CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`« APPLICA TION NUMBER:
`
`22-350
`
`OTHER REVIEWg S)
`
`

`

`DIVISION OF METABOLISM AND ENDOCRINOLOGY PRODUCTS
`SAFETY TEAM
`MEMO TO THE FILE
`
`NBA/Submission #/Submission type: 22-350/000/NDA 1
`
`Product Name: ONGLYZA (saxagliptin)
`
`Application submission date: 30 June 2008
`
`Safety team reviewer: Amy G. Egan, M.D., M.P.H.
`
`Safety review completion date: 30 July 2009
`
`Action goal date: 30 July 2009
`
`Reason for Review: New PPI
`
`Items Reviewed: PI/PPI/CDTL memo
`
`Synopsis of Findings: Saxagliptin is a depeptidyl peptidase-4 inhibitor indicated as an
`adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes
`mellitus. Safety issues identified during the review cycle or based on experience with
`other drugs in the class include severe hypersensitivity reactions and severe cutaneous
`reactions; hepatotoxicity; pancreatitis; decreased lymphoCyte counts; and infections. In
`addition, a safety requirement for all new antidiabetic drugs, including saxagliptin, is to
`rule out an unacceptably increased risk of ischemic cardiovascular events. This is
`consistent with the December 2008 Guidance to Industry, entitled Diabetes Mellitus: _
`Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes.
`All of these safety concerns are being adequately addressed in 3 post-marketing required
`studies/trials — a cardiovascular safety trial and 2 epidemiological studies.
`
`The sponsor’s PPI provides basic information about saxagliptin in patient friendly
`language which has been reviewed and approved by DRISK. There are no significant
`safetyissues 1dent1fedin the P1 or PPI that would suggest that a Medication Guide would
`be more appropriate or that a REMS would be needed.
`
`Determination:
`REMS triggered: Y
`
`.
`
`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:
`
`

`

`Submission
`Linked Applications Type/Number
`
`Sponsor Name
`
`Drug Name / Subject
`
`NDA 22350
`
`ORIG 1
`
`BRISTOL MYERS
`SQUIBB CO
`
`SAXAGLlPTlN
`
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`
`AMY G EGAN
`
`07/30/2009
`
`

`

`
`
`Karen A. Hicks, MD.
`Division of Cardiovascular and Renal Products, HFD-l 10
`
`Food and Drug Administration
`10903 New Hampshire Avenue,,Building 22, Room 4182
`Silver Spring, MD 20993—0002
`Tel: (301) 796-1089
`FAX: (301) 796-9841
`
`Memorandum
`
`FROM:
`
`THROUGH:
`
`‘
`Karen A. Hicks, M.D., Medical Officer
`Division of Cardiovascular and Renal Products
`
`Norman L. Stockbridge, M.D., Ph.D., Director
`Division of Cardiovascular and Renal Products
`
`TO:
`
`Julie Marchick and Rachel Hartford
`
`Project Managers
`Division ofMetabolism and Endocrinology Products (HFD-S 1 0)
`Food and Drug Administration
`Center for Drug Evaluation and Research
`5901-B Ammendale Road
`
`Beltsville, MD 20705-1266
`
`and
`
`Hylton Joffe, M.D.
`'
`Diabetes Team Leader
`Division of Metabolism and Endocrinology Products (HFD-SIO)
`
`SUBJECT:
`
`Draft CV Outcomes Study Design Concept Document D1680C0003 entitled “A
`Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase 4 Trial to Evaluate
`the Effect of Saxagliptin on the Incidence of Major Adverse Cardiovascular Events in
`Patients with Type 2 Diabetes,” dated April 17,2009 (BMS Document No. 930035959)
`(NDA 22,350 Saxagliptin)
`
`DATE RECEIVED:
`
`April 24, 2009
`
`DATE COMPLETED:
`
`July 15, 2009
`
`Materials Reviewed:
`
`1. Draft CV Outcomes Study Design Concept Document D1680C0003 entitled “A Multicenter, Randomized,
`Double-Blind, Placebo-Controlled Phase 4 Trial to Evaluate the Effect of Saxagliptin on the Incidence of Major
`Adverse Cardiovascular Events in Patients with Type 2 Diabetes,” dated April 17, 2009 (BMS Document No.
`930035959)
`
`Page 1 of 10
`
`

`

`I OVERALL RECOMMENDATIONS
`
`1.
`
`The sponsor has provided only a brief synopsis for the proposed postmarketing cardiovascular safety trial. We
`recommend that the sponsor submit the final protocol and statistical analysis plan, along with the Clinical Event
`Committee Charter, as soon as possible. The Division of Cardiovascular and Renal Products would be happy to
`review these materials upon receipt.
`’
`
`COMMENTS TO BE TRANSMITTED TO SPONSOR
`
`We have completed our review of your submission dated April 17, 2009, including your Drafi Outcomes Study
`Design Concept Document D1680C003 entitled, “A Multicenter, Randomized, Double-blind, Placebo-controlled
`Phase 4 Trial to Evaluate the Effect of Saxagliptin on the Incidence of Major Adverse Cardiovascular Events in
`Patients with Type 2 Diabetes” and have the following comments and recommendations:
`
`1.
`
`2.
`
`Please clarify the individual definitions for moderate and severe renal insufficiency.
`
`You propose the following regional allocation:
`0 United States (15-20%)
`.
`south America and Canada (40-45%)
`0
`Europe (15-20%)
`0 Asia/Australia (10-15%)
`
`Additionally, you state key subgroups of interest will be African-Americans, US patients of Hispanic ethnicity,
`and elderly/very elderly men and women.
`
`a. We recommend that the regional allocation for the United States is increased to approximately 30% or
`greater.
`
`b.
`
`c.
`
`Please clarify regional allocation for South America and Canada separately. .
`
`Please clarify regional allocation for Asia and Australia separately.
`
`Please incorporate in the final protocol the events of special interest that will also be followed in, this study such
`as pancreatitis, hepatic toxicity, fractures, hypersehsitivity, skin lesions, and lymphocyte. reduction.
`
`In the trial, you propose to include a restriction on the use of thiazolidinediones (TZDs) in the study design to
`avoid a possible imbalance in the occurrence of first CV events (MACE and heart failure) if a greater number of
`subjects in the placebo are initiated on TZDs, compared to the saxagliptin treatment group. Furthermore, after
`randomization, TZDs will be added for 'glycemic control only if necessary. (Internal Comment: Defer specific
`comment to DMEP)
`'
`
`Page 2 of 10
`
`

`

`5.
`
`Study Recommendations
`
`a.
`
`spaw-
`
`Prior to initiating the study, please submit the following information to the Review Division:
`1.
`Proposed protocol
`Definitions for all protocol endpoints and events of special interest
`Case Report Form
`Clinical Endpoints Committee (CEC) charter, including algorithms to be used for endpoint events such
`as determination of myocardial infarction
`Statistical Analysis Plan
`
`5.
`
`b.
`
`In general, the Division recommends that the following endpoints are adjudicated:
`
`0 Death
`
`0 All Cause Mortality
`' 0 Cardiovascular Death
`0 Non-Cardiovascular Death
`
`0 Acute Coronary Syndrome
`o Myocardial Infarction
`o Hospitalization for Unstable Angina
`
`o
`
`Cerebrovascular Events
`
`0 Cerebrovascular Event (Stroke)
`i.
`Ischemic (Non-hemorrhagic)
`ii. Hemorrhagic
`iii. Unknown
`Transient Ischemic Attack
`
`0
`
`0
`
`Coronary Revascularization Procedures
`0 Coronary Artery Bypass Graft Surgery
`0
`Percutaneous Coronary Intervention
`
`o Hospitalization for Heart Failure
`
`0
`
`Stent Thrombosis (clinical adjudication)
`.
`0 Data needed
`i. Name of device (Bare metal stent versus Drug eluting stent) as well as stent diameter and
`length
`ii. Coronary reference vessel diameter (RVD) and lesion length
`iii. Date of implantation
`iv. Date of stent thrombosis
`
`'
`
`~
`
`Indication for index PCI [ACS (indicate STEMI, non-STEMI, or UAP), non-ACS]
`.v.
`vi. Did patient have multivessel disease?
`vii. Did patient undergo multivessel (three-vessel disease) or left main treatment?
`viii. Left ventricular fimction
`
`ix. Overlapping stents
`x. Bifiircation lesion stenting
`xi. Bypass graft (arterial or venous conduit) stenting
`xii. Presence or absence of renal disease based on glomerular filtration rate as determined by
`the Cockcroft—Gault Equation
`-
`xiii. Was patient on dual antiplatelet therapy (yes/no), and if not, date of aspirin or P2Y12
`inhibitor discontinuation?
`‘
`
`Page 3 of 10
`
`

`

`Other endpoints of interest that do not require formal adjudication include
`
`Hospitalization for other CV causes
`0
`Pulmonary embolus
`o Ruptured Aortic Aneurysm
`
`Carotid Artery Revascularization (surgical versus percutaneous)
`
`Other Peripheral Vascular Revascularization (lower extremity, renal, mesenteric, iliac, subclavian, and
`aortic etc.) (surgical versus percutaneous)
`
`Lower Extremity Amputation
`
`Hospitalization for Cardiac Arrhythmia (specifically, atrial fibrillation, atrial flutter, ventricular
`tachycardia, ventricular fibrillation, torsade de pointes, second degree heart block type 2, third degree
`heart block, and symptomatic bradycardia requiring pacemaker placement)
`
`In your study, investigators should inquire about the interim occurrence of cardiovascular events at each
`study visit through the use of a boxed check-list, and these results should be noted in the study schedule.
`For patients hospitalized for cardiovascular events, all pertinent hospital records, electrocardiograms,
`imaging studies, and laboratory results should be obtained for the purpose of adjudication. If a patient dies
`during the study, autopsy reports should be requested. Endpoint Event Investigator Reporting forms and
`CEO Adjudication forms should also be comprised of boxed check-lists.
`
`Source documents needed for the following events include but are not limited to
`
`1. Death
`
`a. Autopsy (if performed)
`b. Code summary (if available)
`0. Death/discharge summary (if death occurred in-hospital)
`
`Myocardial Infarction/Hospitalization for Unstable Angina/Stem Thrombosis
`Admission History and Physical
`ECG tracings (at baseline'and time of event)
`Cardiac markers (troponin/CK—MB results with units and ULN)
`Other laboratory reports, if requested
`Procedure reports (Cardiac catheterization, PCI, CABG)
`Discharge Summary
`
`mop-9.02m
`
`Stroke or TIA
`
`a. Neurology Consult
`b.
`Imaging reports (MR1, CT, or other imaging report)
`c. Discharge Summary
`
`Coronary Revascularization Procedures
`a.
`Procedure reports (Cardiac catheterization, PCI, CABG)
`b. Discharge Summary
`
`Page 4 of 10
`
`

`

`5. Hospitalization for Heart Failure
`Admission History and Physical
`ECG tracings (at baseline and time of event)
`Cardiac markers (troponin/CK—MB resultswith units and ULN)
`Other laboratory reports (e.g., BNP)
`Chest X-Ray report
`Discharge Summary
`
`mappvs
`
`6. Acute Pancreatitis
`
`Imaging reports
`a.
`b. Discharge Summary
`
`. At the time of the submission of the ClinicalStudy Report, please include verbatim terms in the adverse
`events data set.
`
`All of the prospectively collected cardiovascular events should be reviewed by the Clinical Endpoints
`Committee (CBC), as discrepancies between investigator-reported and adjudicated events mayarise. With
`the clinical study report, the sponsor should submit data sets for both the investigator-reported and CBC
`adjudicated cardiovascular events. Additionally, the sponsor should submit the following 5 listings:
`
`All investigator—reported CV events
`,
`All CBC-adjudicated CV events
`All investigator—reported CV events that were also adjudicated by the CEO to be events
`All investigator-reported CV events that were not thought to be events by the CBC (“downgrades”)
`All CBC-adjudicated CV events that were not considered to be events by the investigator (“upgrades”)
`
`In addition to CEC adjudication of triggered events, we recommend searching-the following standardized
`MedDRA queries (SMQs) for other possible .cardiovascular events that may also require adjudication:
`
`1. Myocardial Infarction
`2
`Ischaemic Heart Disease
`
`Cardiac Arrhythmias
`3
`Cardiac Failure
`4
`5. Embolic and Thrombotic Events
`
`6.
`7
`8
`
`.
`Shock
`Torsade de pointes/QT prolongation
`Cerebrovascular Disorders
`
`,
`
`9. Central Nervous System Haemorrhages and Cerebrovascular Accidents
`10. Vasculitis
`
`The Division also recommends searching the following system organ classes (SOCs), high level terms
`(HLT), lower level terms (LLTs), and preferred terms (PTs) for cardiovascular events that may also require
`adjudication:
`4
`
`SOC: Cardiac Disorders
`SOC: General Disorders and Administration Site Conditions
`
`SOC: Injury, Poisoning, and Procedural Complications
`SOC: Investigations
`-
`SOC: Musculoskeletal and Connective Tissue Disorders
`
`SOC: Nervous System Disorders
`SOC: Respiratory, Thoracic, and Mediastinal Disorders
`SOC: Surgical and Medical Procedures
`
`?°.\'.°‘.U':“P’5‘-’:“
`
`Page 5 of 10
`
`

`

`10.
`11.
`12.
`13.
`14.
`15.
`16.
`17.
`18.
`19.
`20.
`21.
`22.
`23.
`
`SOC: Vascular Disorders
`LLT:
`
`Cerebral Revascularization Synangiosis (search value: revascularization)
`LLT: Coronary Revascularization (search value: revascularization)
`LLT:
`Peripheral Revascularization (search value: revascularization)
`LLT:
`Renal Revascularization (search value: reVascularization)
`LLT:
`Transmyocardial Revascularization (search value: revascularization).
`LLT:
`Acute myocardial ischemia (search value: myocardial ischemia)
`LLT:
`ECG signs of myocardial ischemia (search value: myocardial ischemia)
`LLT:
`Myocardial ischemia (search value: myocardial ischemia)
`LLT:
`Myocardial ischemia recurrent (search value: myocardialischemia)
`LLT:
`Silent myocardial ischemia (search value: myocardial ischemia)
`PT: Acute Myocardial Infarction (search value: myocardial infarction)
`PT: Myocardial Infarction (search value: myocardial infarction)
`PT: Post Procedural Myocardial Infarction (search value: myocardial infarction)
`PT: Silent Myocardial Infarction (search value: myocardial infarction)
`
`Page 6 of 10
`
`

`

`Mien:
`NDA 22,350 Saxagliptin (BMST477118)
`
`Background: Saxagliptin is a dipeptidyl dipeptidase-4 (DPP4) inhibitor developed for the treatment of type 2
`diabetes mellitus. The New Drug Application (NDA 22,350) was submitted to the Division of Metabolism and
`Endocrinology Products on June 30, 2008. On April 1, 2009, there was an Advisory Committee Meeting to discuss
`the safety and efficacy of saxagliptin. The Advisory Committee voted to approve saxagliptin but recommended that
`the sponsor conduct a post-marketing cardiovascular outcomes trial. The sponsor submits this draft design concept
`paper for the CV outcomes trial and expects to finalize the protocolin September 2009.
`
`Protocol Number: D168OCOOO3
`
`Sponsor: Bristol-Myers Squibb Company
`
`Investigators: Pending
`
`Site(s) of Investigation: Pending. Regional allocation is expected to be 15-20% from US, 40—45% fiom South
`America and Canada, 15-20% from Europe, and 10-15% from Asia/Australia. Key subgroups of interest will include
`African-Americans, US patients of Hispanic ethnicity, and elderly/very elderly men and women.
`1
`
`_
`Reviewer Comments:
`I. We recommend that US enrollment in this trial is increased to approximately 30%
`2. The sponsor should clarify the percentage ofpatients expected to be enrolledfrom Canada separately from
`South America and should also clarify the percentage of patients expected to be enrolled from Asia
`separatelyfrom Australia.
`
`IRB Approval: Pending
`
`Title: “A Multicenter, Randomized, Double-Blind, Placebo—Controlled Phase 4 Trial to Evaluate the Effect of
`Saxagliptin on the Incidence of Major Adverse Cardiovascular Events in Patients with Type 2 Diabetes,” dated April
`17, 2009 (EMS Document No. 930035959)
`
`Indication: Treatment of type 2 diabetes mellitus (T2DM)
`
`Study Design: This is a multicenter, randomized, double-blind, placebo controlled Phase 4 study to evaluate the
`effect of saxagliptin on the incidence of major adverse cardiovascular events.
`
`Hypothesis:
`Saxagliptin reduces the risk of experiencing a cardiovascular (CV) event in subjects with type 2 diabetes mellitus
`and additional CV risk factors.
`
`The study plans to address two questions:
`1. Do the results of the study exclude an unacceptable risk of MACE for saxagliptin, based on the criteria
`established by the December 2008 FDA Guidance?
`
`2.
`
`Is treatment with saxagliptin (added to usual care) associated with a reduction in the risk of MACE compared to
`usual care only.
`'
`
`Page 7 of 10
`
`

`

`Objectives:
`.
`Primary: The primary objective is to assess the time to first event for the Composite endpoint of major adverse CV
`events (MACE, including CV death, non-fatal myocardial infarction, and non-fatal stroke) during treatment with
`saxagliptin. compared with placebo when added to current care, in patients with TZDM.
`
`MACE is to be adjudicated by and independent Clinical Endpoints Committee (CBC), using prospectively defined
`criteria without knowledge of treatment group assignment.
`
`Safety: The safety objective is to evaluate-the safety and tolerability of saxagliptin by assessment of overall adverse
`events, adverse events of special interest, laboratory tests including renal function, blood pressure, and body weight.
`
`ENDPOINTS:
`
`Primary: The primary endpoint is major adverse cardiovascular events (MACE), defined as CV death, non—fatal
`myocardial infarction (MI), and non—fatal stroke)
`
`.
`
`Reviewer Comment: The primary endpoint should be MACE defined as CV death, non-fatal MI, fl: non-fatal
`stroke.
`
`Number of Patients: Approximately 10,100 randomized patients (631 primary endpoint events). During the course
`of the" trial, the Sample size may be increased to achieve 631 primary endpoint events if the rate of CV events is
`lower than anticipated.
`-
`
`Duration of Study: This is an event-driven trial. The sponsor estimates that the total duration of the trial will be 5
`years. The trial duration may be increased to achieve 631 primary endpoint events if the rate of CV events is lower
`than anticipated.
`-
`'
`'
`
`Timelines:
`
`Finalized Protocol: September 2009
`
`First patient first visit: 2Q2010
`
`Last patient last visit: 2Q2015
`
`Clinical Study Report: 4Q2015
`
`Inclusion Criteria (Must be present) (Reproduced from Sponsor, pages 9-10)
`1. Written, informed consent
`,
`Diagnosed with TZDM based'on the current American Diabetes Association (ADA) guidelines
`A1C 2 6.5% (based on a documented laboratory measurement in the previous 3 months)
`High risk for a CV event defined as at least one of the following
`
`PENN
`
`a. Clinically evident CV disease defined by prior history of ischemic heart disease (e.g., unstable angina,
`stable angina, MI, need for revasculan'zation), and/or peripheral vascular disease (e.g., intermittent
`claudication), and/or stroke; and/or
`
`b. Multiple risk factors (treated or non treated) for CV disease in addition to TZDM
`
`Exclusion Criteria (Cannot be present) (Reproduced from Sponsor, page 10)
`1.
`Pregnant or breast-feeding patients
`'
`2. Contraindication to therapy as outlined in the saxagliptin product information
`3.
`Involvement in the planning and conduct of the study (applies to both AstraZeneca and Bristol-Myers Squibb
`staff or staff at the study site)
`'
`
`Page 8 of 10
`
`

`

`4.
`5"
`
`_
`Previous randomization in the present study
`-
`Participation'ina clinical study within 60 days of Visit 1
`6. Any conditions that, in the opinion of the investigator, may render the subject unable to complete the study
`including non-CV disease with likely fatal outcome within 5 years
`.
`Individuals at risk for poor protocol or medication compliance
`7.
`8. Current or previous (within 6 months) treatment with an incretin based therapy such as DPP4 inhibitors and or
`glucagon-like peptide (GLP)-l mimetics
`9. Acute vascular (cardiac or stroke) event < 2 months prior to randomization
`
`Dosage/Administration: Subjects will undergo a screening evaluation following an 8~hour fast. Subjects who
`cannot complete all screening procedures may return within 7 days to complete them. Eligible subjects will be
`randomized in a 1:1 ratio to receive either saxagliptin 5 mg (or 2.5 mg for patients with moderate or severe renal
`insufficiency) or placebo for a double-blind treatment period of 48 months. Those subjects who develop moderate to
`severe renal-impairment during the course of the trial will have the dose of study drug blindly adjusted to either
`saxagliptin 2.5 mg or matching placebo, depending on their originally assigned treatment group.
`
`'
`
`For patients with moderate or severe renal impairment, or end-stage renal disease (creatinine clearance [CrCl] S 50
`mL/min, approximately corresponding to serum creatinine levels of 2 1.7 mg/dL in men and 2 1.5 mg/dL in women),
`the dose of saxagliptin should be adjusted from 5 mg to 2.5 mg.
`-
`
`During the randomized treatment period, patients will be encouraged to follow diet and life-style modifications, and ‘
`treatment guidelines with respect to glycemic monitoring and control as well as the use of concomitant medications
`to minimize cardiovascular risk, such as antihypertensive agents, low dose aspirin, and lipid lowering agents are to
`be followed.
`
`Patients will return for office visits every 6 months for evaluation of the primary endpoint, assessment of treatment
`compliance, and study drug distribution.
`'
`
`Telephone follow-up will be conducted at 3—month intervals between office visits.
`
`Every 12 months, subjects will undergo a physical examination and laboratory testing.
`
`The study design is displayed in Figure 1. Since this is an event—driven trial, the 5 year trial duration may be
`modified if the rate of CV events is lower than expected.
`
`Figure 1. Study Design (D1680C0003)
`
`Onglyza (5 mg)
`
`
`
`(Sponsor, Figure 2.1, page 5)
`
`Page 9 oflO
`
`5 yr total duration (CV event driven)
`
`

`

`Background and rescue treatments to be used in this study will include metformin, sulfonylureas, and both short and
`long-acting insulins. After randomization, thiazolidinediones (TZDs) may be added for glycemic control only if
`thought to be necessary. The sponsor plans to include a restriction on the use of TZDs1n the study design to avoid a
`possible imbalancein the occurrence of first CV events (MACE and heart failure) if a greater number of subjectsin
`the placebo arm are initiated on TZDs, compared to the saxagliptin treatment group.
`
`Subjects may not be initiated on DPP4 inhibitors or GLPl mirnetics during this trial.
`
`Reviewer Comments:
`
`1. Per discussion with DMEP, an action will be taken on saxagliptin later in July 2009. Saxagliptin, 5 mg
`daily, is expected to be the maximum dose approvedfor human use.
`»
`
`2. The sponsor should clarify the individual definitionsfor moderate and severe renal insufficiency
`
`Informed Consent: Not included with submission.
`
`Schedule of Evaluations/Procedures: Not included in submission.
`
`Safety Evaluation: The study will have a Clinical Events Committee (CBC) and a data safety monitoring board
`_ (DSMB)
`
`Withdrawal Criteria/Stopping Criteria: Not discussed.
`
`Subjects who discontinue study medication will continue to be followed in the trial for CV events.
`
`Definition of Lost~to—Follow-Up:
`1.
`Inability to reach the patient after 3 documented phone calls, faxes, or e-mails
`2.
`Inability to contact the patient through patient locator agencies (if allowed per national regulation); and
`3. Lack of response by the patient to one letter sent by registered/certified mail ,
`
`All attempts to contact the patient are to be documented in the patient’s medical records.
`
`Statistical Analysis: Sample size calculations (10,100 patients toyield 631 primary endpoint events) include the
`following assumptions.
`1.
`2% event rate at 1 year on placebo
`2.
`2 year accrual period
`3.
`3 year minimum follow-up period
`4.
`2.5% 1-sided level of statistical significance
`
`to rule out an increased CV risk of 1.30 for saxagliptin, compared to placebo, with 91% power.
`
`Superiority of Saxagliptin can also be tested at the 4.95% 2-sided significance level if a hazard ratio (HR) of at most
`0.855 is observed for saxagliptin:placebo, representing a 14.5% reductiOn in risk. With 631 events,‘ the sponsor
`estimates there would be 90% power for testing superiority if the true HR was 0.77 and 85% power for testing
`superiority if the true HR was 0.79.
`
`One or more interim analyses are to be performed, and stopping criteria will be prespecified for either unanticipated
`efficacy or an unsuspected safety risk.
`’
`
`Page 10 oflO
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Karen Hicks
`
`7/15/2009 12:45:04 PM
`MEDICAL OFFICER
`
`Norman Stockbridge
`7/15/2009 02:19:35 PM
`MEDICAL OFFICER
`
`

`

`
`
`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
`
`June 24, 2009
`
`Mary Parks, MD, Director
`Division of Metabolism and Endocrinology Products
`
`Melina Gn'ffis, RPh, Acting Team Leader
`Denise Toyer, PharmD, Deputy Director
`Division of Medication Error Prevention and Analysis
`
`Anne Crandall, PhaImD, Safety Evaluator
`Division of Medication Error Prevention and Analysis
`
`Subject:
`
`Label and Labeling Review
`
`Drug Name(s):
`
`Onglyza (Saxagliptin) Tablets 2.5 mg and 5 mg
`
`Application Type/Number:
`
`NDA 22-350
`
`Applicant/sponsor:
`
`Bristol-Myers Squibb
`
`OSE RCM #2
`
`2009—994
`
`

`

`1
`
`INTRODUCTION
`
`The Division of Medication Error Prevention and Analysis (DMEPA) completed a label
`and labeling review for Onglyza (OSE RCM #2008-967) on February I 1, 2009 in which
`we made recommendations regarding the proposed container labels and labeling. In a
`submission dated April 29, 2009 the Applicant submitted their revisions addressing
`DMEPA’s requested changes.
`
`2 MATERIALS REVIEWED
`
`DMEPA reviewed our previous proprietary name and labeling review for Onglyza (OSE
`review # 2008-967, dated February 11, 2009) and we also reviewed the revised labels
`submitted by the Applicant dated April 29, 2009. See Appendix A for pictures of the
`revised labels.
`
`3 DISCUSSION
`
`The Applicant has revised the container labels and blister labeling according to our
`recommendations, however, the size of the 5mg strength designation on the physician
`sample pack is small and should be increased.
`
`4 CONCLUSIONS AND RECOMNIENDATIONS
`
`The Applicant has satisfactorily revised the labels per our February 11, 2009 request.
`Please forward the remaining additional comment to the Applicant.
`
`If you further questions or need clarification, please contact Mildred Wright, OSE Project
`Manager, at 301—796-1027.
`
`4.1 COMMENTS TO THE APPLICANT
`
`The size of the 5 mg strength designation on the physician sample pack is small and
`should be increased and should be similarly displayed as the strength on the trade
`container labels.
`
`

`

`This is a representation of an electronic record that was signed eiectronicafly and
`nits page is the manifestation of the electronic signature.
`
`
`
`Melina Griffis
`6/24/2009 08:20:04 AM-
`DRUG SAFETY OFFICE REVIEWER
`
`Denise Toyer
`6/24/2009 12:51:05 PM
`DRUG SAFETY OFFICE REVIEWER
`
`

`

`FOOD AND DRUG ADMINISTRATION
`
`Center for Drug Evaluation and Research
`Division of Drug Marketing, Advertising, and Communications
`
`Memorandum
`
`Date:
`
`March 25, 2009
`
`To:
`
`Rachel E. Hartford, Regulatory Health Project Manager, DMEP
`
`From:
`
`Kendra Jones, Regulatory Review Officer, DDMAC
`Sam Skariah, Regulatory Review Officer, DDMAC
`
`Through:
`
`Robert Dean, Group Leader, DDMAC
`Sangeeta Vaswani, Group Leader, DDMAC
`
`NDA 22-350
`Subject:
`DDMAC labeling comments for (saxagliptin)
`
`Prescribing Information and Patient Labeling
`
`DDMAC has reviewed the proposed Prescribing Information and Patient Labeling
`for saxagliptin. DDMAC’s comments are provided directly on the marked up
`version of the document attached. Additionally, DDMAC notes the inclusion of
`the saxagliptin Carton and Container Labels in the EDR. DDMAC offers the
`following comments on the proposed Carton Label:
`
`Carton Label (5mg'C
`
`), Carton Label (5mgQ
`
`2
`
`W4}
`
`6.
`
`5
`
`If you have any questions on the comments provided, please contact Sam Skariah at 301~796~2774 or
`Sam.skariah@,fda.hhs.oIov 'or Kendra Jones at 301—796-3917 or Kendra.I‘orles@fda.hhs.gov.
`
`

`

`ll
`
`‘
`
`,
`
`_
`
`_ Z(7 Page(s) Withheld
`
`__Tf_ § 552(b)(4) Trade Secret / Confidential
`
`*
`
`‘ 7K §__552(b)(4)Draft Labeling ,
`
`.
`
`7
`
`.
`
`-.
`
`§ 552(b),(5)‘Deliberative Process
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Sam Skariah
`3/25/2009 02:53:58 PM
`DDMAC PROFESSIONAL REVIEWER
`
`