`
`CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`21-450
`
`ADMINISTRATIVE and CORRESPONDENCE
`
`DOCUMENTS
`
`
`
`

`

`EXCLUSIVITY SUMMARY for NBA #
`
`21-450
`
`SUPPL #
`
`Trade Name Zomig Nasal Spray
`
`Generic Name Zolmitriptan
`
`Applicant Name AstraZeneca
`Approval Date
`9/26/03
`
`HFD- 120
`
`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 NBA?
`
`YES/_x__/
`
`NO /_/
`
`b)Is it an effectiveness supplement? YES /__/
`
`
`NO / x /
`
`If yes, what type (SE1, SE2, etc.)?
`
`c)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 /_§_/
`
`NO /__1
`
`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?
`
`YES /_/ No /_5_/
`
`-'~*"
`
`Page 1
`
`

`

`is "yes," how many years of
`If the answer to (d)
`exclusivity did the applicant request?
`
`e}Has pediatric exclusivity been granted for this Active
`Moiety?
`‘
`
`YES /__/
`
`N0 / x /
`
`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)
`'Switches should be answered No — Please indicate as such).
`
`If yes, NDA #
`
`Drug Name
`
`YES /___/
`
`NO /_35_/
`
`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 /__m/
`
`NO /_§m/
`
`IF THE ANSWER TO QUESTION 3 IS 'YES,“ G0 DIRECTLY TO THE
`SIGNATURE BLOCKS 0N Page 9
`(even if a study was required for the
`upgrade).
`
`PART II: FIVE-YEAR EXCLUSIVITY FOR NEW CHEMICAL ENTITIES
`
`Page 2
`
`

`

`
`
`(Answer either #1 or #2, as appropriate)
`
`1.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 / x / NO /___/
`
`-If “yes," identify the approved drug product(s) containing the
`active moiety, and, if known,
`the NBA #(s).
`
`NDA # 20-768 Zomig tablets
`
`NDA # 21-231 Zomig~ZMT
`
`NBA #
`
`2.Combination product.
`
`APPEARS THIS WAY
`0N ORIGINAS.
`
`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 agy one 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.)
`NO /__/
`YES /__/
`7
`If "yes," identify the approved drug product(s) containing the
`active moiety, and, if known,
`the NDA #(s).
`
`NDA #
`
`_,,_r
`
`Page 3
`
`
`
`

`

`NBA 4*
`
`NDA #
`
`APPEfoS THIS WAY
`0N ORiGiNAL
`
`VIF THE ANSWER TO QUESTION 1 OR 2 UNDER PART II IS "NO,'I GO
`DIRECTLY TO THE SIGNATURE BLOCKS ON Page 9.
`IF "YES," GO TO PART
`III.
`
`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
`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)
`is "yes" for any investigation referred to in another
`application, do not complete remainder of summary for that
`investigation.
`
`YES
`
`/_§_/
`
`NO/f
`
`IF “NO," G0 DIRECTLY TO THE SIGNATURE BLOCKS ON Page 9.
`
`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 applibation 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
`
`."
`
`_ l.”
`
`Page 4
`
`

`

`
`
`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 /_;5__/
`
`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:
`
`(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 /
`
`/
`
`NO / x /
`
`is "yes," do you personally
`If the answer to 2(b)
`(1)
`know of any reason to disagree with the applicant's
`conclusion?
`If not applicable, answer NO.
`
`YES /__/
`
`NO /_X_/
`
`If yes, explain:
`
`APPEARS THIS WAY
`0N ORiGINAl.
`
`~-~m~
`
`Page 5
`
`

`

`is “no," are you aware of
`If the answer to 2(b)
`(2)
`published studies not conducted or sponsored by the
`lapplicant or other publicly available data that
`could
`independently demonstrate the safety and effectiveness
`of this drug product?
`
`
`NO / x /
`
`If yes, explain:
`
`YES /___/
`
`(c)
`
`If the answers to (b)(1) and (bf(2) were both "no,"
`identify the clinical investigations submitted in the
`application that are essential to the approval:
`
`Investigation #1, Study # Trial 022
`
`Investigation #2, Study #
`
`Investigation #3, Study #
`
`3. In
`to
`
`investigations must be "new"
`addition to being essential,
`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 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.
`
`(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
`
`YES /__/
`
`NO / x /
`
`Investigation #2
`
`I
`
`Investigation #3
`
`YES /
`
`YES /
`
`/
`
`/
`
`NO /
`
`N0 /
`
`/
`
`/
`
`If you have answered "yes" for one or more
`investigations,
`identify each such investigation and the
`NBA in which each was relied upon:
`
`_ iii
`
`Page 6
`
`

`

`
`
`NDA #
`NDA #
`NDA #
`
`Study #
`Study #
`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
`
`Investigation #2
`
`Investigation #3
`
`YES /
`
`YES /
`
`YES /
`
`/
`
`/
`
`/
`
`NO / X /
`
`NO /
`
`NO /
`
`/
`
`/
`
`If you have answered "yes" for one or more
`investigations,
`identify the NBA in which a similar
`investigation was relied on:
`
`NBA #
`
`NDA #
`
`NDA #
`
`Study #
`
`Study #
`
`Study #
`
`(c)
`
`identify each
`If the answers to 3(a) and 3(b) are no,
`"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"):
`
`Investigation #__, Study # Trial 022
`
`InveStigation #__, Study #
`
`Investigation #__. Study #
`
`. 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
`
`_._.,
`
`Page 7
`
`

`

`the study.
`
`.f‘Wk".
`
`APPEARS was my
`0?: WWW.
`
`Page 8
`
`

`

`
`
`
`
`(a)
`
`For each investigation identified in response to
`question 3(a): if the investigation was carried out
`under an IND, was the applicant identified on the FDA
`'1571 as the sponsor?
`
`Investigation #1
`
`IND # 53,343
`
`YES
`
`/ x /
`
`NO /
`
`/ Explain:
`
`Investigation #2
`
`IND #
`
`YES /
`
`/
`
`NO /
`
`/ Explain:
`
`(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
`
`Page 9
`
`
`
`

`

`
`
`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:
`
`Signature of Preparer
`Title:
`
`Date
`
`Signature of Office or Division Director
`
`Date
`
`cc:
`Archival NBA
`HFD—
`/Division File
`HFD-
`/RPM
`HFD—ElO/Mary Ann Holovac
`HFD-104/PEDS/T.Crescenzi
`
`”FEARS 7st W
`0% G??S§fifl{
`
`FOI‘m OGD-01134'7
`Revised 8/7/95; edited BIB/95; revised 8/25/98, edited 3/6/00
`
`Page 10
`
`

`

` ...------n-n-n-nun----—-------------.—--------------u-u-n-..—.-—-----_...----—---_—---.---—-----------_-_--...-—-——-
`
`
`
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`nun-pnnunnn-un-u-u—u-uun-n-n-n-u-u.n-o-u-u-cn-n-un----—-—..-.---_---nus-u--—-----.---.—------------__--n.-p-_—_----
`
`/S/
`
`Russell Katz
`
`9/30/03 04:16:45 PM
`
`{,
`
`AWARE ’iHiS way
`{)N GiilGlNAL
`
`
`
`

`

`
`
`(Complete for all APPROVED original applications and efficacy supplements)
`
`PEDIATRIC PAGE
`
`NDAIBLA # : NDA 21-450 Zomig Nasal Spray
`Supplement Number:
`
`Supplement Type (cg. SE5):
`
`Stamp Date: 3/27103
`
`Action Date: 91'26l03
`
`RFD 420
`
`Trade and generic names/dosage form: zolmitriptan nasal spray
`
`Applicant: AstraZeneca
`
`Therapeutic Class: 38
`
`Indication(s) previously approved:
`
`Migraine — Deferred
`
`Each apprpved indication must have pediatric studies: Completed, Deferred, andfor Waived.
`
`Number of indications for this application(s):
`
`l
`
`Indication #1: Migraine
`
`Is there a full waiver for this indication (check one)?
`
`Ci Yes: Please proceed to Section A.
`
`Partial Waiver {_Deferred
`J No: Please check all that apply:
`NOTE: More than one may apply
`Please proceed to Section B, Section C, andlor Section D and complete as necessary.
`
`Completed
`
`, Section A: Fully Waived Studies
`
`Reason(s) for full waiver:
`
`El Products in this class for this indication have been studiedflabeled for pediatric population
`13 Diseaselcondition does not exist‘in children
`
`El Too few children with disease to study
`0 There are safety concerns
`C] Other:
`
`Ifstudies arefully waived, then pediatric infamation is completefor this indication. Ifthere is another
`indication, please see Attachment A. Otherwise, this Pediatric Page is compiete and should be entered into
`DFS.
`
`

`

`
`
`NDA 21-450
`
`Page 2
`
`Section B: Partial] Waived Studies
`
`Agelweight range being partially waived:
`
`Min
`Max
`
`kg
`kg
`
`
`mo.
`
`mo.
`
`yr.
`yr.
`
`Tanner Stage
`Tanner Stage
`
`Reason(s) for partial waiver:
`
`Products in this class for this indication have been studiedllabeled for pediatric population
`Diseaselcondition does not exist in children
`
`DUUDDDU
`
`Too few children with disease to study
`There are safety concerns
`‘
`Adult studies ready for approval
`Formulation needed
`Other:
`
`0"studies 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.
`
`{
`
`,
`
`action C: Deferred Studies
`
`Agelweight range being deferred:
`
`Min
`Mas
`
`kg
`kg
`
`Reason(s) for deferral:
`
`mo.
`mo.
`
`
`
`
`yr.
`12
`yr.
`1‘7
`
`Tanner Stage
`Tanner Stage
`
`/ Products in this class for this indication have been studiedllabeled for pediatric population
`El Disease/condition does not exist in children
`El Too few children with disease to study
`El There are safety concerns
`E] Adult studies ready for approval
`El Formulation needed
`
`Other: Sponsor conducted studies following March 26, 1999 Written Reguest for Zomig Tablets
`[EDA 20-768, IND 45,141]
`
`
`
`Date studies are due (mmlddlyy):
`
`930103
`
`ifstudies are completed, proceed to Section D. Otherwise, this Pediatric Page is complete and should be
`entered into DFS.
`
`

`

`NDA 21-450
`
`Page 3
`
`o‘ection D: Completed Studies
`
`I
`
`
`
`Agelweight range of completed studies:
`
`Min
`
`Mu
`
`kg
`kg
`
`I
`
`mo.
`
`mo.
`
`
`yr. 12
`yr. 1'7
`
`
`Tanner Stage
`
`Tanner Stage
`
`Comments:
`
`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 electronic signature page}
`
`Regulatory Project Manager
`
`. cc: NDA
`RFD-950] Terrie Crescenzi
`
`RFD-960! Grace Carmouze
`
`(revised 9-24-02)
`
`FOR QUESTIONS ON COMPLETING THIS FORM CONTACT, PEDIATRIC TEAM, RFD-960
`301-594-7337
`
`APPEARS THIS WAY
`0N ORIGINAL
`
`

`

`
`
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.m—Wm—O—I—I—fl—
`
`Eric Bastings
`9/25/03 03:07:56 PM
`
`APPEARS was my
`on amesw
`
`

`

`
`
`Public Health Service
`DEPARTMENT OF HEALTH & HUMAN SERVICES
`
`
`Food and Drug Administration
`Rockville, MD 20857
`
`NDA 21—450
`
`AstraZeneca Pharmaceuticals LP
`
`Attention: Ms. Judy W. Firor
`1800 Concord Pike, PO. Box 8355
`
`Wilmington, DE 19803-8355
`
`Re:
`
`Requestfor a Waiverfor Certain Post-Marketing Reporting Responsibilities
`Under 2] CFR 314.80
`
`Dear Ms. Firor:
`
`In your letter dated December 4, 2003, AstraZeneca Pharmaceuticals LP, U.S. agent for IPR
`Pharmaceuticals, Inc., requested waivers of certain post-marketing periodic safety reporting
`responsibilities under 21 CFR 314.80 for NDA 21-450 Zomig (zolmitriptan) Nasal Spray. You
`requested, under 21 CFR 314.90(a), a waiver from the requirement to submit to the Food and Drug
`Administration (FDA), as part of your post-marketing periodic safety reporting responsibilities, FDA
`form 3500A for each adverse experience that is determined to be both nonserious and expected. In
`addition, you have proposed that, in lieu of the format and timing of a periodic adverse drug
`experience report as required under our present regulations at 21 CFR 314.80(c)(2), you submit your
`annual intemationai Periodic Safety Update Report (PSUR) that combines safety information for all
`dosage forms of Zomig, including tablets, orally disintegrating tablets, and nasal spray. The data lock
`point for this PSUR is based on the international birth date of the product, March 7, 1997.
`
`Based upon the proposals stated in your letter, I concur that certain modifications in your post-
`marketing periodic safety reporting requirements are warranted at this time for the following product:
`
`NDA 21-450 Zomig (zolmitriptan) Nasal Spray
`
`Therefore, as of the date of this letter, the following waiver is granted for the above-listed NDA, as per
`2] CFR 314.90(b):
`
`For the above listed NDA, you may substitute your international Periodic Safety Update Report
`(PSUR) for the periodic adverse drug experience report required and described at 21 CFR
`314.80(c)(2) provided all six of the following conditions are met:
`
`(1)
`
`the PSUR is prepared according to the guideline developed by the International
`Conference on Harmonisation (ICH) designated as ICH-EZC and published in
`the Federal Register on 19 May 1997 [62 FR 27470].
`
`
`
`

`

`
`
`NDA 21-450
`
`Page 2
`
`(2)
`
`the PSUR is submitted on an annual basis based on the international birth date
`
`(IBD) of the product or moiety in the NDA (i.e., March 7, 1997). It is our
`understanding that you will lock your database annually on the month and day
`of the IBD in order to prepare the PSUR. You would then submit the final
`PSUR to us within 60 days of this data lock point as outlined in your letter.
`Please let me know if we have a misunderstanding about the timing of your
`report. Please note that you may generally combine all dosage forms and
`formulations of this moiety, as well as indications, in one PSUR. However,
`when you do so, you must submit one copy of the PSUR to each of your
`approved NDAs whose product is covered in the PSUR as well as a single copy
`of the PSUR for CDER’s Office of Drug Safety to
`
`Central Document Room
`
`Center for Drug Evaluation and Research
`Food and Drug Administration
`5901-B Ammendale Road
`
`Beltsville, MD 20705-1266.
`
`(3)
`
`(4)
`
`while you may generally combine all dosage forms and formulations, as well as
`indications, in one PSUR, you separate into specific sections of the report the
`information on different dosage forms, formulations, and/or indications when
`such separation is needed to accurately portray the safety profile of the specific
`product (e.g., one should not combine, for example, information from
`ophthalmic drop dosage forms and solid oral dosage forms).
`
`you attach, as an appendix to the international PSUR, copies of the 3500A forms
`that you are required to submit as part of a periodic safety report under 21 CFR
`314.80(c)(2) (they may be submitted electronically; see
`http://wwwfda.gov/ohrms/dockets/dockets/923025 1/925025 1.htm}. These
`include both medically confirmed and medically unconfirmed (consumer)
`reports. In addition, you are waived of the requirement to attach 3500As for
`individual safety reports for experiences that are determined to be non-serious
`and appear in the current labeling for the drug product. You should maintain
`records of these nonserious, labeled adverse experiences in your corporate drug
`product safety files. FDA does reserve the right to request these 3500As for the
`non-serious, labeled individual reports and expects that you would send them to
`us within five calendar days of such a request in the future. Information on
`these adverse experiences should be submitted in the section that includes a
`summary tabulation by body system of all adverse experience terms and counts
`of occurrences submitted during the reporting period.
`
`(5)
`
`you attach, as an appendix to the international PSUR, a tabular listing by body
`system of all consumer-reported adverse experience terms and counts of
`occurrences for individual safety cases, if such cases are not already included in
`the international PSUR tabular listings. If not included in other listings, these
`
`
`
`

`

`
`
`NDA 21-450
`
`Page 3
`
`lists should be segregated by classification of report (e.g., serious/unexpected;
`serious/expected; non-serious/unlisted; and non-serious/listed).
`
`(6)
`
`you attach, as an appendix to the international PSUR, a narrative that references
`the changes, if any, that you believe appropriate, based on the new information
`received in the reporting period, in your approved U.S. labeling for the
`product(s) covered by the PSUR. In this appendix, please also include a copy of
`the most recently approved U.S. labeling for the product(s) covered by the
`PSUR.
`
`The waiver outlined in this letter will be in effect until you are notified in writing that it has been
`discontinued. Also, please note that this waiver in no way affects your other reporting reSponsibilities
`under 21 CFR except as specifically outlined in this letter (e.g., this waiver does not affect your
`expedited reporting responsibilities for suspected adverse reactions that are serious and unlabeled).
`
`If you have any questions about this waiver, please do not hesitate to contact me at (301) 827-3219.
`
`
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Paul I. Seligman, M.D., M.P.H.
`Acting Director
`Office of Drug Safety
`Director
`
`Office of Phannacoepidemiology and Statistical Science
`Center for Drug Evaluation and Research
`
`APPEézfiS iiiifi WA?
`0N Ofiifiii‘ifii
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`——-m———-
`---——————-—“”--—--—-—---—--——-—-—"t—nann
`
`Paul Seligman
`12/19/03 12:56:49 PM
`
`

`

`
`
`9—
`
`Page(s) Withheld
`
`4 § 552(b)(4) Trade Secret / Confidential
`
`§ 552(b)(5) Deliberative Process
`
`§ 552(b)(5) Draft Labeling
`
`

`

`
`Message
`
`.
`
`Page. I of 1
`
`Chen, Lana Y
`
`From:
`
`Oliva, Armando
`
`Sent:
`
`Tuesday, August 12, 2003 2:22
`
`To:
`
`Cc:
`
`Chen, Lana Y
`
`Prohaska. Kevin
`
`Subject: Zomig NS labelingdoc
`
`Lana, here is the labeling for the action package. The highlighted changes are those that differ from the approvable
`labeling that we issued last winter. The sponsor has agreed to all of these changes.
`
`I'll send you my team leader memo shortly. Please put together the action package. The approval letter should contain the
`follmlling language:
`
`F
`
`’
`
`7
`
`APPEARS THIS WAY
`
`0N ORIGINAL
`
`8/19/03
`
`
`

`

`9% Page(s) Withheld
`
`§ 552(b)(4) Trade Secret / Confidential
`
`§ 552(b)(5) Deliberative Process
`
`/ § 552(b)(5) Draft Labeling
`
`
`
`
`
`

`

`
`
`
`
`Public Health Service
`
`E J) : DEPARTMENT OF HEALTH & HUMAN SERVICES
`
`.
`
`I
`
`an“.
`
`Food and Drug Administration
`Rockville MD 2085?
`
`MEMORANDUM
`
`Date:
`From:
`To:
`Subject:
`
`- August 12, 2003
`Armando Oliva, MD
`Russell Katz, MD, Division Director, DNDP
`NDA 21-450; Zomig Nasal Spray
`
`The sponsor proposes to market an intranasal formulation of zolmitriptan for the
`treatment of acute migraine. Zolmitriptan currently is marketed as an oral tablet (2.5mg,
`5mg) and as an orally disintegrating tablet (2.5mg, 5mg). The submission addressed in
`the memo is the response to the approvable letter issued 12/ 19/02 for the original Zomig
`Nasal Spray NDA. Dr. Kevin Prohaska provides the clinical review and Dr. Yong-Cheng
`Wang provides the biometrics review;
`
`The original application contained the results from a single randomized controlled trial
`
`(hereafier trial 07?) which demonstrated efficacy of the nasal spray at doses of -—-—-"'”
`5mg. Long-term safety was supported by the results of two long-term safety
`
`studies (078 and 122). The sponsor proposes to market Mdoses:
`5mg.
`
`The main issue precluding approval of the nasal spray was that the efficacy study was
`. conducted using a clinical device, yet the tote-marketed device was slightly different
`and it failed to show in vitro equivalence to the clinical device. I refer the reader to the
`approvable letter, which clearly outlines those deficiencies. Several of the in vitro
`bioequivalence parameters were outside the acceptable limits.
`
`The approvable letter suggested three options to address this deficiency:
`
`1. Repeat the in vitro testing using either mechanical actuation or have the break
`ring re-manufactured with more narrow specifications before repeating the study.
`2. Provide in viva pharmacokinetic data to demonstrate bioequivalence.
`3. Provide efficacy data from a well designed, randomized controlled trial.
`
`The sponsor has chosen option #3 and provides efficacy data from an interim analysis of
`an ongoing randomized controlled trial (hereafter 022) that uses the to-be-marketed spray
`device. We agreed to such an approach in a teleconference dated 2/11/03.
`
`Study 022 is an ongoing, large (N=1384), multicenter, randomized, placebo-controlled
`study that evaluates the early efficacy (15 minutes) of zolmitriptan nasal spray (ZNS)
`5mg for acute migraine. We realize that this study is only capable of demonstrating
`efficacy of the 5mg to-be-marketed device (since it is the only dose being studied) —-—
`
`]
`
`

`

`
`
`Armando Oliva. MD, HFD-120
`August 12. 2003
`
`Memorandum
`NBA 21-450 Zomig Nasal Spray
`
`Page 2 of 5
`
`Safety data in this submission consist of four open-label PK studies (00], 002, 110, 124)
`and blinded data from the ongoing 022 study and another study (120). No new safety _
`concerns arise from these data, given the limitations of blinded data. I refer the reader to
`Dr. Prohaska’s review for details and I do not discuss these data further in this memo.
`
`Study 022 plans to enroll 1592 subjects to achieve 1384 evaluable patients to compare the
`efficacy of ZNS 5mg vs. placebo using the early primary endpoint of headache response
`at 15 minutes. The study permits treatment of up to two migraines with study medication.
`The study had a typical design for migraine studies of this type. I refer the reader to Dr.
`Prohaska’s review for study design details. In summary, randomized IHS-defined
`migraine patients treated a moderate or severe migraine headache with study medication
`and recorded subjective efficacy measurements at pre-specified time points post-dosing.
`The primary endpoint for the interim analysis was pro-specified as the headache response
`at 2 hours, defined as a decrease in pain intensity to mild or none at the 2 hour time point,
`using data from the first attack only.
`'
`
`The interim analysis presented here evaluates the headache response at 2 hours in the first
`210 patients from this study. This analysis plan was submitted for review on 2/28/03, and
`uses an alpha spending fimction methodology to preserve the overall type I error of the
`experiment (see statistical review for additional details). The interim analysis was tested
`' at a significance level of 0.0027, and the final analysis will be tested at 0.0479.
`
`The primary efficacy analysis for interim data is shown in Table 1 (taken from the
`medical review, page 6, and the statistical review, page 5). It employed logistic
`regression using treatment, region, and baseline intensity in the model. It shows a 70% 2
`hour response rate for ZNS 5mg vs. 47% for placebo. This was highly statistically
`significant.1
`
`Population
`
`ITT-S-onsor IE?-
`
`Res -onse %
`76 70 4
`-
`76 (70.4)
`
`Res Ionse %
`47 47
`48 (47)
`
`p
`
`0.0006
`
`Table I: Study 022 - Interim Primary Eflicacy Results — 2-HR Headache Response
`
`
`
`ZomigNs ——
`Headache n Headache
`—value
`
`
`
`
`"' The discrepancy in the placebo group resulted from the fact that the sponsor did not include two placebo
`patients in the analysis: one had missing data at 2 hours, and the other had taken escape medication before
`2 hours when migraine headache pain was mild. Dr. Wang included these two patients using an LOCF
`approach for missing data.
`
`I Of note, the response rate for ZNS 5mg is numerically similar to that seen in the earlier efficacy trial that
`used the 5mg clinical device (70% now vs. 69%, table 2 page 3 of my team leader memo for the original
`NDA). The placebo response rate from that study was lower, 31%, compared to 47% in this trial. Due to
`the difference placebo response rates in the two studies, this results in a larger observed treatment effect for
`
`the clinical device (38%) vs. the to-be-marketed device (29%). ____,__
`'
`"
`'
`
`
`

`

`
`
`Page 3 of 5
`Memorandum
`Armando Oliva. MD. HFo-120
`
`August 12, 2003 , NDA 21-450 Zomig Nasal Spray
`
`The sponsor’s analysis failed to demonstrate superiority over placebo with regard to
`nausea, photophobia, and phonophobia in those patients who reported these symptoms at
`baseline (this despite the fact that numerically results were similar in study 077, which
`did demonstrate superiority on the secondary symptoms. Once again, a higher placebo
`response rates in study 022 was largely responsible for the lack of significance).
`
`The Division’s preferred analysis of these endpoints looks at the prevalence of these
`symptoms at 2 hours (Table 2, taken from the biostatistical review, Table 6, page 14).
`These analyses demonstrate a nominally significant advantage of ZNS 5mg over placebo
`with regard to photophobia at 2 hours (p=0.03) and numerical trends for photophobia
`(p=0.17) and nausea (p=0.08).2 If one tests these using the same level of significance for
`this interim analysis that was used for the primary analysis (0.0027), than none of these
`analyses are positive.
`
`Table 2: Study 022 — Associated Symptoms at Two Hours
`
`Nausea
`
`ZNS 5.0 mg
`
`(N = 108)‘
`
`Placebo
`
`(N =102)
`
`("
`
`19 (18.6)
`0.080
`
`37 (34.3)
`0.026
`
`Patients with associated symptom at 2 h (%)b
`-value°
`Photophobia
`Patients with associated symptom at 2 h (%)b
`- valuec
`Phonophobia
`29 (26.9)
`Patients with associated symptom at 2 h (%)b
`0.170
`. valuec
`. Statistical reviewer's results based on the analysis data sets provided by the sponsor.
`' Patients received trial medication and treated a migraine attack.
`" Headache response is as a reduction in headache intensity from moderate or severe to mild or none.
`° P-value is calculated by chi-square test.
`‘ Odds ratio and 95% confidence limits (CI) are estimated by SAS FREQ procedure.
`
`28 (27.7)
`NA
`
`50 (49.5)
`NA
`
`36 (35.6)
`NA
`
`
`
`2 The first efficacy study (077) demonstrated nominal significance of ZNS 5mg at 2 hours on all three
`migraine-assaciated symptoms: nausea, photophobia, and phonophobia. Absolute prevalences of these
`symptoms at 2 hours were similar across the two studies (see table below, taken from my team leader
`memo, table 3, page 5). Lower placebo prevalence rates in study 022 (and perhaps the smaller sample size -
`— N=108 for 022 vs. N=236 for 077 for the 5mg group) contributed to the lack of nominal significance.
`
`Table Error! Main Document Only..- Study 9077 — Prevalence ofAssociated Symptom at 2 Hours
`————-———-—————_—__.___—_________
`1N
`INS
`ZNS
`INS
`Zolmltrlptan
`Placebo
`5.0 mg
`2.5 mg
`1.0 mg
`0.5 mg
`Tab 2.5 my
`mass
`":24
`mass
`N=226
`N=232
`
`stzs
`
`Nausea
`
`33 (37.1)
`75 (32.9)
`76 (34.4)
`11 (30.3)
`67 (29.9)
`59 (25.1)
`<0.01
`0.11
`0.13
`0.55
`.35
`"‘- p'muei
`—-—-——-———————.—-——_.._..___..._._._
`Photophobta
`136 (60.7)
`91 (39.7)
`111 (502)
`103 (44.2)
`92 (41.3)
`75 (31.9)
`("'- p"""”"’
`<0.01
`<0.G‘l
`<0.01
`0.03
`«0.01
`——-—-—-———~—-——————————_——-——_~.____—____
`Phonophobia
`
`_,
`
`(
`
`(96. We“)
`
`61 (26.0)
`
`<0.01
`
`<0.01
`
`02 (21.3)
`
`<0.01
`
`33 (35.0)
`
`<0.01
`
`90 (40.9)
`
`0.06
`
`69 (30.4)
`
`111 (49.8)
`
`

`

`Amanda Olive, MD. urn—120
`August 12. 2003
`
`Memorandum
`NBA 21-450 Zomig Nasal Spray
`
`Page 4 of 5
`
`Discussion
`
`The results of the previous study (077) demonstrated the efficacy of zolmitriptan when
`administered with the device used in that study (clinical device). The interim analysis of
`study 022 was conducted to demonstrate efficacy of zolmitritan 5mg when administered
`with the to-he-marketed device. This analysis demonstrates efficacy against migraine
`pa