CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`
`
`
`APPLICATION NUMBER:
`200678Orig1s000
`
`
`
`OTHER REVIEW(S)
`
`
`
`
`
`

`

`Date:
`To:
`
`Through:
`
`
`From:
`
`Department of Health and Human Services
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Surveillance and Epidemiology
`
`PATIENT LABELING REVIEW
`October 14, 2010
`Mary Parks, M.D., Director
`Division of Metabolism and Endocrinology Products
`(DMEP)
`LaShawn Griffiths, RN, MSHS-PH, BSN
`Acting Team Leader, Patient Labeling Reviewer
`Division of Risk Management (DRISK)
`
`Barbara Fuller, RN, MSN, CWOCN
`Patient Labeling Reviewer
`Division of Risk Management
`
`Latonia M. Ford, RN, BSN, MBA
`Patient Labeling Reviewer
`Division of Risk Management
`DRISK Review of Patient Labeling (Patient Package Insert)
`TRADENAME (saxagliptin/metformin hydrochloride extended-
`release) Tablets
`
`NDA 200678
`
`Bristol-Myers Squibb (BMS) Company
`2010-2031
`
`Subject:
`Drug Name (established
`name):
`
`Application
`Type/Number:
`Applicant:
`OSE RCM #:
`
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`
`1
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`

`

`
`
` 1
`
`
`
`INTRODUCTION
`This review is written in response to a request by the Division of Metabolic and
`Endocrine Products (DMEP) for the Division of Risk Management (DRISK) to
`review the Applicant’s proposed Patient Package Insert (PPI) for TRADENAME
`(saxagliptin/metformin HCl extended-release) Tablets.
`Bristol-Myers Squibb (BMS) Company submitted a New Drug Application (NDA) for
`TRADENAME (saxagliptin/metformin HCl extended-release) tablets on December 29, 2009.
`TRADENAME (saxagliptin/metformin HCl extended-release) tablets is indicated as an
`adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes
`mellitus when treatment with both saxagliptin and metformin is appropriate.
`DRISK conferred with DMEPA and a separate DMEPA review of the PPI has been
`submitted and placed in DARRTS dated July 2, 2010.
`2 MATERIAL REVIEWED
`• Draft TRADENAME (saxagliptin/metformin HCL extended-release) Tablets
`Patient Package Insert (PPI) received on December 29, 2009, revised by the
`Review Division throughout the current review and sent by the Review Division
`to DRISK on September 29, 2010.
`• Draft TRADENAME (saxagliptin/metformin HCL extended-release) Tablets
`Prescribing Information (PI) received on December 29, 2009, revised by the
`Review Division throughout the current review and sent by the Review Division
`to DRISK on September 29, 2010.
`• Approved Janumet (sitagliptin/metformin HCl) Tablets comparator labeling
`dated, September 24, 2010
`• Approved Onglyza (saxagliptin) Tablets comparator labeling dated, July 31, 2009
`3 REVIEW METHODS
`To enhance patient comprehension, materials should be written at a 6th to 8th grade
`reading level, and have a reading ease score of at least 60%. A reading ease score of
`60% corresponds to an 8th grade reading level. In our review of the PPI the target
`reading level is at or below an 8th grade level.
`
`
`
`Additionally, in 2008 the American Society of Consultant Pharmacists Foundation
`(ASCP) in collaboration with the American Foundation for the Blind (AFB)
`published Guidelines for Prescription Labeling and Consumer Medication
`Information for People with Vision Loss. The ASCP and AFB recommended using
`fonts such as Verdana, Arial or APHont to make medical information more
`accessible for patients with vision loss. We have reformatted the PPI document
`using the Verdana font, size 11.
`In our review of the PPI we have:
`•
`simplified wording and clarified concepts where possible
`
`
`
`
`
`2
`
`

`

`•
`•
`•
`
`removed unnecessary or redundant information
`ensured that the PPI is consistent with the PI
`ensured that the PPI meets the criteria as specified in FDA’s Guidance for
`Useful Written Consumer Medication Information (published July 2006)
`
`
`4 CONCLUSIONS
`The PPI is acceptable with our recommended changes.
`5 RECOMMENDATIONS
`• Please send these comments to the Applicant and copy DRISK on the
`correspondence.
`• Our annotated versions of the PPI are appended to this memo. Consult DRISK
`regarding any additional revisions made to the PI to determine if corresponding
`revisions need to be made to the PPI
` Please let us know if you have any questions.
`
`
`
`
`
`3
`
`16 Page(s) of Draft Labeling have been
`Withheld inFull as b4 (CCI/TS)
`immediately following this page
`
`

`

`---------------------------------------------------------------------------------------------------------
`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
`10/15/2010
`Saxagliptin and metformin DRISK Final PPI
`
`LASHAWN M GRIFFITHS
`10/15/2010
`
`Reference ID: 2850469
`
`

`

`M E M O R A N D U M
`
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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`PUBLIC HEALTH SERVICE
`-
`FOOD AND DRUG ADMINISTRATION
`
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`
`
`.CENTER FOR DRUG EVALUATION AND RESEARCH
`
`DATE:
`
`TO:
`
`FROM:
`
`
`
`October 7, 2010
`
`
`
`Mary H. Parks, M.D.
`Director
`
`
`
`
`
`
`
`Division of Metabolic and Endocrine Products
`
`
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`
`
`Gopa Biswas, Ph.D.
`
`
`Arindam Dasgupta, Ph.D.
`
`
`
`
`Division of Scientific Investigations (HFD—48)
`
`THROUGH:
`
`
`
`
`
`
`
`‘ 530%; K,
`Martin K. Yau, Ph.D.
`‘34“ (0/9/(0
`
`
`
`
`Acting Team Leader — Bioequivalence Branch
`
`
`
`
`Division of Scientific Investigations
`
`SUBJECT:
`
`
`
`
`
`
`
`
`
`(”W
`Review of EIRs covering NDA 200678,
`
`
`
`(Saxagliptin—Metformin HCl extended—release fixed-dose
`
`
`
`
`
`
`
`combination) Tablets 5/500 mg, 5/1000 mg, 2.5/1000 mg,
`
`sponsored by Bristol—Myers Squibb Company.
`
`
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`
`At
`the request of the Division of Metabolic and Endocrine
`Products (DMEP),
`
`
`
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`
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`the Division of Scientific Investigations (DSI)
`
`
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`
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`conducted an audit of the clinical and analytical portions of
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`
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`the following bioequivalence studies:
`
`
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`VStudy Number: CV181112
`
`
`Study Title:
`
`
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`"Bioequivalence Study of the Fixed—Dose Combination of
`
`
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`
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`5—mg Saxagliptin/lOOO—mg Metformin XR (Manufactured in
`
`
`
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`Mt Vernon,
`IN) Relative to 5 mg of Onglyza and 2 X
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`
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`500—mg Glucophage XR Co—administered to Healthy
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`gSfibjects in the Fed State and Steady State
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`
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`Pharmacokinetic Assessment of the Fixed—Dose
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`Combination of 5—mg Saxagliptin/lOOO—mg Metformin XR"
`
`
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`The clinical portion of the study was conducted at PPD, Inc.,
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`
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`
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`Austin, TX.
`The analytical portions were conducted at
`mm
`
`
`
`Following the
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`
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`
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`inspections at the clinical site (July 26—29, 2010) and the
`(b) (4)
`
`
`
`analytical site at
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`
`
`M“KSaxagliptin—Metformin HCl
`Page 2 — NDA 200678,
`
`
`
`
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`extended—release fixed—dose combination) Tablets 5/500 mg,
`
`
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`5/1000 mg, 2.5/1000 mg
`
`
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`
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`
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`there were no significant findings and no Form FDA-483 was
`issued.
`
`
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`
`
`(mm, a
`Following the inspection at
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`
`
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`
`Firm’s response dated
`Form FDA—483 was issued (Attachment 1).
`
`
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`July 13, 2010 was received by DSI
`(Attachment 2). Our
`
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`
`
`evaluation of the 483 observations and the firm's response
`follows:
`
`
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`1.Analyte interference was not evaluated for EMS—477118, its
`
`
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`metabolite EMS-510849 and metformin.
`The subject samples
`
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`contained all three analytes at the time of analysis.
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`(”W acknowledged the
`In their written response,
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`
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`observation.
`They provided additional data to show that there
`
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`was no interference by metformin in the detection of EMS—477118
`
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`(Saxagliptin) and its metabolite EMS—510849.
`The data is found
`
`
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`to be adequate and acceptable.
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`2. Failure to validate sample stability at room temperature
`
`
`
`during method validation for:
`(mm
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`7
`(”W at room
`(”W subject samples were stored in
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`temperature before injection for more than 6 h for runs 1, 2
`
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`(subjects 101-103, 104—106 & 128-130), 11h for run 12
`& 10,
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`(Per 3-subjects 115, 117, 123, 126, & 128—129) and 14 h for
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`runs 3 & 11 (subjects 107—109 & Per 3—subjects 101, 103,
`
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`105, 108-109, 111, & 114).
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`In response to the observation,
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`data to demonstrate
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`stability at room temperature for 31 hours.
`
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`adequate and acceptable.
`
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`(”W provided additional
`
`(”W storage
`
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`The results are
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`3. Freeze thaw stability was not demonstrated in that one
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`aliquot each of low, high and dilution QC was subjected to
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`six F/T cycles and then divided into 6 aliquots before
`analysis.
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`(”W acknowledged this observation and provided
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`additional data for freeze thaw (F/T) stability using 6 aliquots
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`of low, high and dilution QC.
`The results demonstrate F/T
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
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`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`
`
`@MKSaxagliptin—Metformin HCl
`Page 3 — NDA 200678,
`
`
`
`
`
`extended—release fixed—dose combination) Tablets 5/500 mg,
`
`
`
`5/1000 mg, 2.5/1000 mg
`
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`stability for 6 cycles and are found acceptable upon review.
`The firm has also revised the SOP to include minimum of 3
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`aliquots for each concentration for validation of F/T stability.
`
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`4. Failure to apply appropriate acceptance criteria for
`
`
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`
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`Incurred Sample Reproducibility (ISR) for metabolite BMS
`
`
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`
`
`510849.
`A W“)acceptance criteria was applied instead of
`20% for BMS4510849.
`
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`The firm has revised the SOP for ISR and changed the acceptance
`criteria from (WWto 20% for metabolites. However, 99.99% of
`
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`the samples exhibited differences <20% between the original and
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`re—assayed data indicating that the assay was robust for EMS—
`
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`Thus,
`the above observation is not likely to have
`510849.
`
`
`
`significant impact on study outcome.
`
`Conclusion:
`
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`
`
`the Division of Scientific
`Following the above inspections,
`
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`
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`__nvestigations recommends that the cl:_nical and analytical
`
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`portions of the Study CVlBlllZ be accepted for Agency review.
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`After you have reviewed this transmittal memo, please append it
`
`
`
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`to the original NDA submission.
`
`
`
`
`
`WW
`
`
`
`
`Arindam Dasgupta, Ph.Dt
`
`
`
`
`
`
`Gopa Biswas, Ph.D.
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

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`(b) (4)
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`(b) (4)
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`(b) (4)
`
`8 Page(s) have been Withheld in Full as
`b4 (CCI/TS) immediately following this
`page
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`GOPA BISWAS
`10/08/2010
`
`Reference ID: 2847936
`
`

`

`
`
`
`
`DIVISION OF METABOLISM AND ENDOCRINOLOGY PRODUCTS
`SAFETY TEAM
`MEMO TO THE FILE
`
`
` (saxagliptin/metformin HCl extended-release) tablets
`
`
`NDA#/Submission #/Submission type: 200678/000/N
`
`Product Name:
`
`Application submission date: 29 December 2009
`
`Safety team reviewer: Amy G. Egan, M.D., M.P.H.
`
`Safety review completion date: 4 October 2010
`
`Action goal date: 29 October 2010
`
`Reason for Review: New PPI
`
`Items Reviewed: PI/PPI/Clinical review
`
`Synopsis of Findings:
` is a fixed-dose combination of saxagliptin, a DPP-
`4 inhibitor, and extended-release metformin, a biguanide. There are 3 proposed dosage
`strengths, 5mg/500mg, 5mg/1000mg, and 2.5mg/1000mg. Saxagliptin was approved
`July 31, 2009 with a PPI; metformin HCl extended-release was approved October 13,
`2000 without a PPI or a Medication Guide; however, Medication Guides are approved
`with other metformin-containing combination products including Janumet
`(sitagliptin/metformin HCl), ActoplusMet (pioglitazone/metformin HCl), ActoplusMet
`XR (pioglitazone/metformin HCl XR), and Avandamet (rosiglitazone/metformin HCl).
`Metaglip (glipizide and metformin HCl) and Glucovance (glyburide and metformin HCl)
`have PPIs.
`
`According to the medical review, no new safety issues were identified with co-
`administration of saxagliptin and metformin XR. The known safety issues with
`saxagliptin include: hypersensitivity, and lymphopenia; dosage adjustment is required
`for moderate or severe renal impairment. The known safety issues with metformin XR
`include: lactic acidosis due to metformin accumulation, especially in the setting of
`compromised renal function, and a decrease in Vitamin B12 levels.
`
`Unlike sitagliptin, saxagliptin remains unlabeled with respect to the occurrence of
`pancreatitis. At the time of approval, there were 6 (0.2%) cases of pancreatitis in patients
`treated with saxagliptin versus 2 (0.2%) cases in patients treated with comparator. An
`OSE review of AERS was conducted in May 2010 that revealed two reports of acute
`pancreatitis associated with saxagliptin use. In the last PSUR (dated January 31, 2010 to
`April 30, 2010), there were 7 cases of pancreatitis reported. The sponsor has been asked
`to provide a summary/analysis of all postmarketing pancreatitis cases along with drug
`
`(b) (4)
`
`(b) (4)
`
`

`

`utilization data, and to provide a cumulative summary of the data on pancreatitis in future
`PSURs. Additionally, saxagliptin will undergo a 915 review beginning 31 January 2011
`at which time a more comprehensive approach to this safety issue will be undertaken to
`determine if the saxagliptin label should be revised to include language regarding acute
`pancreatitis and whether a Medication Guide-only REMS should be required.
`
`At this time, I do not recommend that the PPI be converted to a Medication Guide or that
`a REMS be required.
`
`
`Determination:
`
`REMS triggered: Y N I
`
`
`If yes (Y) or indeterminate (I), was submission referred to the SRT?: Y N
`
`Date submitted:
`
`Date response received:
`
`SRT response:
`
`If no (N), why not?:
`
`
`If no (N), please check one (or more) of the following reasons below:
`
`
`
`
`
`
`__X__No significant safety issue identified
`
`_____Only editorial changes made
`
`_____Changes pertain only to proper use of a device
`
`_____Other:
`
`
`
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`AMY G EGAN
`10/07/2010
`
`Reference ID: 2846759
`
`

`

`NDA/BLA REGULATORY FILING REVIEW
`(Including Memo of Filing Meeting)
`
`Application Information
`NDA Supplement #:S- N/A
`Efficacy Supplement Type SE- N/A
`BLA STN # N/A
` (rejected),
`
` (rejected),
`
` (under
`
`Action Goal Date (if different):
`October 29, 2010
`
`
`
`
` 505(b)(1)
` 505(b)(2)
` 505(b)(1)
` 505(b)(2)
`
` Standard
` Priority
`
`
`
`
` Tropical disease Priority
`review voucher submitted
`
`NDA # 200678
`BLA# N/A
`Proprietary Name:
`review)
`Established/Proper Name: Saxagliptin-Metformin HCl extended release
`Dosage Form: Tablets
`Strengths: 5/500 mg, 5/1000 mg, 2.5/1000 mg
`Applicant: Bristol-Myers Squibb
`Agent for Applicant (if applicable): N/A
`Date of Application: December 29, 2009
`Date of Receipt: December 29, 2009
`Date clock started after UN: N/A
`PDUFA Goal Date:
`October 29, 2010
`Filing Date: February 27, 2010
`Date of Filing Meeting: February 16, 2010
`Chemical Classification: (1,2,3 etc.) (original NDAs only): 4
`Proposed Indication(s): Treatment of Type 2 Diabetes Mellitus
`
`Type of Original NDA:
`AND (if applicable)
`Type of NDA Supplement: N/A
`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?
`
`N/A
`
`
`
`
`
`
`
` Fast Track
` Rolling Review
` Orphan Designation
`
` Rx-to-OTC switch, Full
` Rx-to-OTC switch, Partial
` Direct-to-OTC
`
`
`Other: N/A
`
` N/A
` N/A
` 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
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`Collaborative Review Division (if OTC product): N/A
`List referenced IND Number(s): IND 063634 and IND 076500
`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: N/A
`
`If yes, has OC/DMPQ been notified of the submission?
`
`Comments: N/A
`
`
`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: None
`
`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
`
`
`
`
`
`
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`
`

`

`
`
`
`If yes, consult the Director, Division of Regulatory Policy II,
`Office of Regulatory Policy (HFD-007)
`
`Comments: N/A
`
`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: N/A
`
`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.
`
`
` YES
`# years requested: N/A
` NO
`
` Not applicable
`
` YES
` NO
`
`
`
`
`
`
`505(b)(2) (NDAs/NDA Efficacy Supplements only)
` Not applicable
`
`
`
`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)).
`
`
`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).
`
`
`
`
`
`
`
` YES
` NO
`
` YES
` NO
`
` YES
` NO
`
`
`
`
`
`
`
`
`
`
`
`
`
`
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`
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`

`
`
`
`4.
`
`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
`
` YES
` NO
`
`
`
`
`
`If yes, please list below: N/A
`
`Exclusivity Expiration
`Exclusivity Code
`Application No.
`Drug Name
`
`
`
`
`
`
`
`
`
`
`
`
`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: N/A
`
`
`
` 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: N/A
`
`If electronic submission, does it follow the eCTD guidance?
`(http://www.fda.gov/cder/guidance/7087rev.pdf)
`
`If not, explain (e.g., waiver granted): N/A
`
`
`N/A
`
`
`
`
`
`
`
`
` YES
` NO
`
` YES
` NO
`
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`
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`
`

`

`
`
`
`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)
`
` YES
` NO
`
` YES
` NO
`
` YES
` NO
`
` YES
` NO
`
`
`
`
`
`
`
` Not Applicable
`
` 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:
`
`
` YES
` NO
`
`
`N/A
`
`
` YES
` NO
`
`Debarment Certification
`Correctly worded Debarment Certification with authorized
`signature?
`
`If foreign applicant, both the applicant and the U.S. Agent must
`
` YES
` NO
`
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`
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`
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`

`
`
`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:
`
`
` 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?
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Not Applicable
` YES
` NO
`
` YES
` NO
`
` YES
` NO
`
`If no, request in 74-day letter.
`
`
`
`•
`•
`
`If yes, 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)
`
`
`Comments:
`
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`
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`
`

`

`
`
`
`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:
`
`N/A
`
`
` 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)
` YES
` NO
`
`
`Check all types of labeling submitted.
`
`
`
`
`
`Comments:
`
`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:
`REMS consulted to OSE/DRISK?
`
`Comments:
`Carton and immediate container labels, PI, PPI, and
`proprietary name (if any) sent to OSE/DMEDP?
`
`Comments:
`
` YES
` NO
`
` YES
` NO
`
`
`
`
`
`
` YES
` NO
`
` Not Applicable
` YES
` NO
`
` Not Applicable
` YES
` NO
` Not Applicable
` YES
` NO
`
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`
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`
`

`

`
`
`
`
`
`Check all types of labeling submitted.
`
`
`
`
`
`Comments: N/A
`
`
`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
`
` YES
` NO
`
` YES
` NO
`
` YES
` NO
`
`Is electronic content of labeling submitted?
`
`If no, request in 74-day letter.
`
`Comments: N/A
`Are annotated specifications submitted for all stock keeping
`units (SKUs)?
`
`If no, request in 74-day letter.
`
`Comments: N/A
`If representative labeling is submitted, are all represented
`SKUs defined?
`
`If no, request in 74-day letter.
`
`Comments: N/A
`
`Proprietary name, all labeling/packaging, and current
`approved Rx PI (if switch) sent to OSE/DMEDP?
`
`Comments: N/A
`
`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:
`
`Any Special Protocol Assessment (SPA) agreements?
`If yes, distribute letter and/or relevant minutes before filing
`meeting.
`
`Comments:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` YES
`Date(s): OCTOBER 15, 2009
` NO
`
` YES
`Date(s):
` NO
`
`Version 6/9/08
`
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`

`
`
`ATTACHMENT
`MEMO OF FILING MEETING
`
`Discipline/Organization
`
`Names
`
`
`
`DATE: FEBRUARY 16, 2010
`
`NDA/BLA #: 200678
`
`
`PROPRIETARY/ESTABLISHED NAMES: Saxagliptin-Metformin HCl extended-release
`fixed-dose combination
`
`APPLICANT: Bristol-Myers Squibb
`
`BACKGROUND: Saxagliptin (Trade name: Onglyza) is an inhibitor of dipeptidyl peptidase-4 (DPP-4)
`and was approved by the FDA as an anti-diabetic drug on July 31, 2009, under NDA 022350. Metformin
`XR (Trade name: Glucophage XR) is an anti-diabetic drug of the biguanide class and was approved by the
`FDA on October 13, 2000, under NDA 021202. Both drug products are marketed by BMS.
`
`
`REVIEW TEAM:
`
`
`Present at
`filing
`meeting?
`(Y or N)
`Y
`Y
`Y
`
`Regulatory Project Management
`
`
`Cross-Discipline Team Leader (CDTL)
`
`Clinical
`
`
`Social Scientist Review (for OTC
`products)
`
`
`Labeling Review (for OTC products)
`
`
`OSE
`
`
`Clinical Microbiology (for antimicrobial
`products)
`
`
`Mehreen Hai
`RPM:
`CPMS/TL: Lina AlJuburi
`Hylton Joffe
`
`Reviewer:
`
`TL:
`
`Reviewer:
`
`TL:
`
`Reviewer:
`
`TL:
`
`Reviewer:
`
`TL:
`
`Reviewer:
`
`TL:
`
`
`Arlet Nedeltcheva-Peneva Y
`
`Hylton Joffe
`
`None needed
`
`None needed
`
`None needed
`
`None needed
`
`None needed
`
`None needed
`
`None needed
`
`None needed
`
`Y
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Version 6/9/08
`
`9
`
`

`

`Reviewer:
`
`
`Weili Huang,
`changed to Ritesh Jain on
`07-21-10
`Sally Choe
`
`Wei Liu
`
`Todd Sahlroot
`
`Lauren Murphree Mihalcik Y
`
`Y
`
`Y
`
`Y
`
`Y
`
`Y
`
`
`
`
`
`Y
`
`Y
`
`
`
`
`
`Y
`
`N
`
`
`
`
`
`Y
`
`
`
`
`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)
`
`
`Other reviewers
`
`
`OTHER ATTENDEES:
`
`
`
`
`505(b)(2) filing issues?
`
`If yes, list issues:
`
`Per reviewers, are all parts in English or English
`translation?
`
`If no, explain:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`TL:
`
`Reviewer:
`
`TL:
`
`Reviewer:
`
`TL:
`
`Reviewer:
`
`TL:
`
`Reviewer:
`
`TL:
`
`Reviewer:
`
`TL:
`
`Reviewer:
`
`TL:
`
`Reviewer:
`
`TL:
`
` Houda Mahayni (Biopharm)
`
`Todd Bourcier
`
`None needed
`
`None needed
`
`Elsbeth Chikhale
`
`Suong Tran
`
`None needed
`
`None needed
`
`Jessica Cole
`
`James McVey
`
`Susan Leibenhaut
`
`
`
` Not Applicable
` YES
` NO
`
` YES
` NO
`
`
`
`Version 6/9/08
`
`10
`
`

`

`
`
`
`Electronic Submission comments
`
`List comments:
`
`CLINICAL
`
`
`
`Comments:
`
`• Clinical study site(s) inspections(s) needed?
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`If no, explain: Clinical studies were previously
`reviewed for Onglyza NDA 022350
`
` Not Applicable
`
` Not Applicable
` FILE
` REFUSE TO FILE
`
` Review issues for 74-day le