`
`
`
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`022410Orig1s000
`
`
`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
`
`June 8, 2010
`Bob Rappaport, MD, Division Director
`Division of Anesthesia and Analgesia
`Products (DAAP)
`
`Mary Willy, PhD, Deputy Director
`Division of Risk Management (DRISK)
`
`Sharon R. Mills, BSN, RN, CCRP
`Senior Patient Labeling Reviewer, Acting Team
`Leader
`Division of Risk Management
`Latonia M. Ford, RN, BSN, MBA
`Patient Product Information Reviewer
`Division of Risk Management
`Addendum to DRISK Review of Patient Labeling
`(Medication Guide), dated August 6, 2009
`Suboxone (buprenorphine and naloxone)
`sublingual film
`NDA 22-410
`
`
`
`Date:
`To:
`
`Through:
`
`From:
`
`Subject:
`
`Drug Name(s):
`
`Application
`Type/Number:
`Applicant/sponsor: Reckitt Benckiser Pharmaceuticals Inc.
`OSE RCM #:
`2010-970
`
`
`

`

`1 INTRODUCTION
`This review is written as an addendum to the Division of Risk
`Management (DRISK) review of the MG for Suboxone
`(buprenorphine and naloxone) sublingual film, originally requested
`by the Division of Anesthesia and Analgesia Products (DAAP), and
`completed on August 6, 2009.
`Please let us know if DAAP would like a meeting to discuss this
`review or any of our changes prior to sending to the Applicant.
`
`2 MATERIAL REVIEWED
`Draft Suboxone (buprenorphine and naloxone) sublingual flim
`Medication Guide (MG) submitted on October 20, 2008, revised by
`DRISK on August 6, 2009, and further revised by the review
`division and provided to DRISK on May 14, 2010.
`3 RESULTS OF REVIEW
`In our review of the MG, 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 208.20
`• ensured that the MG meets the criteria as specified in FDA’s
`Guidance for Useful Written Consumer Medication Information
`(published July 2006)
`After the original MG review was completed on August 6, 2009,
`DAAP sent the Applicant a Complete Response (CR) letter on
`August 21, 2009 because the proposed REMS was not sufficient to
`ensure that the benefits of suboxone sublingual film outweigh the
`risks associated with the use of the drug. DRISK revisions of the
`MG from August 6, 2009 were not provided to the Applicant. We
`received comments from DAAP on May 14, 2010 in response to our
`MG review completed on August 6, 2009. These comments and
`revisions are the subject of this review addendum.
`Our annotated MG is appended to this memo. We retained all of
`our previous comments as well as the comments from DAAP in the
`tracked changes version of the MG.
`Any additional revisions to the PI should be reflected in the MG.
`
`
`Please let us know if you have any questions.
`
`
`
`
`
`1
`
`13 Page(s) of Draft Labeling have been
`Withheld in Full as b4 (CCI/TS) immediately
`following this page
`
`

`

`Application
`Type/Number
`--------------------
`NDA-22410
`
`Submission
`Type/Number
`--------------------
`ORIG-1
`
`Submitter Name
`
`Product Name
`
`--------------------
`RECKITT
`BENCKISER
`PHARMACEUTICA
`LS INC
`
`------------------------------------------
`SUBOXONE
`(BUPRENORPHINE/NALOXONE
`) sublingual film
`
`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`LATONIA M FORD
`06/08/2010
`Suboxone Addendum to DRISK Review of Patient Labeling (Medication Guide), dated August 6,
`2009
`
`MARY E WILLY
`06/08/2010
`I concur
`
`

`

`Department of Health and Human Services
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Surveillance and Epidemiology
`
`
`
`August 6, 2009
`Bob Rappaport, MD, Division Director
`Division of Anesthesia, Analgesia, and Rheumatology
`Products (DAARP)
`Claudia Karwoski, PharmD, Director
`Division of Risk Management (DRISK)
`Jodi Duckhorn, MA, Team Leader
`Division of Risk Management
`Latonia M. Ford, RN, BSN, MBA
`Patient Product Information Reviewer
`Division of Risk Management
`DRISK Review of Patient Labeling (Medication Guide)
`Buprenorphine and Naloxone (Suboxone)
`NDA 22-410
`
`Reckitt Benckiser Pharmaceuticals INC.
`2009-2042
`
`Date:
`To:
`
`Through:
`
`From:
`
`Subject:
`Drug Name(s):
`Application
`Type/Number:
`Applicant/sponsor:
`OSE RCM #:
`
`
`

`

`1
`
`INTRODUCTION
`This review is written in response to a request by the Division of
`Anesthesia, Analgesia Rheumatology Product (DAARP) for the Division of
`Risk Management (DRISK) to review the Applicant’s proposed Medication
`Guide (MG) for Buprenorphine and Naloxone (Suboxone). Please let us
`know if DAARP would like a meeting to discuss this review or any of our
`changes prior to sending to the Applicant.
`
`2 MATERIAL REVIEWED
`(cid:131) Draft Buprenorphine and Naloxone (Suboxone
`) Prescribing
`Information (PI) submitted, October 20, 2008 and revised by the
`Review Division throughout the current review cycle.
`(cid:131) Draft Buprenorphine and Naloxone (Suboxone
`) Medication Guide
`(MG) submitted on October 20, 2008 and revised by the review division
`throughout the review cycle.
`
` 3
`
` RESULTS OF REVIEW
`In our review of the MG, 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
`208.20
`ensured that the MG meets the criteria as specified in FDA’s Guidance
`for Useful Written Consumer Medication Information (published July
`2006)
`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.
`
`
`•
`
`
`
`
`
`1
`
`14 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS)
`immediately following this page
`
`(b) (4)
`
`(b) (4)
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`LATONIA M FORD
`08/06/2009
`
`JODI M DUCKHORN
`08/06/2009
`
`

`

`Application Information
`NDA Supplement #:S-
`Efficacy Supplement Type SE-
`NDA # 22410
`BLA STN #
`BLA#
`Proprietary Name: Suboxone
`Established/Proper Name: buprenorphine and naloxone
`Dosage Form: sublingual film
`Strengths: 8 mg / 2 mg and 2 mg / 0.5 mg
`Applicant: Reckitt Benckiser Pharmaceutical, Inc.
`Agent for Applicant (if applicable):
`Date of Application: October 20, 2008
`Date of Receipt: October 21, 2008
`Date clock started after UN:
`PDUFA Goal Date:
`August 21, 2009
`Filing Date: December 20, 2008
`Date of Filing Meeting: December 2, 2008
`Chemical Classification: (1,2,3 etc.) (original NDAs only) Type 3
`Proposed Indication(s): Maintenance treatment of opioid dependence
`
`Type of Original NDA:
`AND (if applicable)
`Type of NDA Supplement:
`
`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 defaults to Priority.
`
`Resubmission after withdrawal?
`Resubmission after refuse to file?
`Part 3 Combination Product?
`
`
`
`
`
`
`
`
`
`
`
`
`
` Fast Track
` Rolling Review
` Orphan Designation
`
` Rx-to-OTC switch, Full
` Rx-to-OTC switch, Partial
` Direct-to-OTC
`
`
`Other:
`
`NDA/BLA REGULATORY FILING REVIEW
`(Including Memo of Filing Meeting)
`
`Action Goal Date (if different):
`August 7, 2009
`
`
` 505(b)(1)
` 505(b)(2)
` 505(b)(1)
` 505(b)(2)
`
` Standard
` Priority
`
`
`
`
` Tropical disease Priority
`review voucher submitted
`
` 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 benefit and safety (21 CFR 314.610/21 CFR
`601.42)
`
`Version 6/9/08
`
`1
`
`

`

`
`
`Collaborative Review Division (if OTC product):
`List referenced IND Number(s):
`75811
`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 name to the
`supporting IND(s) if not already entered into tracking system.
`
`
`
`
`Are all classification codes/flags (e.g. orphan, OTC drug,
`pediatric data) 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/ora/compliance ref/aiplist.html
`
`If yes, explain:
`
`If yes, has OC/DMPQ been notified of the submission?
`
`Comments:
`
`
`User Fees
`Form 3397 (User Fee Cover Sheet) submitted
`
`
`
`
`
`
` YES
` NO
`
` YES
` NO
`
` YES
` NO
`
` YES
` NO
`
` YES
` NO
`
` YES
` NO
` Paid
` Exempt (orphan, government)
` Waived (e.g., small business,
`public health)
` Not required
`Note: 505(b)(2) applications are no longer exempt from user fees pursuant to the passage of FDAAA. It is
`expected that all 505(b) applications, whether 505(b)(1) or 505(b)(2), will require user fees unless
`otherwise waived or exempted (e.g., business waiver, orphan exemption).
`
`
`User Fee Status
`
`
`Comments:
`
`Exclusivity
`Does another product have orphan exclusivity for the same
`indication? Check the Electronic Orange Book at:
`http://www.fda.gov/cder/ob/default.htm
`
`If yes, is the product considered to be the same product
`according to the orphan drug definition of sameness [21 CFR
`316.3(b)(13)]?
`
` YES
` NO
`
` YES
` NO
`
`
`
`
`
`
`Version 6/9/08
`
`2
`
`(b) (4)
`
`

`

`
`
`
`If yes, consult the Director, Division of Regulatory Policy II,
`Office of Regulatory Policy (HFD-007)
`
`Comments: This NDA is a "line extension" of an NDA
`(N20733) for sublingual tablets. The Sponsor is the same,
`and much of the underlying data is the same as was
`submitted under N20733, and was approved and granted
`orphan exclusivity.
`
`Because the Sponsor is the same as the previously approved
`product, the exclusivity for 20733 does not block exclusivity
`for 22410.
`Has the applicant requested 5-year or 3-year Waxman-Hatch
`exclusivity? (NDAs/NDA efficacy supplements only)
`
`Note: An applicant can receive exclusivity without requesting it;
`therefore, requesting exclusivity is not required.
`
`Comments: Although it does not appear that the Sponsor has
`specifically requested exclusivity, they do note that this
`product has been granted orphan designation.
`
`This Sponsor has previously been granted orphan exclusivity
`for another dosage form of this same combination.
`
`If the proposed product is a single enantiomer of a racemic
`drug previously approved for a different therapeutic use
`(NDAs only):
`
`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.
`
`
`
`
`1. Is the application for a duplicate of a listed drug and
`eligible for approval under section 505(j) as an ANDA?
`
`
`2. 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)).
`
` YES
`# years requested:
` NO
`
` Not applicable
`
` YES
` NO
`
`
`
`
`
`
`
`
` YES
` NO
`
` YES
` NO
`
`
`
`
`
`
`
`505(b)(2) (NDAs/NDA Efficacy Supplements only)
` Not applicable
`
`Version 6/9/08
`
`3
`
`

`

`
`
`
`3. 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.,
`4.
`5-year, 3-year, orphan or pediatric exclusivity)? Check
`the Electronic Orange Book at:
`http://www.fda.gov/cder/ob/default.htm
`
` YES
` NO
`
`
`
`
`
` YES
` NO
`
`
`
`
`
`
`
`
`
`
`
`
`If yes, please list below:
`
`Exclusivity Expiration
`Exclusivity Code
`Drug Name
`Application No.
`
`
`
`
`
`
`
`
`
`
`
`
`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.
`Format and Content
`
` All paper (except for COL)
` All electronic
` Mixed (paper/electronic)
`
`
`
`Do not check mixed submission if the only electronic component
`is the content of labeling (COL).
`
`
`Comments:
`
`
`
` CTD
` Non-CTD
` Mixed (CTD/non-CTD)
`
`If mixed (paper/electronic) submission, which parts of the
`application are submitted in electronic format?
`
`If electronic submission:
`paper forms and certifications signed (non-CTD) or
`electronic forms and certifications signed (scanned or digital
`signature)(CTD)?
`
`Forms include: 356h, patent information (3542a), financial
`disclosure (3454/3455), user fee cover sheet (3542a), and clinical
`trials (3674); Certifications include: debarment certification,
`patent certification(s), field copy certification, and pediatric
`certification.
`Comments:
`
`If electronic submission, does it follow the eCTD guidance?
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` YES
` NO
`
` YES
`
`Version 6/9/08
`
`4
`
`

`

`
`
`(http://www.fda.gov/cder/guidance/7087rev.pdf)
`
`If not, explain (e.g., waiver granted):
`
`Form 356h: Is a signed form 356h included?
`
`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?
`
`Comments:
`
`Index: Does the submission contain an accurate
`comprehensive index?
`
`Comments:
`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)
`
` NO
`
` YES
` NO
`
` YES
` NO
`
` YES
` NO
`
` YES
` NO
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Not Applicable
`
` YES
` NO
`
` YES
` NO
`
` YES
` NO
`
`
`If no, explain:
`
`Controlled substance/Product with abuse potential:
`
`Abuse Liability Assessment, including a proposal for
`scheduling, submitted?
`
`Consult sent to the Controlled Substance Staff?
`Comments:
`
`
`
`
`
`
`BLAs/BLA efficacy supplements only:
`
`Companion application received if a shared or divided
`manufacturing arrangement?
`
`If yes, BLA #
`Patent Information (NDAs/NDA efficacy supplements only)
`Patent information submitted on form FDA 3542a?
` YES
`
` NO
`Comments:
`
`
`Debarment Certification
`Correctly worded Debarment Certification with authorized
`
` YES
`
`Version 6/9/08
`
`5
`
`

`

`
`
` NO
`
` YES
` NO
`
`signature?
`
`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…”
`
`Comments:
`Field Copy Certification (NDAs/NDA efficacy supplements only)
` Not Applicable (electronic
`Field Copy Certification: that it is a true copy of the CMC
`technical section (applies to paper submissions only)
`submission or no CMC technical
`section)
`
`
` YES
`
` NO
`If maroon field copy jackets from foreign applicants are received,
`return them to CDR for delivery to the appropriate field office.
`Financial Disclosure
`Financial Disclosure forms included with authorized
`signature?
`
`Forms 3454 and/or 3455 must be included and must be signed by
`the APPLICANT, not an Agent.
`
`Note: Financial disclosure is required for bioequivalence studies
`that are the basis for approval.
`
`Comments:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Not Applicable
` YES
` NO
`
` YES
` NO
`
` YES
` NO
`
`Pediatrics
`
`PREA
`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.
`
`Are the required pediatric assessment studies or a full waiver
`of pediatric studies included?
`
`
`If no, is a request for full waiver of pediatric studies OR a
`request for partial waiver/deferral and a pediatric plan
`included?
`
`
`
`
`•
`•
`
`If no, request in 74-day letter.
`
`If yes, does the application contain the
`certification(s) required under 21 CFR 314.55(b)(1),
`
`Version 6/9/08
`
`6
`
`

`

`
`
`(c)(2), (c)(3)/21 CFR 601.27(b)(1), (c)(2), (c)(3)
`
`
`Comments: orphan designated
`
`BPCA (NDAs/NDA efficacy supplements only):
`
`Is this submission a complete response to a pediatric Written
`Request?
`
`If yes, contact PMHS (pediatric exclusivity determination by the
`Pediatric Exclusivity Board is needed).
`
`Comments:
`
`
`
`
` YES
` NO
`
`Prescription Labeling
` Not applicable
` Package Insert (PI)
` Patient Package Insert (PPI)
` Instructions for Use
` MedGuide
` Carton labels
` Immediate container labels
` Diluent
` Other (specify)
`
`
`Check all types of labeling submitted.
`
`
`
`
`
`Comments: Also includes ancillary labeling components:
`Physician's Brochure, Pharmacists Brochure, and Patients
`Brochure.
`
`Is electronic Content of Labeling submitted in SPL format?
`
`If no, request in 74-day letter.
`
`Comments:
`Package insert (PI) submitted in PLR format?
`
`
`If no, was a waiver or deferral requested before the
`application was received or in the submission?
`If before, what is the status of the request?
`
`If no, request in 74-day letter.
`
`
`Comments:
`All labeling (PI, PPI, MedGuide, carton and immediate
`container labels) consulted to DDMAC?
`
`Comments:
`MedGuide or PPI (plus PI) consulted to OSE/DRISK? (send
`WORD version if available)
`
`Comments: Although a MG wasn't submitted, the ancillary
`components were consulted to OSE with the request to assist
`in converting them into a MG.
`REMS consulted to OSE/DRISK?
`
` YES
` NO
`
` YES
` NO
`
` YES
` NO
`
` YES
` NO
`
`
`
`
`
`
` Not Applicable
` YES
` NO
`
` Not Applicable
`
`Version 6/9/08
`
`7
`
`

`

`
`
`
`Comments:
`Carton and immediate container labels, PI, PPI, and
`proprietary name (if any) sent to OSE/DMEDP?
`
`Comments:
`
`
` YES
` NO
` Not Applicable
` YES
` NO
`
`OTC Labeling
` 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
`
`
`Check all types of labeling submitted.
`
`
`
`
`
`Comments:
`
`
`Is electronic content of labeling submitted?
`
`If no, request in 74-day letter.
`
`Comments:
`Are annotated specifications submitted for all stock keeping
`units (SKUs)?
`
`If no, request in 74-day letter.
`
`Comments:
`If representative labeling is submitted, are all represented
`SKUs defined?
`
`If no, request in 74-day letter.
`
`Comments:
`
`Proprietary name, all labeling/packaging, and current
`approved Rx PI (if switch) sent to OSE/DMEDP?
`
`Comments:
`
`
`
`
`
`
`
`
`
`
`
` YES
` NO
`
` YES
` NO
`
` YES
` NO
`
`Meeting Minutes/SPA Agreements
`End-of Phase 2 meeting(s)?
` YES
`Date(s):
`If yes, distribute minutes before filing meeting.
`
` NO
`
`
`
`
`Comments:
`
`Pre-NDA/Pre-BLA/Pre-Supplement meeting(s)?
`If yes, distribute minutes before filing meeting.
`
`Comments:
`
`
`
`
`
`
`
`
`
`
`
` YES
`Date(s):
` NO
`
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`
`
`
`
`
`
`
`Any Special Protocol Assessment (SPA) agreements?
`If yes, distribute letter and/or relevant minutes before filing
`meeting.
`
`Comments:
`
`
`
`
`
`
`
` YES
`Date(s):
` NO
`
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`

`
`
`ATTACHMENT
`
`MEMO OF FILING MEETING
`
`
`
`Discipline/Organization
`
`Names
`
`
`
`
`DATE: December 3, 2008
`
`NDA/BLA #: 22-410
`
`
`PROPRIETARY/ESTABLISHED NAMES: Suboxone
`
`APPLICANT: Reckitt Benckiser
`
`BACKGROUND: "Line extension" of the previously approved buprenorphine/naloxone
`sublingual tablets for the same indication.
`(Provide a brief background of the drug, (e.g., molecular entity is already approved and this NDA is for an
`extended-release formulation; whether another Division is involved; foreign marketing history; etc.)
`
`REVIEW TEAM:
`
`
`Present at
`filing
`meeting?
`(Y or N)
`Y
`N
`Y
`
`Matthew Sullivan
`RPM:
`CPMS/TL: Sara Stradley
`Celia Winchell
`
`Regulatory Project Management
`
`
`Cross-Discipline Team Leader (CDTL)
`
`Clinical
`
`
`Reviewer:
`
`TL:
`
`Reviewer:
`
`TL:
`
`Reviewer:
`
`TL:
`
`Reviewer:
`
`TL:
`
`Clinical Microbiology (for antimicrobial Reviewer:
`
`Social Scientist Review (for OTC
`products)
`
`
`Labeling Review (for OTC products)
`
`
`OSE
`
`
`Celia Winchell
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Y
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
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`10
`
`(b) (4)
`
`

`

`
`
`products)
`
`
`
`TL:
`
`
`products)
`
`
`
`
`
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`

`

`
`
`
`Clinical Pharmacology
`
`
`Biostatistics
`
`
`Nonclinical
`(Pharmacology/Toxicology)
`
`
`Statistics, carcinogenicity
`
`
`Product Quality (CMC)
`
`
`Facility (for BLAs/BLA supplements)
`
`Microbiology, sterility (for NDAs/NDA
`efficacy supplements)
`
`Bioresearch Monitoring (DSI)
`
`
`Sheetal Agarwal
`
`Suresh Doddapaneni
`
`
`
`
`
`Beth Bolan
`
`Dan Mellon
`
`
`
`
`
`Xavier Ysern
`
`Ali Al Hakim
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reviewer:
`
`TL:
`
`Reviewer:
`
`TL:
`
`Reviewer:
`
`TL:
`
`Reviewer:
`
`TL:
`
`Reviewer:
`
`TL:
`
`Reviewer:
`
`TL:
`
`Reviewer:
`
`TL:
`
`Reviewer:
`
`TL:
`
`
`
`Y
`
`Y
`
`
`
`
`
`Y
`
`Y
`
`
`
`
`
`Y
`
`Y
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Other reviewers
`
`
`OTHER ATTENDEES: Rigo Roca, Deputy Division Director
`
`Bob Rappaport, Division Director
`
`Jim Hunter, CSS
`
`
`
`
`505(b)(2) filing issues?
`
`If yes, list issues:
`
`Per reviewers, are all parts in English or English
`translation?
`
`If no, explain:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Not Applicable
` YES
` NO
`
` YES
` NO
`
`
`
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`
`

`

`
`
`
`Electronic Submission comments
`
`List comments: (see note below under Clinical)
`
`CLINICAL
`
`
`
`Comments: Has comments regarding certain data
`definition files.
`
`• Clinical study site(s) inspections(s) needed?
`
`
`If no, explain:
`
`
`
` 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:
`
`
`
`
`• Advisory Committee Meeting needed?
`
`Comments:
`
`
`
`
`
`
`
`
`
`
`
`
`
`If no, for an original NME or BLA application, include the
`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?
`
` Not Applicable
` YES
` NO
`
`Comments:
`
`
`
`
`
`
`
`
`
`
`
`
`CLINICAL MICROBIOLOGY
`
`
`
`
`
`
`
`Comments:
`CLINICAL PHARMACOLOGY
`
`
`
`
`
`
`
`
`
` Not Applicable
` FILE
` REFUSE TO FILE
`
` Review issues for 74-day letter
`
` Not Applicable
` FILE
` REFUSE TO FILE
`
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`
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`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 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
`
` 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:
`
`• Clinical pharmacology study site(s) inspections(s)
`needed?
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`BIOSTATISTICS
`
`
`
`Comments:
`
`NONCLINICAL
`(PHARMACOLOGY/TOXICOLOGY)
`
`
`
`Comments:
`
`PRODUCT QUALITY (CMC)
`
`
`
`
`
`
`
`Comments:
`
`• Categorical exclusion for environmental assessment
`(EA) requested?
`
`
`
`
`
`
`
`If no, was a complete EA submitted?
`
`If EA submitted, consulted to EA officer (OPS)?
`
`Comments:
`
`
`
`
`
`
`
`
`
`
`
`
`• Establishment(s) ready for inspection?
`
`
`
` (cid:131)
`
` Establishment Evaluation Request (EER/TBP-EER)
`submitted to DMPQ?
`
`
`
`
`Comments:
`
`• Sterile product?
`
`
`
`
`
`
`
`
`
`
`
`
`Version 6/9/08
`
`14
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`If yes, was Microbiology Team consulted for
`validation of sterilization? (NDAs/NDA
`supplements only)
`FACILITY (BLAs only)
`
`
`
`Comments:
`
`
`
`
`
`
`
`
` YES
` NO
`
` Not Applicable
` FILE
` REFUSE TO FILE
`
` Review issues for 74-day letter
`
`
`REGULATORY PROJECT MANAGEMENT
`
`
`Signatory Authority: Bob Rappaport
`
`GRMP Timeline Milestones: Provided to team
`
`Comments:
`
`
`
`
`
`
`
`
`
`
`
`
`REGULATORY CONCLUSIONS/DEFICIENCIES
`
`The application is unsuitable for filing. Explain why:
`
`
`The application, on its face, appears to be suitable for filing.
`
`
` No review issues have been identified for the 74-day letter.
`
` 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 codes, as well as any other pertinent
`classification codes (e.g., orphan, OTC) are correctly entered into tracking system.
`
`If RTF action, notify everybody who already received a consult request, OSE PM., and
`Product Quality PM. 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.
`
`If BLA or priority review NDA, send 60-day letter.
`
` Send review issues/no review issues by day 74
`
`Other
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Version 6/9/08
`
`15
`
`

`

`
`
`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
`
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`

`
`
`
`
`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 supplement but is not necessary for approval,