CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`
`
`
`
`APPLICATION NUMBER:
`22511Orig1s000
`
`
`
`OTHER REVIEW(S)
`
`
`
`
`
`

`

`Department of Health and Human Services
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Surveillance and Epidemiology
`
`
`
`April 20, 2010
`
`Donna Griebel, M.D., Director
`Division of Gastroenterology Products (DGP)
`
`Claudia Karwoski, PharmD, Director
`Division of Risk Management (DRISK)
`Sharon Mills, RN, BSN, CCRP
`Senior Patient Labeling Reviewer, Acting Team Leader
`Division of Risk Management (DRISK)
`
`Jessica Diaz, RN, BSN
`Patient Labeling Reviewer
`Division of Risk Management (DRISK)
`
`
`DRISK Review of Patient Labeling (Medication Guide
`
`VIMOVO (naproxen and esomeprazole magnesium)
`Delayed Release Tablets
`NDA 22-511
`
`Pozen, Inc.
`
`2009-1607
`
`Date:
`
`To:
`
`
`Through:
`
`From:
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`Subject:
`
`Drug Name(s):
`
`Application
`Type/Number:
`Applicant/sponsor:
`
`OSE RCM #:
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`

`

`1
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`2
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`3
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`INTRODUCTION
`This memorandum is in response to a request by the Division of Gastroentergology
`Products (DGP) for the Division of Risk Management (DRISK) to review the Medication
`Guide for VIMOVO (naproxen and esomeprazole magnesium) Delayed Release Tablets.
`On June 30, 2009, Pozen, Inc in collaboration with Astra Zeneca submitted New Drug
`Application (NDA) 22-511 for VIMOVO (naproxen and esomeprazole magnesium)
`Delayed Release Tablets. The proposed indication for VIMOVO (naproxen and
`esomeprazole magnesium) Delayed Release Tablets is for relief of signs and symptoms
`of osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis and to decrease the risk
`of developing gastric ulcers in patients at risk for developing NSAID-associated gastric
`ulcers.
`Please let us know if DGP would like a meeting to discuss theis review or any of our
`changes prior to sending to the Applicant.
`
`MATERIAL REVIEWED
`• Draft VIMOVO (naproxen and esomeprazole magnesium) Tablets Prescribing
`Information (PI) submitted June 30, 2009, and revised by the review division throughout
`the review cycle.
`(cid:131) Draft VIMOVO (naproxen and esomeprazole magnesium) Delayed Release Tablets PI
`with Medication Guide submitted November 11, 2009 and revised by the review division
`throughout the review cycle and provided to DRISK on April 13, 2010
`RESULTS OF REVIEW
`In our review of the Medication Guide, we have:
`• simplified wording and clarified concepts where possible
`• ensured that the MG is consistent with the PI
`removed unnecessary or redundant information
`•
`• ensured that the MG meets the Regulations as specified in 21
` CFR 208.24
`• ensured that the MG meets the criteria as specified in FDA’s Guidance Useful
`Written Consumer Medication Information (published July 2006)
`• ensured that the Vimovo MG is consistent with the currently approved NSAID
`MG template
`• added information after the required NSAID language about the esomeprazole
`magnesium component of the product, and general information about Vimovo
`
`
`
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`
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`
`
`Our annotated MG is appended to this memo. Any additional revisions to the PI
`should be reflected in the MG.
`
`
`Please let us know if you have any questions.
`
`21 Pages of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately
`following this page.
`
`

`

`Application
`Type/Number
`--------------------
`NDA-22511
`
`Submission
`Type/Number
`--------------------
`ORIG-1
`
`Submitter Name
`
`Product Name
`
`--------------------
`POZEN INC
`
`------------------------------------------
`PN 400
`NAPROXEN/ESOMEPRAZOLE
`MAGNESIUM
`
`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`JESSICA M DIAZ
`04/20/2010
`
`CLAUDIA B KARWOSKI
`04/20/2010
`concur
`
`

`

`
`
`
`
`RPM FILING REVIEW
`(Including Memo of Filing Meeting)
`To be completed for all new NDAs, BLAs, and Efficacy Supplements (except SE8 and SE9)
`
`Application Information
`NDA Supplement #:S-
`Efficacy Supplement Type SE-
`BLA STN #
`
`NDA # 22-511
`BLA#
`Proprietary Name: Vimovo
`Established/Proper Name: naproxen and esomeprazole magnesium
`Dosage Form: Tablets
`Strengths: 375mg/20mg and 500mg/20mg
`Applicant: Pozen
`Agent for Applicant (if applicable):
`Date of Application: 30 JUN 2009
`Date of Receipt: 30 JUN 2009
`Date clock started after UN:
`PDUFA Goal Date: 30 APR 2010
`
`
`
` 505(b)(1)
` 505(b)(2)
` 505(b)(1)
` 505(b)(2)
`
` Standard
` Priority
`
`Action Goal Date (if different):
`
`Date of Filing Meeting: 19 AUG 2009
`Filing Date: 29 AUG 2009
`Chemical Classification: (1,2,3 etc.) (original NDAs only) Type 4
`Proposed indication(s)/Proposed change(s): Signs and symptoms of osteoarthritis, rheumatoid arthritis, and ankylosing
`spondylitis in patients at risk of developing NSAID associated gastric ulcers
`
`Type of Original NDA:
`AND (if applicable)
`Type of NDA Supplement:
`
`If 505(b)(2): Draft the “505(b)(2) Assessment” form found at:
`http://inside.fda.gov:9003/CDER/OfficeofNewDrugs/ImmediateOffice/ucm027499.html
`and refer to Appendix A for further information.
`Review Classification:
`
`If the application includes a complete response to pediatric WR, review
`classification is Priority.
`
`If a tropical disease priority review voucher was submitted, review
`classification is Priority.
`
`Resubmission after withdrawal?
`Part 3 Combination Product?
`
`If yes, contact the Office of Combination
`Products (OCP) and copy them on all Inter-
`Center consults
` Fast Track
` Rolling Review
` Orphan Designation
`
`
`
`
` Tropical Disease Priority
`Review Voucher submitted
`
`
`
`Resubmission after refuse to file?
` Drug/Biologic
` Drug/Device
` Biologic/Device
`
`
`
` PMC response
` PMR response:
` FDAAA [505(o)]
` PREA deferred pediatric studies [21 CFR
`314.55(b)/21 CFR 601.27(b)]
` Accelerated approval confirmatory studies (21 CFR
`314.510/21 CFR 601.41)
` Animal rule postmarketing studies to verify clinical
`
`
`
` Rx-to-OTC switch, Full
` Rx-to-OTC switch, Partial
` Direct-to-OTC
`
`
`Other:
`
`Version: 9/9/09
`
`1
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`

`

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`YES NO NA Comment
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`X
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`X
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`X
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`YES NO NA Comment
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`X
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`YES NO NA Comment
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`X
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`benefit and safety (21 CFR 314.610/21 CFR 601.42)
`Collaborative Review Division (if OTC product):
`List referenced IND Number(s): IND 76,301
`Goal Dates/Names/Classification Properties
`PDUFA and Action Goal dates correct in tracking system?
`
`If not, ask the document room staff to correct them immediately.
`These are the dates used for calculating inspection dates.
`Are the proprietary, established/proper, and applicant names
`correct in tracking system?
`
`If not, ask the document room staff to make the corrections. Also,
`ask the document room staff to add the established/proper name
`to the supporting IND(s) if not already entered into tracking
`system.
`Are all classification properties [e.g., orphan drug, 505(b)(2)]
`entered into tracking system?
`
`If not, ask the document room staff to make the appropriate
`entries.
`Application Integrity Policy
`Is the application affected by the Application Integrity Policy
`(AIP)? Check the AIP list at:
`http://www.fda.gov/ICECI/EnforcementActions/ApplicationIntegr
`ityPolicy/default.htm
`If yes, explain in comment column.
`
`If affected by AIP, has OC/DMPQ been notified of the
`submission? If yes, date notified:
`
`
`
`User Fees
`Is Form 3397 (User Fee Cover Sheet) included with
`authorized signature?
`
`
`User Fee Status
`
`If a user fee is required and it has not been paid (and it
`is not exempted or waived), the application is
`unacceptable for filing following a 5-day grace period.
`Review stops. Send UN letter and contact user fee staff.
`
`
`
`If the firm is in arrears for other fees (regardless of
`whether a user fee has been paid for this application),
`the application is unacceptable for filing (5-day grace
`period does not apply). Review stops. Send UN letter
`and contact the user fee staff.
`Note: 505(b)(2) applications are no longer exempt from user fees pursuant to the passage of FDAAA. All 505(b)
`applications, whether 505(b)(1) or 505(b)(2), require user fees unless otherwise waived or exempted (e.g., small
`business waiver, orphan exemption).
`
`Payment for this application:
`
`
` Paid
` Exempt (orphan, government)
` Waived (e.g., small business, public health)
` Not required
`Payment of other user fees:
`
`
` Not in arrears
` In arrears
`
`Version: 9/9/09
`
`2
`
`(b) (4)
`
`

`

`
`
`YES NO NA Comment
`
`
`505(b)(2)
`(NDAs/NDA Efficacy Supplements only)
`Is the application for a duplicate of a listed drug and eligible
`for approval under section 505(j) as an ANDA?
`Is the application for a duplicate of a listed drug whose only
`difference is that the extent to which the active ingredient(s)
`is absorbed or otherwise made available to the site of action
`less than that of the reference listed drug (RLD)? (see 21
`CFR 314.54(b)(1)).
`Is the application for a duplicate of a listed drug whose only
`difference is that the rate at which the proposed product’s
`active ingredient(s) is absorbed or made available to the site
`of action is unintentionally less than that of the listed drug
`(see 21 CFR 314.54(b)(2))?
`
`Note: If you answered yes to any of the above questions, the
`application may be refused for filing under 21 CFR 314.101(d)(9).
`Is there unexpired exclusivity on the active moiety (e.g., 5-
`year, 3-year, orphan or pediatric exclusivity)? Check the
`Electronic Orange Book at:
`http://www.fda.gov/cder/ob/default.htm
`
`If yes, please list below:
`Exclusivity Expiration
`Exclusivity Code
`Drug Name
`Application No.
`
`
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`
`
`If there is unexpired, 5-year exclusivity remaining on the active moiety for the proposed drug product, a 505(b)(2)
`application cannot be submitted until the period of exclusivity expires (unless the applicant provides paragraph IV
`patent certification; then an application can be submitted four years after the date of approval.) Pediatric
`exclusivity will extend both of the timeframes in this provision by 6 months. 21 CFR 108(b)(2).Unexpired, 3-year
`exclusivity will only block the approval, not the submission of a 505(b)(2) application.
`Exclusivity
`YES NO NA Comment
`Does another product have orphan exclusivity for the same
`
`X
`
`
`indication? Check the Electronic Orange Book at:
`http://www.fda.gov/cder/ob/default.htm
`If another product has orphan exclusivity, is the product
`considered to be the same product according to the orphan
`drug definition of sameness [21 CFR 316.3(b)(13)]?
`
`If yes, consult the Director, Division of Regulatory Policy II,
`Office of Regulatory Policy (HFD-007)
`Has the applicant requested 5-year or 3-year Waxman-Hatch
`exclusivity? (NDAs/NDA efficacy supplements only)
`
`If yes, # years requested: 3
`
`Note: An applicant can receive exclusivity without requesting it;
`therefore, requesting exclusivity is not required.
`
`
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`X
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`X
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`X
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`X
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`X
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`Version: 9/9/09
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`3
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`

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`Is the proposed product a single enantiomer of a racemic drug
`previously approved for a different therapeutic use (NDAs
`only)?
`If yes, did the applicant: (a) elect to have the single
`enantiomer (contained as an active ingredient) not be
`considered the same active ingredient as that contained in an
`already approved racemic drug, and/or (b): request
`exclusivity pursuant to section 505(u) of the Act (per
`FDAAA Section 1113)?
`
`If yes, contact Mary Ann Holovac, Director of Drug Information,
`OGD/DLPS/LRB.
`
`
`
`
`
`Do not check mixed submission if the only electronic component
`is the content of labeling (COL).
`
`
`If mixed (paper/electronic) submission, which parts of the
`application are submitted in electronic format?
`Overall Format/Content
`If electronic submission, does it follow the eCTD
`guidance1?
`If not, explain (e.g., waiver granted).
`Index: Does the submission contain an accurate
`comprehensive index?
`Is the submission complete as required under 21 CFR 314.50
`(NDAs/NDA efficacy supplements) or under 21 CFR 601.2
`(BLAs/BLA efficacy supplements) including:
`
`
` legible
` English (or translated into English)
` pagination
` navigable hyperlinks (electronic submissions only)
`
`
`If no, explain.
`Controlled substance/Product with abuse potential:
`Is an Abuse Liability Assessment, including a proposal for
`scheduling, submitted?
`
`
`
`If yes, date consult sent to the Controlled Substance Staff:
`BLAs only: Companion application received if a shared or
`divided manufacturing arrangement?
`
`If yes, BLA #
`
`
`
`Format and Content
`
`X
`
`
`
`
`
`X
`
`
`
`
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`
`
`
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` All paper (except for COL)
` All electronic
` Mixed (paper/electronic)
`
` CTD
` Non-CTD
` Mixed (CTD/non-CTD)
`
`
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`
`
`YES NO NA Comment
`X
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`X
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`X
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`X
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`X
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`Version: 9/9/09
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`4
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`

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`YES NO NA Comment
`X
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`X
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`YES NO NA Comment
`
`
`
`Forms and Certifications
`Electronic forms and certifications with electronic signatures (scanned, digital, or electronic – similar to DARRTS,
`e.g., /s/) are acceptable. Otherwise, paper forms and certifications with hand-written signatures must be included.
`Forms include: user fee cover sheet (3397), application form (356h), patent information (3542a), financial
`disclosure (3454/3455), and clinical trials (3674); Certifications include: debarment certification, patent
`certification(s), field copy certification, and pediatric certification.
`Application Form
`Is form FDA 356h included with authorized signature?
`
`If foreign applicant, both the applicant and the U.S. agent must
`sign the form.
`Are all establishments and their registration numbers listed
`on the form/attached to the form?
`Patent Information
`(NDAs/NDA efficacy supplements only)
`Is patent information submitted on form FDA 3542a?
`
`Financial Disclosure
`Are financial disclosure forms FDA 3454 and/or 3455
`included with authorized signature?
`
`Forms must be signed by the APPLICANT, not an Agent.
`
`Note: Financial disclosure is required for bioequivalence studies
`that are the basis for approval.
`Clinical Trials Database
`Is form FDA 3674 included with authorized signature?
`
`Debarment Certification
`Is a correctly worded Debarment Certification included with
`authorized signature? (Certification is not required for
`supplements if submitted in the original application)
`
`If foreign applicant, both the applicant and the U.S. Agent must
`sign the certification.
`
`Note: Debarment Certification should use wording in FD&C Act
`section 306(k)(l) i.e.,“[Name of applicant] 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, “To the best of my knowledge…”
`
`X
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`
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`
`
`YES NO NA Comment
`X
`
`
`
`
`YES NO NA Comment
`X
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`
`
`
`YES NO NA Comment
`X
`
`
`
`
`Version: 9/9/09
`
`5
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`

`

`YES NO NA Comment
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`X
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`YES NO NA Comment
`X
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`X
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`X
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` X
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`X
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`Field Copy Certification
`(NDAs/NDA efficacy supplements only)
`For paper submissions only: Is a Field Copy Certification
`(that it is a true copy of the CMC technical section) included?
`
`Field Copy Certification is not needed if there is no CMC
`technical section or if this is an electronic submission (the Field
`Office has access to the EDR)
`
`If maroon field copy jackets from foreign applicants are received,
`return them to CDR for delivery to the appropriate field office.
`
`
`Pediatrics
`PREA
`
`Does the application trigger PREA?
`
`If yes, notify PeRC RPM (PeRC meeting is required)
`
`Note: NDAs/BLAs/efficacy supplements for new active ingredients,
`new indications, new dosage forms, new dosing regimens, or new
`routes of administration trigger PREA. All waiver & deferral
`requests, pediatric plans, and pediatric assessment studies must be
`reviewed by PeRC prior to approval of the application/supplement.
`If the application triggers PREA, are the required pediatric
`assessment studies or a full waiver of pediatric studies
`included?
`
`If studies or full waiver not included, is a request for full
`waiver of pediatric studies OR a request for partial waiver
`and/or deferral with a pediatric plan included?
`
`If no, request in 74-day letter
`If a request for full waiver/partial waiver/deferral is
`included, does the application contain the certification(s)
`required under 21 CFR 314.55(b)(1), (c)(2), (c)(3)/21 CFR
`601.27(b)(1), (c)(2), (c)(3)
`
`If no, request in 74-day letter
`BPCA (NDAs/NDA efficacy supplements only):
`
`Is this submission a complete response to a pediatric Written
`Request?
`
`If yes, notify Pediatric Exclusivity Board RPM (pediatric
`exclusivity determination is required)
`
`
`Version: 9/9/09
`
`6
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`

`

`YES NO NA Comment
`X
`
`
`.
`
` Not applicable
` Package Insert (PI)
` Patient Package Insert (PPI)
` Instructions for Use (IFU)
` Medication Guide (MedGuide)
` Carton labels
` Immediate container labels
` Diluent
` Other (specify)
`YES NO NA Comment
`X
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` Not Applicable
` Outer carton label
` Immediate container label
` Blister card
` Blister backing label
` Consumer Information Leaflet (CIL)
` Physician sample
` Consumer sample
` Other (specify)
`YES NO NA Comment
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`Proprietary Name
`Is a proposed proprietary name submitted?
`
`If yes, ensure that it is submitted as a separate document and
`routed directly to OSE/DMEPA for review.
`Prescription Labeling
`Check all types of labeling submitted.
`
`
`
`
`Is Electronic Content of Labeling (COL) submitted in SPL
`format?
`
`If no, request in 74-day letter.
`Is the PI submitted in PLR format?
`
`If PI not submitted in PLR format, was a waiver or
`deferral requested before the application was received or in
`the submission? If requested before application was
`submitted, what is the status of the request?
`
`If no waiver or deferral, request PLR format in 74-day letter.
`All labeling (PI, PPI, MedGuide, IFU, carton and immediate
`container labels) consulted to DDMAC?
`MedGuide, PPI, IFU (plus PI) consulted to OSE/DRISK?
`(send WORD version if available)
`
`REMS consulted to OSE/DRISK?
`
`Carton and immediate container labels, PI, PPI sent to
`OSE/DMEPA?
`
`OTC Labeling
`Check all types of labeling submitted.
`
`
`Is electronic content of labeling (COL) submitted?
`
`If no, request in 74-day letter.
`
`Version: 9/9/09
`
`7
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`

`

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`X
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`X
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`X
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`
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`Are annotated specifications submitted for all stock keeping
`units (SKUs)?
`
`If no, request in 74-day letter.
`If representative labeling is submitted, are all represented
`SKUs defined?
`
`If no, request in 74-day letter.
`All labeling/packaging, and current approved Rx PI (if
`switch) sent to OSE/DMEPA?
`Consults
`Are additional consults needed? (e.g., IFU to CDRH; QT
`study report to QT Interdisciplinary Review Team)
`
`If yes, specify consult(s) and date(s) sent:
`
`DAARP: July 15, 2009
`DAARP Stats Team: July 15, 2009
`
`
`Meeting Minutes/SPAs
`End-of Phase 2 meeting(s)?
`Date(s): July 17, 2007
`
`If yes, distribute minutes before filing meeting
`Pre-NDA/Pre-BLA/Pre-Supplement meeting(s)?
`Date(s): March 23, 2009
`If yes, distribute minutes before filing meeting
`Any Special Protocol Assessments (SPAs)?
`Date(s):
`
`If yes, distribute letter and/or relevant minutes before filing
`meeting
`1http://www fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm072349
`.pdf
`
`
`YES NO NA Comment
`X
`
`
`
`
`YES NO NA Comment
`X
`
`
`Done as Advice
`
`Letter
`
`X
`
`
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`X
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`Version: 9/9/09
`
`8
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`
`
`ATTACHMENT
`
`MEMO OF FILING MEETING
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`DATE: 19 AUG 09
`
`BLA/NDA/Supp #: 22-511
`
`
`PROPRIETARY NAME: Vimovo
`
`ESTABLISHED/PROPER NAME: naproxen and esomeprazole magnesium
`
`DOSAGE FORM/STRENGTH: 375mg/20mg and 500mg/20mg
`
`APPLICANT: Pozen
`
`PROPOSED INDICATION(S)/PROPOSED CHANGE(S):
`
`Signs and symptoms of osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis in
`patients at risk of developing NSAID associated gastric ulcers.
`
`BACKGROUND: PreNDA Meeting held on March 27, 2009. On June 4, 2009, AstraZeneca
`authorized Pozen to refer to Nexium under NDA 21-153. AstraZeneca will market the drug post
`approval. January 29, 2009, Office of Compliance identified investigator, Dr. Howard Marker as
`submitting false information to the sponsor. Dr. Marker was responsible for some subjects under
`Protocol PN400-301 conducted under IND 76,301.
`
`
`
`REVIEW TEAM:
`
`
`Discipline/Organization
`
`Names
`
`Regulatory Project Management
`
`
`Cross-Discipline Team Leader (CDTL)
`
`Clinical
`
`
`Social Scientist Review (for OTC
`products)
`
`
`RPM:
`CPMS/TL:
`Ruyi He
`
`Reviewer:
`
`TL:
`
`Reviewer:
`
`TL:
`
`
`Chantal Phillips
`
`
`Eric Wynn
`
`
`
`
`
`
`
`Present at
`filing
`meeting?
`(Y or N)
`Y
`
`Y
`
`Y
`
`
`
`
`
`
`
`Version: 9/9/09
`
`9
`
`

`

`
`
`OTC Labeling Review (for OTC
`products)
`
`
`Clinical Microbiology (for antimicrobial
`products)
`
`
`
`Clinical Pharmacology
`
`
`Biostatistics
`
`
`Nonclinical
`(Pharmacology/Toxicology)
`
`Statistics (carcinogenicity)
`
`
`Immunogenicity (assay/assay
`validation) (for BLAs/BLA efficacy
`supplements)
`
`Product Quality (CMC)
`
`
`Quality Microbiology (for sterile
`products)
`
`CMC Labeling Review (for BLAs/BLA
`supplements)
`
`Facility Review/Inspection
`
`OSE/DMEPA (proprietary name)
`
`Reviewer:
`
`TL:
`
`Reviewer:
`
`TL:
`
`
`Reviewer:
`
`TL:
`
`Reviewer:
`
`TL:
`
`Reviewer:
`
`TL:
`
`Reviewer:
`
`TL:
`
`Reviewer:
`
`TL:
`
`Reviewer:
`
`TL:
`
`Reviewer:
`
`TL:
`
`Reviewer:
`
`TL:
`
`Reviewer:
`
`TL:
`
`Reviewer:
`
`TL:
`
`
`
`
`
`
`
`
`
`
`Jane Bai
`
`Sue Chih Lee
`
`Freda Cooner
`
`Mike Welch
`
`Charles Wu
`
`Sushanta Chakder
`
`
`
`
`
`
`
`
`
`Rajiv Agarwal
`
`Marie Kowblansky
`
`
`
`
`
`
`
`
`
`
`
`
`
`Maria Waslik (covering
`RPM)
`
`
`
`
`
`
`
`
`
`
`Y
`
`Y
`
`Y
`
`Y
`
`Y
`
`Y
`
`
`
`
`
`
`
`
`
`N
`
`Y
`
`
`
`
`
`
`
`
`
`
`
`
`
`Y
`
`
`
`Version: 9/9/09
`
`10
`
`

`

`
`
`OSE/DRISK (REMS)
`
`Bioresearch Monitoring (DSI)
`
`
`
`Other reviewers
`
`Other attendees
`
`
`
`FILING MEETING DISCUSSION:
`
`
`
`GENERAL
`
` •
`
` 505(b)(2) filing issues?
`
`
`
`
`
`
`If yes, list issues: Confirm with Maria Walsh on
`esomeprazole as immediate release regarding (b)(2)
`• Per reviewers, are all parts in English or English
`translation?
`
`If no, explain:
`
`
`
`
`• Electronic Submission comments
`
`
`List comments:
`
`
`
`
`
`
`
`
`
`
`
`Reviewer:
`
`TL:
`
`Reviewer:
`
`TL:
`
`
`
`
`
`
`
`
`
`
`
`
`Donna Griebel, Tien Mien Chen, Ellen
`Fields, Jin Chen, Katherine Meaker,
`Sharon Hertz, Anil Nayyar
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Not Applicable
` YES
` NO
`
` YES
` NO
`
` Not Applicable
`
` Not Applicable
` FILE
` REFUSE TO FILE
`
` Review issues for 74-day letter
`
` YES
` NO
`
` YES
`Date if known:
` NO
` To be determined
`
`
`
`
`Reason:
`
`
`
`
`
`
`
`
`
`
`
`
`CLINICAL
`
`
`
`Comments:
`
`• Clinical study site(s) inspections(s) needed?
`
`
`
`
`
`
`
`
`
`
`
`
`
`• Advisory Committee Meeting needed?
`
`Comments:
`
`
`
`
`
`
`
`
`
`
`
`
`
`If no, for an original NME or BLA application, include the
`
`If no, explain:
`
`
`
`Version: 9/9/09
`
`11
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
` Not Applicable
` YES
` NO
`
` Not Applicable
` FILE
` REFUSE TO FILE
`
` Review issues for 74-day letter
`
` Not Applicable
` FILE
` REFUSE TO FILE
`
` Review issues for 74-day letter
`
` YES
` NO
`
` Not Applicable
` FILE
` REFUSE TO FILE
`
` Review issues for 74-day letter
`
` Not Applicable
` FILE
` REFUSE TO FILE
`
` Review issues for 74-day letter
`
`
`
`
`
` •
`
`
`
`
`
`reason. For example:
`o this drug/biologic is not the first in its class
`o the clinical study design was acceptable
`o the application did not raise significant safety
`or efficacy issues
`o the application did not raise significant public
`health questions on the role of the
`drug/biologic in the diagnosis, cure,
`mitigation, treatment or prevention of a
`disease
`
`If the application is affected by the AIP, has the
`division made a recommendation regarding whether
`or not an exception to the AIP should be granted to
`permit review based on medical necessity or public
`health significance?
`
`Comments:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`CLINICAL MICROBIOLOGY
`
`
`
`
`
`
`
`Comments:
`CLINICAL PHARMACOLOGY
`
`
`
`Comments: Missing PK/PD comparability studies
`(reference: PreBLA meeting, 9/15/09 tcon, Advice letter
`dated 9/30/09)
`
`
`
`
`
`• Clinical pharmacology study site(s) inspections(s)
`needed?
`
`
`BIOSTATISTICS
`
`
`
`Comments:
`
`NONCLINICAL
`(PHARMACOLOGY/TOXICOLOGY)
`
`
`
`Comments:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Version: 9/9/09
`
`12
`
`

`

`
`
`IMMUNOGENICITY (BLAs/BLA efficacy
`supplements only)
`
`
`
`Comments:
`
`PRODUCT QUALITY (CMC)
`
`
`
`Comments:
`
`Environmental Assessment
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` •
`
` Categorical exclusion for environmental assessment
`(EA) requested?
`
`If no, was a complete EA submitted?
`
`
`
`
`If EA submitted, consulted to EA officer (OPS)?
`
`Comments:
`
`Quality Microbiology (for sterile products)
`
`
`
`
`
`
`
`
`
`
`
` •
`
` Was the Microbiology Team consulted for validation
`of sterilization? (NDAs/NDA supplements only)
`
` Not Applicable
` FILE
` REFUSE TO FILE
`
` Review issues for 74-day letter
`
` Not Applicable
` FILE
` REFUSE TO FILE
`
` Review issues for 74-day letter
`
` Not Applicable
`
` YES
` NO
`
` YES
` NO
`
` YES
` NO
`
` Not Applicable
`
` YES
` NO
`
` Not Applicable
`
` YES
` NO
`
` YES
` NO
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Comments:
`
`Facility Inspection
`
`
`
`
`
`
`
`
`
`
`
` •
`
` Establishment(s) ready for inspection?
`
` Establishment Evaluation Request (EER/TBP-EER)
`submitted to DMPQ?
`
`
`
` (cid:131)
`
`
`
`
`Comments:
`
`
`
`
`
`
`
`
`
`
`
`
`Version: 9/9/09
`
`13
`
`

`

`
`
`
`
`Facility/Microbiology Review (BLAs only)
`
`
`
`
`
`
`
`Comments:
`CMC Labeling Review (BLAs/BLA supplements
`only)
`
`
`Comments:
`
`
`
`
`
`
`
`
`
`
`
` Not Applicable
` FILE
` REFUSE TO FILE
`
` Review issues for 74-day letter
`
` Review issues for 74-day letter
`
`
`
`
`
`
`
`
`Version: 9/9/09
`
`14
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Review issues have been identified for the 74-day letter. List (optional):
`
` Standard Review
`
` Priority Review
`
`
`
`
`
`ACTIONS ITEMS
`
`Ensure that the review and chemical classification properties, as well as any other
`pertinent properties (e.g., orphan, OTC) are correctly entered into tracking system.
`
`If RTF, notify everybody who already received a consult request, OSE PM, and Product
`Quality PM (to cancel EER/TBP-EER).
`
`If filed, and the application is under AIP, prepare a letter either granting (for signature by
`Center Director) or denying (for signature by ODE Director) an exception for review.
`
`BLA/BLA supplements: If filed, send 60-day filing letter
`
`If priority review:
`• notify sponsor in writing by day 60 (For BLAs/BLA supplements: include in 60-day
`filing letter; For NDAs/NDA supplements: see CST for choices)
`
` •
`
` notify DMPQ (so facility inspections can be scheduled earlier)
` Send review issues/no review issues by day 74
`
`Other
`
`
`Review Classification:
`
`
`Version: 9/9/09
`
`15
`
`REGULATORY PROJECT MANAGEMENT
`
`
`
`
`
`
`
`
`
`
`
`
`Signatory Authority: Donna Griebel,Director
`
`21st Century Review Milestones (see attached) (optional):
`
`Comments:
`
`
`REGULATORY CONCLUSIONS/DEFICIENCIES
`
`The application is unsuitable for filing. Explain why:
`
`Application is missing PK/PD comparability data. Please see ClinPharm File Review
`
`The application, on its face, appears to be suitable for filing.
`
`Review Issues:
`
`
` No review issues have been identified for the 74-day letter.
`
`
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`_______________________________________
`Chantal Phillips, CDR, USPHS
`Regulatory Health Project Manager
`
`
`
`
`
`
`
`
`_______________________________________
`Brian Strongin, R.Ph., M.B.A.
`Chief Project Management Staff
`
`Version: 9/9/09
`
`16
`
`

`

`
`
`Appendix A (NDA and NDA Supplements only)
`
`NOTE: The term "original application" or "original NDA" as used in this appendix
`denotes the NDA submitted. It does not refer to the reference drug product or "reference
`listed drug."
`
`An original application is likely to be a 505(b)(2) application if:
`
`
`(1) it relies on published literature to meet any of the approval requirements, and the
`applicant does not have a written right of reference to the underlying data. If
`published literature is cited in the NDA but is not necessary for approval, the
`inclusion of such literature will not, in itself, make the application a 505(b)(2)
`application,
`(2) it relies for approval on the Agency's previous findings of safety and efficacy for
`a listed drug product and the applicant does not own or have right to reference the
`data supporting that approval, or
`(3) it relies on what is "generally known" or "scientifically accepted" about a class of
`products to support the safety or effectiveness of the particular drug for which the
`applicant is seeking approval. (Note, however, that this does not mean any
`reference to general information or knowledge (e.g., about disease etiology,
`support for particular endpoints, methods of analysis) causes the application to be
`a 505(b)(2) application.)
`
`
`Types of products for which 505(b)(2) applications are likely to be submitted include:
`fixed-dose combination drug products (e.g., heart drug and diuretic (hydrochlorothiazide)
`combinations); OTC monograph deviations (see 21 CFR 330.11); new dosage forms; new
`indications; and, new salts.
`
`An efficacy supplement can be either a (b)(1) or a (b)(2) regardless of whether the
`original NDA was a (b)(1) or a (b)(2).
`
`An efficacy supplement is a 505(b)(1) supplement if the supplement contains all of the
`information needed to support the approval of the change proposed in the supplement.
`For example, if the supplemental application is for a new indication, the supplement is a
`505(b)(1) if:
`
`(1) The applicant has conducted its own studies to support the new indication (or
`otherwise owns or has right of reference to the data/studies),
`
`(2) No additional information beyond what is included in the supplement or was
`embodied in the finding of safety and effectiveness for the original application or
`previously approved supplements is needed to support the change. For example,
`this would likely be the case with respect to safety considerations if the dose(s)
`was/were the same as (or lower than) the original application, and.
`
`(3) All other “criteria” are met (e.g., the applicant owns or has right of reference to
`the data relied upon for approval of the supplement, the application does not rely
`
`Version: 9/9/09
`
`17
`
`

`

`
`
`
`
`for approval on published literature based on data to which the applicant does not
`have a right of reference).
`
`An efficacy supplement is a 505(b)(2) supplement if:
`
`(1) Approval of the change proposed in the supplemental application would require
`data beyond that needed to support our previous finding of safety and efficacy in
`the approval of the original application (or earlier supplement), and the applicant
`has not conducted all of its own studies for approval of the change, or obtained a
`right to reference studies it does not own. For example, if the change were for a
`new indication AND a higher dose, we would likely require clinical efficacy data
`and preclinical safety data to approve the higher dose. If the applicant provided
`the effectiveness data, but had to rely on a different listed drug, or a new aspect of
`a previously cited listed drug, to support the safety of the new dose, the
`supplement would be a 505(b)(2),
`
`(2) The applicant relies for approval of the supplement on published literature that is
`based on data that the applicant does not own or have a right to reference. If
`published literature is cited in the supplem