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`CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`APPLICATION NUMBER:
`200678Orig1s000
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`STATISTICAL REVIEW(S)
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`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Pharmacoepidemiology and Statistical Science
`Office of Biostatistics
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`
`Statistical Review and Evaluation
`CLINICAL STUDIES
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`NDA/Serial Number:
`Drug Name:
`Indication(s):
`Applicant:
`Date(s):
`Review Priority:
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`
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`Biometrics Division:
`Statistical Reviewer:
`Concurring Reviewers:
`
`Medical Division:
`Clinical Team:
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`200678/0000
`
`Treatment of Subjects with Type 2 diabetes
`Bristol-Myers Squibb Company
`Received 12/29/2009
`Standard (10-month)
`
`Division of Biometrics 2 (HFD-715)
`Wei Liu, Ph.D.
`J. Todd Sahlroot, Ph.D. (Deputy Director)
`
`Metabolism and Endocrinological Products (HFD-510, DMEP)
`Arlet Nedeltcheva-Peneva, M.D.
`Hylton Joffe, M.D. (Team Leader)
`Mary Parks, M.D. (Division Director)
`Raymond Chiang
`
`
`Project Manager:
`
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`Keywords: NDA review, combination drug, active control/superiority, clinical studies
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`(b) (4)
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`BACKGROUND
`1.
`The coadministration of saxagliptin and metformin has been studied in patients with type 2
`diabetes inadequately controlled on metformin alone and in treatment-naive patients
`inadequately controlled on diet and exercise alone. The applicant has submitted the results of 5
`core Phase 1 studies in normal volunteers and 3 clinical phase 3 studies (CV181039, CV181014,
`and CV181066) in patients with type 2 diabetes also taking metformin. Data from the Onglyza
`NDA (22-350), approved by FDA on July 31, 2009, contribute largely to the clinical safety and
`efficacy data supporting this application. The phase 3 studies CV181039 and CV181014 were
`submitted as part of NDA 22-350 and were reviewed by Joy Mele, M.S., statistician in the
`Division of Biometrics 2. Study CV181066 was a 4-week, multicenter, randomized, double-
`Blind, placebo-controlled phase 3 trial to evaluate the efficacy and safety of saxagliptin in
`comparison to placebo as add-on treatment to metformin XR in subjects (N=93) with Type 2
`diabetes who have inadequate glycemic control with diet and exercise and a stable dose of
`metformin XR ≥ 1500 mg/day. Based on the short 4-week treatment period and small number of
`patients involved, we view this study as a supportive study only. The sponsor is not proposing
`labeling for this study.
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`SUMMARY AND CONCLUSION
`2.
`The efficacy of the coadministration of saxagliptin and metformin in this NDA submission is
`based on studies CV181039 (n=1306) and CV181014 (n=743) which were reviewed in NDA 22-
`350. In the proposed labeling of this submission, the sponsor is relying on the approval of
`Onglamet using the same clinical data. Material in the clinical studies section of label is identical
`to the relevant sections of the Onglamet label. Because there is no new relevant clinical efficacy
`data and the proposed label relies entirely on the previously submitted data, there is no
`compelling need for a statistical review of this NDA.
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`
`2
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`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`WEI LIU
`10/01/2010
`
`JON T SAHLROOT
`10/01/2010
`concur
`
`Reference ID: 2843973
`
`

`

`STATISTICS FILING CHECKLIST FOR A NEW NDA/BLA
`
`Applicant: Bristol-Myers Squibb
`NDA/BLA Type: New NDA
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`Stamp Date: 12/29/2009
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`
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`NDA Number: 200678
`Drug Name: Saxagliptin
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`On initial overview of the NDA/BLA application for RTF:
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`1
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`2
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`Content Parameter
`Index is sufficient to locate necessary reports, tables, data,
`etc.
`ISS, ISE, and complete study reports are available
`(including original protocols, subsequent amendments, etc.)
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`3
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`Safety and efficacy were investigated for gender, racial,
`and geriatric subgroups investigated (if applicable).
`4 Data sets in EDR are accessible and do they conform to
`applicable guidances (e.g., existence of define.pdf file for
`data sets).
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`Yes No NA
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`✓
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`Comments
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`✓
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`✓
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`✓
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`No ISS and
`ISE, but
`CV181038 and
`CV181066,
`respectively
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`Yes No
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`NA Comment
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`IS THE STATISTICAL SECTION OF THE APPLICATION FILEABLE? ___Yes_____
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`If the NDA/BLA is not fileable from the statistical perspective, state the reasons and provide
`comments to be sent to the Applicant.
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`Please identify and list any potential review issues to be forwarded to the Applicant for the 74-
`day letter.
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`Content Parameter (possible review concerns for 74-
`day letter)
`Designs utilized are appropriate for the indications requested.
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`✓
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`Endpoints and methods of analysis are specified in the
`protocols/statistical analysis plans.
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`Interim analyses (if present) were pre-specified in the protocol
`and appropriate adjustments in significance level made.
`DSMB meeting minutes and data are available.
`Appropriate references for novel statistical methodology (if
`present) are included.
`Safety data organized to permit analyses across clinical trials
`in the NDA/BLA.
`Investigation of effect of dropouts on statistical analyses as
`described by applicant appears adequate.
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`File name: 5_Statistics Filing Checklist for a New NDA_
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`✓
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`✓
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`✓
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`✓
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`✓
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`ANCOVA:
`treatment
`and baseline
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`Use the LOCF
`procedure
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`(b) (4)
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`STATISTICS FILING CHECKLIST FOR A NEW NDA/BLA
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`Wei Liu
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`Reviewing Statistician
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`Supervisor/Team Leader
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`02/17/2010
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` Date
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`Date
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`File name: 5_Statistics Filing Checklist for a New NDA_
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`
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`(b) (4)
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`Application
`Type/Number
`--------------------
`NDA-200678
`
`Submission
`Type/Number
`--------------------
`ORIG-1
`
`Submitter Name
`
`Product Name
`
`--------------------
`BRISTOL MYERS
`SQUIBB
`
`------------------------------------------
` (saxagliptin +
`metformin XR) Tablets
`
`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`WEI LIU
`02/17/2010
`
`JON T SAHLROOT
`02/17/2010
`
`(b) (4)
`
`