daiejm
`-
`Revieu & FONSI (indicate.date of. review)
`-
`- Re\new 81. Environmental lriipact Statement (indicaiedale ofeach review)
`i.\1icro (validation of sterilization & product sterility) revie\v(s) (indicate datefor each
`
`review)
`-.- Facilities inspection (provide EER report)
`
`1,
`1
`:
`
`See CMC
`
`l
`l
`
`May 17, 1999, July 28, 1999 (2),
`Februa
`23, 2000
`, Date completed:
`1, (X) Acceptable November 9, 2002
`( ) Withheld recommendation
`
`
`
`
`4' Methods validation
`( ) Completed
`(X) Requested
`
`( ) Not yet requested
`
`
`Pharm/tox review(s), including referenced IND reviews (indicate datefor each review)
` July 15, 1999
`
`;
`
`N/A
`!
`
`
`Nonclinical inspection review summary
`
`
`
`
`'2' C ACIECAC report
`
`Statistical review(s) of carcinogenicity studies (indicate dare for each review)
`
`
`oa
`
`

`

`l”.|'
`
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`—-.—------—----—----------------------------------------------------------------------------------------------------
`
`Lori Gorski
`
`12/24/02 10:08:15 AM
`
`
`
`

`

`
`
`94
`
`Draft Labeling Page(s) Withheld
`
`

`

`
`
`Office of Drug Safety
`
`
`
`Memo
`
`To:
`
`From:
`
`Lee Simon, MD
`Director, Division of Anti-inflammatory, Analgesic, and Ophthalmologic Drug Products
`HFD-SSO
`
`Marci Lee, PharmD
`Safety Evaluator, Division of Medication Errors and Technical Support
`HFD—420
`
`Through:
`
`Denise Toyer, PharmD
`Team Leader, Division of Medication Errors-and Technicat Support
`HFD-420
`“
`
`Carol Holquist, RPh
`Deputy Director, Division of Medication Errors and Technical Support
`HFD-420
`
`CC:
`
`Lori Gorski
`
`Project Manager, Division of Anti-Inflammatory, Analgesic, and Ophthalmologic Drug Products
`HFD—550
`
`Date:
`
`Re:
`
`December 8, 2002
`
`ODS Consult 00-0232—1; Restasis (Cyclosporine Ophthalmic Emulsion); NDA 21-023
`
`—m_———w_—__—_____m,__fl__—__%_—_—.
`
`'" NOTE: "this review contains preprietary and confidential information that should not be released to the
`public.m
`
`This memorandum is in response to a November 19, 2002 request from your Division for a re-review
`of the proprietary name, Restasis.
`In our consult dated October 2, 2000 (ODS Consult #00-0232),
`the Division of Medication Errors and Technical Support (DMETS) did not have any objections to the
`use of the proprietary name, Restasis- However, DMETS' primary safety concerns involved the
`proposed labels, labeling, and packaging. DMETS made several recommendations to improve the
`safe use of Restasis in our initial review. We did not receive revised container labels or carton
`labeiing and therefore cannot determine if the safety concerns from the initial review were
`considered (See Appendix A).
`
`Based upon review of the revised package insert iabeling, DMETS acknowledges that packaging the
`product in single—use containers and labeiing them as single-use addresses the concern surrounding
`
`
`
`
`

`

`
`
`
`
`the W,
`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 milliliter is 0.1 - 0.13 mL. Therefore, there is a risk that patients may save
`the vial and use the remaining drug in the interest of saving money. The risks of using the drug
`beyond the single dose needs to be clearly communicated to practitioners, patients and caregivers
`especially since the product does not contain a preservative. Another way to minimize this risk is to
`use the least amount of overfill beyond the volume needed for two drops. Additionally, if space
`permits. we recommend that the terminology
`‘—"_"-
`,
`be added to the labels and
`labeling.
`
`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. See Table 1 for a
`side-by~side comparison of Restasis, Rescula, and 9—— . DMETS anticipates that although there
`are some similarities in the clinical context of use between Restasis and Rescula, these product
`names are different enough to coexist safely in the US marketplace. Additionally, the risk for
`confusion with Restasis and
`-———-
`is an issue to consider again when
`-——-
`is closer to
`approval.
`
`-—-—-
`__ Table 1. Comparison of Restasis, Rescula and
`
`_ Proprietary Name
`_ m Rescula
`.
`
`A: oroved NDA
`. Status
`_
`! Established Name
`Unoprostone
`
`Cyclosporine
`
`-
`
`l
`. Sponsor
`
`Indication
`
`
`Allergen, Inc.
`
`
`To increase tear
`
`Oohthalmic Solution
`Novartis
`O nhthalmics
`Glaucoma
`
`"_"—"'“-s
`
`--—-----___
`
`r—M
`
`e—--—-—~
`
`fl“
`
`‘
`
`_
`
`production
`
`
`
`Dosage Strength
`
`l
`_
`i How Supplied
`0.4 mL single—use
`_
`ulastic vials
`
`
`1 dro- BID DU
`Usual Dose and Ran-e
`1 dro- BID OS/OD
`-'_l§_ BID
`_
`, Route of Administration
`EYE
`Dosa-e formulation
`OPHTH solution
`Storae conditions
`Room term
`
`0.15% _
`“_
`
`5 mL
`
`In summary, DMETS has no objections to the use of the proprietary name Restasis but request
`consideration of the label and labeling comments outlined in this review for safer use of the product.
`
`DMETS considers this a final review. However, if the approval of the NDA is delayed beyond 90 days
`from the date of this review, the name must be re-evaluated. A re-review of the name before NDA
`approval will rule out any objections based upon approvals of other proprietary and/or established
`names from this date forward.
`If you have any questions or need clarification, please contact
`Sammie Beam, Project Manager, at 301-827-3242.
`
`*“NOTE: This review contains proprietary and confidential information that should not be released to
`the public.***
`
`2
`
`
`
`

`

`APPENDIX A
`
`=7 5' Labeling, Packaging and Safety Related Issues from Initial ODS Consult it 00-0232
`
`1n the review of the draft labeling for Restasis, ODS has attempted to focus on safety issues relating to
`possible medication errors. We have identified areas of possible improvement, in the interest of minimizing
`potential user error.
`
`A. PACKAGING CONFIGURATIONICONTAINER LABELING (0.4 mL containers)
`
`1.
`
`‘
`
`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. To date, the sponsor has not submitted final copy of the paper
`label that will appear on the flange (personal communication, HFD-SSO). We would
`strongly recommend that this labeling, once submitted, be reviewed by ODS. 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
`m_ 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
`corporate website for one product, Bion Tears, specifically states the following:
`'Preferred by severe dry eye patients (Sjogren’s syndrome) over 4 other brands‘. 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 U. S. 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 thefollowing 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.
`
`is quite restrictive and could be confusing to the user.
`—-————‘—“"‘—’
`2. The phrase ‘
`Some clarification should be provided regarding the following issues.
`
`a. How many doses or drops will each vial deliver? If more than two drops are deliverable,
`then-the statement above seems to imply that W
`
`l
`
`.
`.
`.
`.
`.
`_
`“Data on me, Alcon Laboratories, Inc." Source: http:l/www.alconlabs.con‘iluslco/condmonslB lgBionTearsghlml,
`
`*“NOTE: This review contains proprietary and confidential information that should not be released to
`the public."‘
`
`3
`
`
`
`

`

`HM
`" «as . _; : «auxaqé—amsnwfiwwmmmmmm _
`to the statement above, if strictty adhered to by the user.
`
`.
`
`a C COrd i ng
`
`b.
`
`In the interest of economy and conserving the drug product. it also seems likely that a
`patient be will inclined to use the remainder cf the dropper, if the dosing is close to a 12—
`hour interval. Given the nature of cyclosporin therapy in an ophthalmic, preservative-
`free solution, can a local infection result from droppers used within, for example, 13
`hours? Because the WWW,%.
`
`-*“ _ significant confusion and misuse seem iikeiy.
`
`3. We have some concerns with the description of this package as a "vial".
`
`4. The
`
`
`
`, is absent from the Vial label (see 21 CFR 201.51).
`
`B. CARTON LABELING (32—count tray)
`
`
`
`WWM“‘”M“L
`
`”Hm-mm;
`
`7C. PACKAGE lNSERT LABELiNG
`
`for the Greek “,uL", as u[L] is frequentty mistaken
`1. We suggest substitution .of the word ’“"
`for m[l_]. particularly with scripted instructions.
`
`2. Under How Supplied, delete the phrase “iii! in 0.9 mL LDPE vial”, as inclusion of the