CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICA TION NUMBER:
`
`2 1 -994
`
`ADMINISTRATIVE and CORRESPONDENCE
`
`DOCUMENTS
`
`

`

`EXCLUSIVITY SUMMARY
`
`NDA # 21—994
`
`SUPPL #
`
`.
`
`HFD # 520
`
`Trade Name Travatan Z
`
`Generic Name Travoprost Ophthalmic Solution, 0.004%
`
`Applicant Name Alcon, Inc.
`
`Approval Date, If Known September 21, 2006
`
`PART I
`
`IS AN EXCLUSIVITY DETERNIINATION NEEDED?
`
`1.
`
`An exclusivity determination will be made for all original applications, and all efficacy
`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 a 505(b)(l), 505(b)(2) or efficacy supplement?
`
`YES E NOI:I
`
`If yes, what type? Specify 505(b)(1), 505(b)(2), SE1, SE2, SE3,SE4, SE5, SE6, SE7, SE8
`
`505(b)(1)
`
`0) Did it require the review of clinical data other than to support a safety claim or change in
`labeling related to safety? (If it required review only of bioavailability or bioequivalence
`data, answer "no.")
`
`YES [I NO-
`
`Ifyour answer is "no" because you believe the study is a bioavailability study and, therefore,
`not eligible for exclusivity, EXPLAINwhy 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.
`
`Study was designed to demonstrate bioequivalence to Travatan using a clinical '-
`endpoint, intraocular pressure (IOP).
`
`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:
`
`Page 1
`
`

`

`d) Did the applicant request exclusivity?
`
`YES I]
`
`NO
`
`If the answer to (d) is "yes," how many years of exclusivity did the applicant request?
`
`e) Has pediatric exclusivity been granted for this Active Moiety?
`YES I]
`
`NO E
`
`If the answer to the above question in YES, is this approval a result of the Studies submitted in
`response to the Pediatric Written Request?
`
`IF YOU HAVE ANSWERED "NO" TO ALL OF THE ABOVE QUESTIONS, GO DIRECTLY TO
`THE SIGNATURE BLOCKS AT THE END OF THIS DOCUMENT.
`
`2.
`
`Is this drug product or indication a DESI upgrade?
`
`YES I] ‘
`
`NO IX]
`
`IF THE ANSWER TO QUESTION 2 IS "YES," GO DIRECTLY TO THE SIGNATURE BLOCKS
`ON PAGE 8 (even if a study was required for the upgrade).
`‘
`
`FIVE-YEAR EXCLUSIVITY FOR NEW CHENIICAL ENTITIES
`PART II
`(Answer either #1 or #2 as appropriate)
`
`AK
`
`1. Single active ingredient product.
`
`I
`
`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.
`
`If "yes," identify the approved drug product(s) containing the active moiety, and, ifknown, the NDA
`#(s).
`
`YES IX]
`
`NO‘ I] ‘
`
`'Page 2
`
`

`

`NDA#
`
`21—25 7
`
`Travatan (travoprost ophthalmic solution), 0.004%
`
`NDA#
`
`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 M w 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 NDA,
`is considered not previously
`approved.)
`
`YES El
`
`NO IXI
`
`If "yes," identify the approved drug product(s) containing the active moiety, and, ifknown, 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 8.
`(Caution: The questions in part II of the summary should
`only be answered “NO” for original approvals of new molecular entities.)
`-
`IF “YES,” GO TO PART III.
`
`PART-III
`
`THREE-YEAR EXCLUSIVITY FOR NDAS 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 ofthe application
`and conductedor sponsored by the appliCan ." 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 contains clinical investigations only by virtue of a right of reference to clinical
`investigations in another application, answer "yes,“ then skip to question 3(a). If the answer to 3(a)
`
`Page 3
`
`

`

`is "yes“ for any investigation referred to in another application, do not complete remainder of
`summary for that investigation.
`,
`
`YES
`
`[:1
`
`NO [X
`
`IF "NO," GO DIRECTLY TO THE SIGNATURE BLOCKS ON PAGE 8.
`
`2 A clinical investigation is "essential to the approval" If the 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 approvalas an ANDA or
`505(b)(2) application because of what13 already known about a previously approved product), or 2)
`there are published reports of studies (other than those conducted or spensored 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.
`
`(a) In light ofpreviously approved applications, is a 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 El
`
`No 1:]
`
`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 -8:
`
`(b) Did the applicant submit a list ofpublished 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 E]
`
`‘ NO [I
`
`(1) If the answer to 2(b)1s "yes," do you personally know of any reason to disagree
`with the applicant's conclusion? If not applicable, answer NO
`
`YES 1:] NOD
`
`If yes, explain:
`
`I
`
`(2) If the answer to 2(b) is "no," are you aware ofpublished 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?
`
`YES [:1
`
`NO E]
`
`Page 4
`
`

`

`If.yes, explain:
`
`(0)
`
`Ifthe answers to (b)(l) and (b)(2) were both "no," identify the clinical investigations
`submitted in the application that are essential to the approval:
`
`Studies comparing two products with the same ingredient(s) are considered to be bioavailability
`studies for the purpose of this section:
`
`3. In addition to being essential, investigations must be "new" to support exclusivity. The agency
`interprets "new clinical investigation" to mean an investigation that 1) has not been relied on by the
`agency to demonstrate the effectiveness ofa previously approved drug for any indication and 2) does
`not duplicate the results ofanother 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.
`
`a) 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
`
`'
`
`Investigation #2
`
`YES [:1
`
`NO E]
`
`YES {:1
`
`No |:]
`
`If you'have answered "yes" for one or more investigations, identify each such investigation
`and the NDA in which each was relied upon:
`
`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
`
`Investigation #2.
`
`'
`
`YES [:1
`
`NO '3
`
`YES El
`
`NO E]
`
`Page 5
`
`

`

`If you have answered "yes" for one or more investigation, identify the NDA in which a '
`similar investigation was relied on:
`
`c) Ifthe answers to 3(a) and 3(b) are no, identify each "new" 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"):
`
`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 1ND, was the applicant identified on the FDA 1571 as the sponsor?
`
`Investigation #1
`
`IND #
`
`.
`YES [:1
`-
`
`l
`l
`1 NO 1:}
`1 Explain
`
`l !
`
`‘
`
`YES [:1
`»
`
`! NO [:1
`1 Explain
`
`Investigation #2
`
`IND #
`
`(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?
`
`Page 6
`
`

`

`‘ Investigation #1
`
`!
`
`iNoEI
`1 Explain:
`
`l!
`
`.
`
`1 NO [I
`! Explain:
`
`YEslj
`Explain:
`
`Investigation #2
`
`YES 1:]
`Explain:
`
`(0) Notwithstanding an answer of "yes" to (a) or (b), are 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.)
`
`YESDW NO 1:]
`
`If yes, explain:
`
`. Name of person completing form: Michael Puglisi
`- Title: Regulatory Project Manager
`Date: September 12, 2006
`'
`
`Name of Office/Division Director signing form: Wiley A. Chambers, M.D.
`Title: Deputy Director, Division of Anti~lnfective and Ophthalmology Products
`
`Form OGD-Ol 1347; Revised 05/10/2004; formatted 2/15/05
`
`Page 7
`
`

`

`--------------------------------i----~—-u---—-u------------------------------------------—--—-------—-------------
`
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of» the electronic signature.
`-—-_---——----u-u—u-u---------_-_------__-----------_----__.---_——----------------_---_--—-—--------------------------
`
`Wiley Chambers
`11/2/2006 10:43 :47_ PM
`
`Appears This Woy ’
`On Original
`
`.‘(fi
`
`

`

`{(ompiete ier ali flied Oiiginai applications and eific‘xcy supplements)
`
`PEDIATRIC PAGE
`
`5NDA#:
`
`21—994
`
`
`Stamp Date: November 21 2005
`
`Action Date:
`
`September 21, 2006
`
`HFD- 520
`
`Trade and generic names/dosage form: Travatan Z ttravoprost ophthalmic solution) 0.004%
`
`Applicant: Alcon Inc.
`
`Each approved indication must have pediatric studies: Completed, Deferred, and/or Waived.
`
`Number of indications for this application(s):
`
`1
`
`Indication #1: For the reduction of elevated intraocular pressure in patients with open angle glaucoma or
`ocular hypertension who are intolerant of other intraocular pressure lowering medications or
`insufficiently responsive (failed to achieve target IOP determined after multiple measurements over time)
`to other intraocular pressure lowering medications.
`
`15 there a full waiver for this indication (check one)?
`
`C]
`
`‘1 Yes: Please proceed to Section A.
`
`El No: Please check all that apply: _Partial Waiver
`,
`'
`NOTE. More than one may apply
`Please proceed to Section B, Section C, and/or Section D and complete as necessary , ,
`
`Completed
`
`' Deferred
`
`,.
`.,
`
`.
`
`.
`
`l Section A: Fully Waived Studies
`
`Reason(s) for full waiver:
`
`.
`
`‘.
`
`‘
`
`‘
`
`El Products in this class for' this indication have been studied/labeled for pediatric population
`Cl Disease/condition does not exist in children
`
`Cl Too few children with disease to study
`Cl
`\/ There are safety concerns
`
`5] Other:
`
`Ifstudies are fully waived, then pediatric information is complete for this indication. Ifthere is another indication, please see
`Attachment A. Otherwise, this Pediatric Page is complete and should be entered into DFS.
`
`I
`
`“,5?an
`
`Section B: Partially Waived Studies
`
`Age/weight range being partially waived:
`
`
`Min
`
`Max
`
`kg
`kg
`
`‘ Reason(s) for partial waiver:
`
`1110.
`mo.
`
`yr.
`yr.
`
`.Tanner Stage
`Tanner Stage
`
`Products in this class for this indication have been studied/labeled for pediatric population
`Disease/condition does not exist in children
`Too few children with disease to study
`There are safety concerns
`Adult studies ready for approval
`Formulation needed
`
`llDDDDDD
`
`\\
`
`

`

`NDA 21-994
`
`Page 2
`
`CI Other:
`
`[fstudies are deferred, proceed to Section C. Ifstudies are completed, proceed to Section D. Otherwise, this Pediatric Page is
`complete and should be entered into DFS.
`
`Section C: Deferred Studies
`
`,
`
`Age/weight range being deferred:
`
`Min
`
`Max
`
`kg
`kg
`
`mo.
`mo.
`
`.
`
`yr.
`yr.
`
`.
`
`Tanner Stage
`Tanner Stage
`
`Reason(s) for deferral:
`
`CI Products in this class for this indication have been studied/labeled for pediatric population
`[3 Disease/condition does not exist in children
`El Too few children with disease to study
`Cl There are safety concerns
`El Adult studies ready for approval
`U Formulation needed
`Other:
`
`Date studies are due (mm/dd/yy):
`
`[fstudies are completed, proceed to Section D. Otherwise, this Pediatric Page is complete and‘shoald he entered into DFS.
`
`Section D: Completed Studies
`
`Age/weight range of completed studieszi
`
`‘
`
`'
`
`\
`
`\
`
`Min
`
`Max
`
`Comments:
`
`kg
`kg
`
`n10.
`mo.
`
`yr.
`yr.
`
`Tanner Stage
`Tanner Stage
`
`I
`
`9%;
`
`Ifthere are additional indications, please proceed to Attachment A. Otherwise, this Pediatric Page is complete and should be entered
`into DFS.
`
`This page was completed by:
`
`{See appended electroninsignemre page}
`
`Michael Puglisi
`Regulatory Project Manager
`
`cc: NDA 21-2‘75/s-0 13
`HFD-960/ Grace Carmouze '
`
`FOR QUESTIONS ON COMPLETING THIS FORM CONTACT THE DIVISION OF PEDIATRIC DRUG
`
`DEVELOPMENT,-HFD-960, 301—594-7337;
`
`(revised 12—22-03)
`
`

`

`This'Is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Wiley Chambers
`10/26/2006 10: 29: 33 PM
`
`Appears This Way
`On Original
`
`

`

`Fax
`
`
`
`Division of Anti-Infective and
`
`Ophthalmology Products
`Center for Drug Evaluation and Research, HFD-520
`10903 New Hampshire Avenue, Building 22
`Silver Spring, MD 20993
`
`To:
`
`Angela Kothe, O.D., PhD.
`
`From: Mike Puglisi/ Project Manager
`
`Fax:
`
`817-551-4630
`
`Fax:
`
`301-796-9881
`
`Phone:
`
`Phone: 301—796-0791
`
`Pages: 3 (including cover page)
`
`Date: September 15, 2006
`
`Re: CMC Comments re: NDA 21-994
`
`III Urgent
`
`El For Review Cl Please Comment El Please Reply [I Please Recycle
`
`THIS DOCUMENT IS INTENDED ONLY FOR THE USE OF THE PARTY TO WHOM IT IS ADDRESSED AND MAY
`CONTAIN INFORMATION THAT IS PRIVILEGED, CONFIDENTIAL AND PROTECTED FROM DISCLOSURE UNDER
`APPLICABLE LAW. If you are not the addressee, or a person authorized to deliver the document to the addressee, you are hereby
`notified that any review, disclosure, dissemination or other action based on the content ofthe communication is not authorized. Ifyou
`have received this document in error, please immediately notify us by telephone and return it to us at the above address by mail.
`Thank you.
`
`0 Comments:
`
`Angela,
`
`Attached please find the CMC reviewer’s comments concerning Travatan Z (NDA 21-994).
`Please let me know if you have any questions about these comments. Thanks.
`
`Mike
`
`Appears This Way
`On Original
`
`

`

`NDA 21-994
`
`Reviewer’s Comments:
`
`FDA Response to Issue 1:
`
`September 15, 2006
`
`Storage statementfor the trade samples is not supported with appropriate stability data as to how long
`
`the product is stored at «~—-..after it is dispensed, e. g., storage 1"
`months at “has the
`long term storage condition, then removed and storedforIn Use" time at room temperature e.g. m
`M as appropriate.
`
`Labeling with 2 different storage statements in order to diflerentiate the trade andprofessional samples
`can be confusingfor a patient.
`
`Also, confusingfor shippers andpharmacies andfor patients ifthe products with similar trade names,
`i. e., approved drug TRA VA TAN (NDA 21—25 7) and TRA VA TAN Z (this NDA) have diflerent storage
`statements.
`
`Please revise the expiration datefor the trade samples to ._——-—-- with storage temperaturefrom 2 to
`25°C
`
`FDA Response to Issue 2:
`
`FDA concurs for the commitment to validate a test methodfor analysis of ' WT- in HCO-40
`(raw material) and set limits and report in thefirst Annual Report after discussions with the Agency.
`
`
`For _ “limit in thefinished drug product, it is necessary to demonstrate through commercial scale
`stability batches that controlling the level of ——-—~v in the raw material indeed controls the
`level as well as the particulate matter with the proposed pH limits. The data provided in the 9/1/06
`Amendment does notprovide suflicient datafor W. to make any such conclusions. This information
`needs to be established before deleting such a testfor ‘ ...._——-—— limit in the drugproduct.
`
`FDA Response to Issue 3 .-
`
`FDA concurs with the travoprost standard to the system suitability testingfor the unrelated impurities
`which will includeg-w—
`
`FDA Comments on Label
`
`Descrigtion Section
`
`Componentsfor sonia are included as requested byFDA. ThatlS adequate. “Preservedin the bottle
` m .
`
`.
`-
`_
`u
`.4.
`with an ionic bufi’ered system, sonia”.
`,___, ”W””m“
`
`
`o Page 2
`
`

`

`NDA 21-994
`
`How Sugglied Section
`
`September 15, 2006
`
`The storage statementsfor the trade samples are not supported with the appropriate stability data, i. e.,
`long term storage and “in use ” storage and therefore should match with the same storage statement as
`the professional samples, i. e., 2 - 25C with M expiration date. .
`
`Container Labels
`
`Three labels includefor 2.5 and 5 mL Trade samples and 2.5 mL Professional samples. The label
`
`statements are acceptable with
`expiration date.
`
`CartOn Labels
`
`The three labels includefor 2.5 and 5 mL Trade samples and 2.5 mL Professional samples. Include
`“so/Zia ” with the bufler components listed in the carton label similar to the description statement in the
`package insert. “Preserved in the bottle with an ionic buflered system, sonia ”. This is now
`
`
`"NMW ‘
`'
`
`All three (2 trade and one professional) storage statements are 2—25°C. That is acceptable. The
`expiration date is ’ -“—“for both professional and trade samples with the storage statements
`proposed on the carton.
`
`Appears This Way
`On Original
`
`0 Page 3
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Michael Puglisi
`9/15/2006 12:00:01 PM
`
`Appears This Way
`On Original
`
`

`

`NDA 21-994 Regulatory Filing Review
`Page 1
`
`NDA REGULATORY FILING REVIEW
`
`(Including Memo of Filing Meeting)
`
`NDA #
`
`21-994
`
`Trade Name: Travatan Z
`
`Established Name: travaoprost ophthalmic solution
`Strengths: 0.004%
`
`Applicant: Alcon. Inc.
`
`Date of Application: November 18, 2005
`Date of Receipt: November 21, 2005
`
`Date of Filing Meeting: January 9, 2006
`Filing Date: January 19, 2006
`'
`User Fee Goal Date: September 21, 2006
`
`Indication(s) requested: for the reduction of elevated intraocular pressure in patients with open-
`angle glaucoma or ocular hypertension who are intolerant of other intraocular pressure
`lowering medications or insufficiently responsive (failed to achieve target IOP determined after
`multiple measurements over time) to another intraocular pressure lowering medication
`
`Type of Original NDA:
`OR
`
`Type of Supplement:
`
`‘
`
`(b)(l) X.
`
`(b)(2)
`
`I:I
`
`(b)(l) E]
`
`,
`
`(b)(2)
`
`I:I
`
`W072?
`
`(1)
`
`(2)
`
`Ifyou have questions about whether the application is a 505(b)(1) or 505(b)(2) application, see
`Appendix A. A supplement can be either a (b)(I) or a (b)(2) regardless ofwhether the original NDA
`was a (b)(I) or a (b)(2). Ifthe application is a (b)(2), complete Appendix B.
`
`Ifthe application is a supplement to an NDA, please indicate whether the NDA is a (b)(I) or a (b)(2)
`application:
`
`Therapeutic Classification:
`Resubmission after withdrawal?
`
`S X
`no
`
`Chemical Classification: (1,2,3 etc.)
`Other (orphan, OTC, etc.)
`
`5
`n/a
`
`P D
`Resubmission after refuse to file?
`
`no
`
`Form 3397 (User Fee Cover Sheet) submitted:
`
`YES X
`
`NO [:1
`
`User Fee Status:
`
`Exempt (orphan, government)
`Paid X
`Waived (e.g., small business, public health)
`I:I
`
`I:I
`
`N072? Ifthe NDA is a 505(b)(2) application, and the applicant did not pay afee in reliance on the 505(b)(2)
`exemption (see box 7 on the User Fee Cover Sheet), confirm that a userfee is not required. The applicant is
`required to pay a userfee lf.’ (1) the product described in the 505(b)(2) application is a new molecular entity
`or (2) the applicant claims a new indication for a use that that has not been approved under section 505(b).
`Examples ofa new indication for a use include a new indication, a new dosing regime, a new patient
`
`Version: 12/15/04
`
`

`

`NDA 21-994 Regulatory Filing Review
`Page 2
`
`population ana’an Air-to-OZ'CJwiton. He best way to deter/nine ftne appn'oant 13' donning a new indication
`for a are 13' to oonzpare t/ie aopaeant’ypropoyed/aoeang to [aoe/ing tnatnay a/reaaj/ oeen approVed/or tne
`pro/not deycnoea’in tne appa'oation. mgnngn tne oftfirenoey oetween tneproposedandapproved[aoea'ng
`fyon needarstirtance in determining ftne appa'oant 125’ o/ainnng a new Indication/or a we, please contact tne
`userfee Staff"
`
`Is there any 5-year or 3-year exclusivity on this active moiety in an approved (b)(1) or (b)(2)
`application?
`YES X
`
`NO
`
`If yes, explain: There is remaining exclusivity for Alcon’s original formulation of Travavtan
`(NDA 21-257).
`
`Does another drug have orphan drug exclusivity for the same indication? YES
`
`[I
`
`NO X
`
`If yes, is the drug considered to be the same drug according to the orphan drug definition of sameness
`[21 CFR 316.3(b)(13)]?
`'
`
`YES E]
`
`NO D
`
`If yes, consult the Director, Division of Regulatory Policy 11, Office of Regulatory Policy (HFD-007).
`
`Is the application affected by the Application Integrity Policy (AIP)?
`
`YES
`
`I:I
`
`NO X
`
`If yes, explain:
`
`If yes, has OC/DMPQ been notified of the submission?
`
`YES I:I
`
`NO D
`
`Does the submission contain an accurate comprehensive index?
`
`YES X
`
`NO [I
`
`Was form 356h included with an authorized signature?
`
`YES X
`
`NO E]
`
`If foreign applicant, both the applicant and the US. agent must sign.
`
`Submission complete as required under 21 CFR 314.50?
`
`YES X
`
`NO D
`
`If no, explain:
`
`If an electronic NDA, does it follow the Guidance?
`
`N/A X
`
`YES El
`
`NO I:
`
`If an electronic NDA, all forms and certifications must be in paper and require a signature.
`Which parts of the application were submitted in electronic format?
`
`Additional comments:
`
`If an electronic NDA in Common Technical Document format, does it follow the CTD guidance?
`N/A X
`YES
`[:I
`NO I:]
`
`Is it an electronic CTD (eCTD)?
`
`YES El
`
`NO X
`
`If an electronic CTD, all forms and certifications must either be in paper and signed or be
`electronically signed.
`
`Additional comments:
`
`Patent information submitted on form FDA 3542a?
`
`YES X
`
`NO D
`
`Version: 12/15/04
`
`

`

`NDA 21-994 Regulatory Filing Review
`Page 3
`
`Exclusivity requested?
`
`YES,
`
`Years
`
`NO X
`
`NOTE: An applicant can receive exclusivity without requesting it; therefore, requesting exclusivity is
`not required.
`
`Correctly worded Debarment Certification included with authorized signature? YES X NO I]
`
`If foreign applicant, both the applicant and the US. Agent must sign the certification.
`
`NOTE: Debarment Certification should use wording in FD&C Act section 306(k)(1) i. e.,
`“[Name ofapplicant] hereby certifies that it did not and will not use in any capacity the services of
`any person debarred under section 306 of the Federal Food, Drug, and Cosmetic Act in connection
`with this application. ” Applicant may not use wording such as “T0 the best ofmy knowledge .
`.
`.
`. ”
`
`Financial Disclosure forms included with authorized signature?
`
`YES X
`
`NO I:]
`
`(Forms 3454 and 3455 must be included and must be signed by the APPLICANT, not an agent.)
`NOTE: Financial disclosure is requiredfor bioequivalence studies that are the basisfor approval.
`
`Field Copy Certification (that it is a true copy of the CMC technical section)? Y X
`
`NO I:I
`
`PDUFA and Action Goal dates correct in COMIS?
`
`YES X
`
`NO El
`
`If not, have the document room staff correct them immediately. These are the dates EES uses for
`calculating inspection dates.
`
`Drug name and applicant name correct in COMIS? If not, have the Document Room make the
`corrections. Ask the Doc Rm to add the established name to COMIS for the supporting IND if it is not
`already entered.
`
`List referenced IND numbers: IND 51,000
`
`End-of-Phase 2 Meeting(s)?
`
`Date(s)
`
`If yes, distribute minutes before filing meeting.
`
`Pre-NDA Meeting(s)?
`
`Date(s)
`
`If yes, distribute minutes before filing meeting.
`
`Project Management
`
`NO X
`
`NO X
`
`Was electronic “Content of Labeling” submitted?
`
`YES X
`
`NO E]
`
`If no, request in 74-day letter.
`
`I
`
`All labeling (PI, PPI, MedGuide, carton and immediate container labels) consulted to DDMAC?
`YES X
`NO [I
`
`Risk Management Plan consulted to ODS/IO?
`
`N/A X
`
`YES
`
`[I
`
`NO I:I
`
`Trade name (plus PI and all labels and labeling) consulted to ODS/DMETS? Y X
`
`NO I:]
`
`MedGuide and/or PPI (plus PI) consulted to ODS/DSRCS? N/A X
`
`YES E]
`
`NO D
`
`Version: 12/15/04
`
`

`

`NDA 21-994 Regulatory Filing Review
`. Page 4
`
`0
`
`If a drug with abuse potential, was an Abuse Liability Assessment, including a proposal for
`scheduling, submitted?
`
`N/A X
`
`YES D
`
`NO El
`
`If Rx-to-OTC Switch application:
`
`N/A
`
`0
`
`0
`
`OTC label comprehension studies, all OTC labeling, and current approved PI consulted to
`ODS/DSRCS?
`N/A El
`YES |:|
`
`NO D
`
`Has DOTCDP been notified of the OTC switch application?
`
`YES 1:]
`
`NO I:I
`
`Clinical
`
`0
`
`If a controlled substance, has a consult been sent to the Controlled Substance Staff?
`YES El
`
`N/A
`NO El
`
`Chemistry
`
`0
`
`0
`
`0
`
`Did applicant request categorical exclusion for environmental assessment? YES X
`If no, did applicant submit a complete environmental assessment?
`YES
`I:]
`If EA submitted, consulted to Florian Zielinski (HFD-357)?
`YES
`E]
`
`NO E]
`NO {:I
`NO El
`
`Establishment Evaluation Request (EER) submitted to DMPQ?
`
`YES X
`
`NO El
`
`If a parenteral product, consulted to Microbiology Team (HFD-805)?
`
`YES X
`
`NO El
`
`PREPARED BY:
`-
`
`MICHAEL PUGLISI
`REGULATORY PROJECT MANAGER
`CDER/OND/OAP/DAIOP
`
`Appears This Way
`On Original
`
`Version: 12/15/04
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Michael Puglisi
`9/12/2006 01:37:19 PM
`CSO
`
`Michael Puglisi
`9/12/2006 01:42:47 PM
`CSO
`
`Appears This Way ‘
`On Original
`
`

`

`
`
`Division of Anti-Infective and
`
`Ophthalmology Products
`Center for Drug Evaluation and Research, HEB-520
`10903 New Hampshire Avenue,.Building 22
`Silver Spring, MD 20993
`'
`
`To:
`Angela Kothe, O.D., PhD.
`From: Mike Puglisi/ Project Manager
`
`
`Fax:
`817-551—4630
`Fax:
`301—796—9881 .
`
`
`Phone:
`
`Phone: 301-796—0791
`
`Pages: 2 (including cover page)
`> Date: September 12, 2006
`_______—_____—______—__________..___.————————-———-——————
`
`Re: CMC Comments re: NDA 21—994
`
`El Urgent
`
`E! For Review El Please Comment [II Please Reply [I Please Recycle
`
`___—_—_____________—_____________—_——————————-——————-—-
`
`THIS DOCUMENT IS INTENDED ONLY FOR THE USE OF THE PARTY TO WHOM IT IS ADDRESSED AND MAY
`CONTAIN INFORMATION THAT IS PRIVILEGED, CONFIDENTIAL AND PROTECTED FROM DISCLOSURE UNDER
`APPLICABLE LAW. Ifyou are not the addressee, or a person authorized to deliver the document to the addressee, you are hereby
`notified that any review, disclosure, dissemination or other action based on the content ofthe communication is not authorized. If you
`have received this document in error, please immediately notify us by telephone and return it to us at the above address by mail.
`7.;
`Thank you.
`
`0 Comments:
`
`Angela,
`
`Attached please find the CMC reviewer’s comments concerning Travatan Z (NDA 21-994).
`Please let me know if you have any questions about these comments. Thanks.
`
`Mike
`
`Appears This Way
`On Original
`
`

`

`NDA 21994
`
`Reviewer ’s Comments:
`
`I
`
`_
`
`September 12, 2006
`
`1. The ophthalmic solution should meetthe particulate matter criteria. The updated stability data
`at ' mm... RHprovidedfor 78 weeks support a H , shelflife. The expiry dating can be
`
`extended infuture Annual Reports based upon full shelf-life data obtainedfrom the“
`commercial batches under the stability protocol. Please revise your proposed expiry period
`accordingly.
`'
`
`2. A test and acceptance criteriafor ' —1-——-¢-___ should be included in the HCO—40
`specification and in the drug product specification.
`
`3. For the impurities HPLC test, it is recommended to include a standard at the quantitation limit
`as part ofsystem suitability testing to ensure detectability ofimpurities down to that level.
`
`. 98992
`I
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`/S/
`
`Michael Puglisi
`9/12/2006 01:16:12 PM
`
`

`

`H
`
`Page(s) Withheld
`
`Trade Secret / Confidential
`
`Draft Labeling
`
`/ V Deliberative Process
`
`Withheld Track Number: Administrative- '
`
`

`

`Division of Anti-Infective and
`
`Ophthalmology Products
`Center for Drug Evaluation and Research, HFD-520
`10903 New Hampshire Avenue, Building 22
`Silver Spring, MD 20993
`
`
`
`
`To:
`Angela Kothe, O.D., PhD.
`From: Mike Puglisi/ Project Manager
`
`
`Fax:
`817-551-4630
`Fax:
`301-796—9881
`
`Phone:
`Phone: 301—796-0791
`
`
`
`
`Pages: 3 (including cover page) . Date: July 5, 2006
`
`Re: CMC Information Request re: NDA 21-994
`
`El For Review El Please Comment El Please Reply D Please Recyble
`D Urgent
`
`
`25
`
`THIS DOCUMENT IS INTENDED ONLY FOR THE USE OF THE PARTY TO WHOM IT IS ADDRESSED AND MAY'
`CONTAIN INFORMATION THAT IS PRIVILEGED, CONFIDENTIAL AND PROTECTED FROM DISCLOSURE UNDER
`q APPLICABLE LAW. If you are not the addressee, or a person authorized to deliver the document to the addressee, you are hereby
`notified that any review, disclosure, dissemination or other action based on the content bfthe communication is not authorized. If you
`have received this document in error, please immediately notify usby telephone and return it to us at the above address by mail.
`Thank you.
`V
`Comments:
`
`' 0
`
`Angela,
`
`Attached is a list of information being requested by the CMC reviewer for TravatanZ (NDA 21-994).
`Please respond in an amendment to the NDA. Please let me know if you have any questions about this
`request. Thanks.
`'
`
`Mike
`
`Appears This Way
`On Original
`
`

`

`NDA 21-994
`
`_
`
`.
`
`.
`
`_
`
`July 5, 2006
`
`Reviewer ’3 Comments:
`
`(1). Please provide stability data oftravoprost stock solutionfor manufacturing the drug product to support
`that it is stablefor 6 months.
`'
`
`(2). It is not clear ifthe in-process chemical testing of travoprost bulk solution is performed on each batch ,
`since the some testing is performed on thefnished drugproduct Please clarifir. Also, indicate ifthein-
`
` WWmme-aflswmr m1-» mmmastmz-w .
`
`process testing is performed
`
`(3). No information is provided on the "W“ U ofthe drugproduct. Please indicate ifafailed batch will
`- be reprocessed ‘
`
`(4). The batch analysis datafor unrelated impuritiesfor all lots is ’ mm. Since these impurities primarily
`arisefrom the container closure and the label, the in-process