CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`209803Orig1s000
`209805Orig1s000
`209806Orig1s000
`STATISTICAL REVIEW(S)
`
`
`
`
`
`
`

`

`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Translational Sciences
`Office of Biostatistics
`
`S T A T I S T I C A L R E V I E W A N D E V A L U A T I O N
`CLINICAL STUDIES
`
`NDA#:
`
`NDA 209805
`
`Drug Name:
`Indication(s):
`
`Applicant:
`Date(s):
`
`Ertugliflozin and Sitagliptin Fixed Dose Combination Tablets
`As an adjunct to diet and exercise to improve glycemic control in
`adults with Type 2 Diabetes Mellitus when treatment with both
`ertugliflozin and sitagliptin is appropriate.
`Merck Sharp and Dohme Corporation
`Submitted Date: 12/19/2016
`PDUFA Goal Date: 12/19/2017
`Primary Review Completion Date: 08/28/2017
`
`Review Priority:
`
`Standard
`
`Biometrics Division:
`II
`Statistical Reviewer:
`Alexander Cambon
`Concurring Reviewers: Yun Wang, Acting Team Leader
`
`Medical Division:
`Clinical Team:
`Project Manager:
`
`Division of Metabolism and Endocrinology Products
`Frank Pucino/William Chong
`Elizabeth Godwin
`
`Keywords: active control/non-inferiority, analysis of covariance, sensitivity analyses,
`missing data, drop-outs, jump to reference, return to baseline
`
`
`
`Reference ID: 4145163
`
`

`

`1
`
`2
`
`3
`
`4
`
`5
`
`Table of Contents
`EXECUTIVE SUMMARY ..................................................................................................................................3
`BRIEF OVERVIEW OF CLINICAL STUDIES.....................................................................................................................3
`STATISTICAL ISSUES ....................................................................................................................................................3
`CONCLUSIONS AND RECOMMENDATIONS....................................................................................................................3
`INTRODUCTION ................................................................................................................................................4
`2.1
`OVERVIEW.......................................................................................................................................................4
`2.1.1
`Class and Indication ...............................................................................................................................4
`2.1.2
`Select Submission History and Communication to Sponsor...................................................................4
`2.1.3
`Specific Studies Reviewed.......................................................................................................................4
`2.2
`DATA SOURCES ...............................................................................................................................................4
`STATISTICAL EVALUATION .........................................................................................................................5
`3.1
`DATA AND ANALYSIS QUALITY.......................................................................................................................5
`3.2
`EVALUATION OF EFFICACY..............................................................................................................................5
`3.2.1
`Study Design and Endpoints ...................................................................................................................5
`3.2.2
`Statistical Methodologies........................................................................................................................5
`3.2.3
`Patient Disposition, Demographic and Baseline Characteristics ..........................................................5
`3.2.4
`Results and Conclusions .........................................................................................................................5
`3.3
`EVALUATION OF SAFETY.................................................................................................................................5
`FINDINGS IN SPECIAL/SUBGROUP POPULATIONS................................................................................5
`4.1
`SEX, RACE, AGE, AND GEOGRAPHIC REGION ..................................................................................................5
`SUMMARY AND CONCLUSIONS ...................................................................................................................6
`5.1
`STATISTICAL ISSUES ........................................................................................................................................6
`5.2
`COLLECTIVE EVIDENCE...................................................................................................................................6
`5.3
`CONCLUSIONS AND RECOMMENDATIONS........................................................................................................6
`5.4
`LABELING RECOMMENDATIONS ......................................................................................................................6
`
`Reference ID: 4145163
`
`2
`
`

`

`1 EXECUTIVE SUMMARY
`
`Merck Sharp and Dohme is seeking approval for efficacy and safety of fixed dose combination
`(FDC) ertugliflozin and sitagliptin tablets (E+S) for treatment of adults with type 2 diabetes
`mellitus (T2DM). Ertugliflozin is a new molecular entity (NME), and the new drug application
`for ertugliflozin (NDA 209803) was submitted simultaneously with this NDA. Sitagliptin (brand
`name Januvia) has been previously approved for treatment of T2DM. The proposed indication
`for E + S is as an adjunct to diet and exercise to improve glycemic control in adults with T2DM
`when treatment with both ertugliflozin and sitagliptin is appropriate. The sponsor submitted this
`NDA on December 19, 2016.
`
`Brief Overview of Clinical Studies
`
`This efficacy statistical review encompasses three confirmatory safety and efficacy trials,
`including one active-controlled study (P005) and two placebo-controlled studies with different
`background therapies (P006 and P017). Study P005 was a full factorial study with metformin
`(M) background comparing E+S to E alone and to S alone. Study P006 was a placebo study with
`metformin and sitagliptin background (M+S), and P017 was a placebo study with diet and
`exercise (DE) background comparing E+S to placebo. In all these studies, two doses of
`ertugliflozin were used: ertugliflozin 5 mg (E5) and ertugliflozin 15 mg (E15). For sitagliptin, a
`100 mg dose was used (S100). These three studies were used to support this NDA 209805.
`Change in HbA1c (%) from baseline was the primary efficacy endpoint for all three studies.
`More detail on study design for these three studies including sample size and background
`medication can be found in this section of the Statistical Review for ertugliflozin (NDA 209803)
`dated August 25, 2017, and in Table 1 of the same review.
`
`Statistical Issues
`
`Statistical issues concerning missing data, dropouts, and rescue rates are described in Section
`3.2.2.3 in the statistical review for NDA 209803, and Section 5.1 in this review. Sensitivity
`analyses used to address these issues did not alter our conclusions.
`
`Conclusions and Recommendations
`
`The primary endpoint for all three studies used to support this NDA is reduction in HbA1c (%).
`The primary endpoint analysis for factorial study P005 demonstrates the statistically significant
`contribution of each of the individual components E and S, to the combination E+S (i.e. E+S is
`superior to both E alone and to S alone). The primary endpoint analysis for study P017
`demonstrates the superiority of E+S against placebo. Study P006 further demonstrates the
`statistically significant contribution of the E component to E+S. Please refer to Sections 3.2.4 in
`the statistical review for NDA 209803, and Section 5 in this review for further details. This NDA
`is approvable from the statistical point of view.
`
`3
`
`Reference ID: 4145163
`
`

`

`2
`
`INTRODUCTION
`
`2.1
`
`Overview
`
`This submission included three confirmatory safety and efficacy trials. The primary endpoint for
`each of these is HbA1c (%) change from baseline. The sponsor is seeking approval for efficacy
`and safety of FDC ertugliflozin and sitagliptin tablets (E+S) to improve glycemic control in
`adults with T2DM.
`
`Refer to Table 1, Section 2.1.3 of the Statistical Review for NDA 209803 for further details of
`study design for studies P005, P006, and P017, including background medication and sample
`size for each of the three studies.
`
`2.1.1 Class and Indication
`
`FDC ertugliflozin and sitagliptin tablets (E+S - proposed proprietary name Steglujan), is a
`combination of an oral sodium glucose co-transporter 2 (SGLT2) inhibitor with a DPP-4
`inhibitor. An example of an approved FDC drug involving an SGLT2 and a DPP-4 inhibitor is
`Glyxambi, a combination of empagliflozin (trade name Jardiance, an SGLT2 inhibitor), and
`linagliptin (trade name Tradjenta, a DPP-4 inhibitor). SGLT2 inhibitors prevent kidneys from
`reabsorbing glucose back into the blood. The excess glucose in the blood is then removed from
`the body via urine. DPP-4 inhibitors increase incretin levels, which inhibit glucagon release,
`which in turn increases insulin secretion, decreases gastric emptying, and decreases blood
`glucose levels. The proposed indication for E+S is to improve glycemic control in adults with
`Type 2 diabetes mellitus (T2DM).
`
`2.1.2 Select Submission History and Communication to Sponsor
`
`Refer to Statistical Review of NDA 209803 for submission and communication history,
`including select history of IND submissions and comments concerning preventing and
`addressing missing data.
`
`2.1.3 Specific Studies Reviewed
`
`Three of the seven studies in Table 1 of the Statistical Review of NDA 209803 (ertugliflozin - E)
`are used to support this review for E+S. These are the factorial study (P005), Study P017, and
`Study P006. Efficacy results of all three of these studies are included in tables in Section 14 of
`the draft label for this NDA (E+S).
`
`2.2 Data Sources
`
`The data and final study report for NDA 209805 were submitted electronically as an eCTD
`submission. The submission, organized as an .enx file, is archived at the following link.
`
`\\CDSESUB1\EVSPROD\NDA209805\209805.enx
`
`4
`
`Reference ID: 4145163
`
`

`

`3 STATISTICAL EVALUATION
`
`3.1 Data and Analysis Quality
`
`The SDTM and ADaM data sets are located in the proper sections of the submission, and
`analysis reviewer guides are provided which define variables and their locations.
`
`3.2
`
`Evaluation of Efficacy
`
`3.2.1 Study Design and Endpoints
`
`The primary and secondary efficacy endpoints for the three studies are shown in Table 2 of the
`Statistical Review for NDA 209803. All endpoints for the three studies are assessed at 26 weeks.
`Secondary endpoints typically include Fasting Plasma Glucose (FPG), HbA1c < 7%, Body
`Weight, and Systolic Blood Pressure (SBP). Study P017 includes the secondary endpoints of
`Post Meal Glucose (PMG) and Diastolic Blood Pressure (DBP).
`
`Refer to this section in the Statistical Review for NDA 209803 for further details.
`
`3.2.2 Statistical Methodologies
`
`Refer to this Section in the Statistical review for NDA 209803 for details on the sponsor’s and
`statistical reviewer’s analyses approach, and issues we have with missing values and retrieve
`dropouts.
`
`3.2.3 Patient Disposition, Demographic and Baseline Characteristics
`
`Refer to this section in the Statistical Review for NDA 209803.
`
`3.2.4 Results and Conclusions
`
`Refer to this section in the Statistical Review for NDA 209803 for analyses results for all three
`studies: P005, P006 and P017, and my conclusions.
`
`3.3 Evaluation of Safety
`
`Please see the clinical review of Dr. Frank Pucino for NDA 209803 for the evaluation of safety.
`
`4 FINDINGS IN SPECIAL/SUBGROUP POPULATIONS
`
`4.1
`
`Sex, Race, Age, and Geographic Region
`
`Please see this section in the Statistical Review for NDA 209803 for the three studies.
`
`5
`
`Reference ID: 4145163
`
`

`

`5 SUMMARY AND CONCLUSIONS
`
`5.1
`
`Statistical issues
`
`The following statistical issues were identified in this application. Sensitivity analyses used to
`address these issues did not alter our conclusion that efficacy was demonstrated.
`
` Missing data, which ranged from 7% to 21% across the arms in the three studies, were
`strongly associated with treatment discontinuation.
` There were very few retrieved dropouts.
` The sponsor’s primary analysis treated observations after initiation of rescue therapy as
`missing.
` Data after treatment discontinuation were completely excluded (i.e. not included in the
`analysis set) in the sponsor’s initially submitted primary and sensitivity analyses.
` The placebo study P017, which had a background of diet and exercise only, had high
`rescue rates on the placebo arm (31%).
`
`5.2 Collective Evidence
`
`The primary efficacy endpoint was change from baseline in HbA1c (%) in the three studies
`reviewed for this NDA. The full factorial study demonstrates superiority of E5/E15 + S100
`compared to S100 alone, as well as superiority of E5/E15+S100 compared to E5/E15 alone,
`against a background of M. This in turn demonstrates the efficacy contribution of each of the two
`components (E and S) to the combination of E+S and, in so doing, satisfies a key requirement of
`the combination drug law in CFR 21 Section 300.50. Study P006 demonstrates the statistically
`significant contribution of the E component (E5/E15) when added to a background of S100+M;
`(superiority of E+S+M vs. S+M). Study P017 demonstrates the efficacy of the combination E+S
`(E5/E15 +S100) against a background of diet and exercise only.
`
`These findings were consistent using the sponsor’s primary analysis, and also across our
`sensitivity analyses which addressed possible shortcomings in the primary analyses.
`
`5.3 Conclusions and Recommendations
`
`In my view, the collective evidence from this review supports the claim of using E+S to improve
`glycemic control in adults with T2DM, when treatment with both ertugliflozin and sitagliptin is
`appropriate. This NDA is approvable from the statistical point of view.
`
`5.4 Labeling Recommendations
`
`Please see this section in the Statistical Review for NDA 209803 for the three studies.
`
`Reference ID: 4145163
`
`6
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`ALEXANDER CAMBON
`08/28/2017
`
`MARK D ROTHMANN
`08/28/2017
`Signing for Yun Wang
`
`Reference ID: 4145163
`
`

`

`
`
`US. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Translational Sciences
`Oflice of Biostatistics
`
`STATISTICAL REVIEW AND EVALUATION
`
`CLINICAL STUDIES
`
`NDA#:
`
`NDA 209806
`
`Drug Name:
`
`Emugliflozin and Metformin Fixed Dose Combination Tablets
`
`Indication(s):
`
`As an adjunct to diet and exercise to improve glycemic control in
`adults with Type 2 Diabetes Mellitus
`M“)
`
`Applicant:
`
`Date(s):
`
`Merck Sharp and Dohme Corporation
`
`Submitted Date: 12/ 19/2016
`
`PDUFA Goal Date: 12/19/2017
`
`Primary Review Completion Date: 08/28/2017
`
`Review Priority:
`
`Standard
`
`Biometrics Division:
`
`11
`
`Statistical Reviewer:
`
`Alexander Cambon
`
`Concurring Reviewers: Yun Wang, Acting Team Leader
`
`Medical Division:
`
`Division of Metabolism and Endocrinology Products
`
`Clinical Team:
`
`Frank Pucino/William Chong
`
`Project Manager:
`
`Elizabeth Godwin
`
`Keywords: active control/non-inferiority, analysis of covariance, sensitivity analyses,
`missing data, drop-outs, jump to reference, return to baseline
`
`Reference ID: 4145183
`
`

`

`1
`
`2
`
`3
`
`4
`
`5
`
`Table of Contents
`EXECUTIVE SUMMARY ..................................................................................................................................3
`BRIEF OVERVIEW OF CLINICAL STUDIES.....................................................................................................................3
`STATISTICAL ISSUES ....................................................................................................................................................3
`CONCLUSIONS AND RECOMMENDATIONS....................................................................................................................3
`INTRODUCTION ................................................................................................................................................3
`2.1
`OVERVIEW.......................................................................................................................................................3
`2.1.1
`Class and Indication ...............................................................................................................................4
`2.1.2
`Select Submission History and Communication to Sponsor...................................................................4
`2.1.3
`Specific Studies Reviewed.......................................................................................................................4
`2.2
`DATA SOURCES ...............................................................................................................................................5
`STATISTICAL EVALUATION .........................................................................................................................5
`3.1
`DATA AND ANALYSIS QUALITY.......................................................................................................................5
`3.2
`EVALUATION OF EFFICACY..............................................................................................................................5
`3.2.1
`Study Design and Endpoints ...................................................................................................................5
`3.2.2
`Statistical Methodologies........................................................................................................................6
`3.2.3 Patient Disposition, Demographic and Baseline Characteristics .................................................................7
`3.2.4
`Results and Conclusions .........................................................................................................................7
`3.3
`EVALUATION OF SAFETY.................................................................................................................................7
`FINDINGS IN SPECIAL/SUBGROUP POPULATIONS................................................................................7
`4.1
`SEX, RACE, AGE, AND GEOGRAPHIC REGION ..................................................................................................7
`SUMMARY AND CONCLUSIONS ...................................................................................................................8
`5.1
`STATISTICAL ISSUES ........................................................................................................................................8
`5.2
`COLLECTIVE EVIDENCE...................................................................................................................................8
`5.3
`CONCLUSIONS AND RECOMMENDATIONS........................................................................................................8
`5.4
`LABELING RECOMMENDATIONS ......................................................................................................................9
`
`Reference ID: 4145183
`
`2
`
`

`

`1 EXECUTIVE SUMMARY
`
`Merck Sharp and Dohme is seeking approval for efficacy and safety of fixed dose combination
`(FDC) ertugliflozin/metformin hydrochloride tablets (E + M) for treatment of adults with type 2
`diabetes mellitus (T2DM). Ertugliflozin is a new molecular entity (NME), and the new drug
`application for ertugliflozin (NDA 209803) was submitted simultaneously with this NDA on
`December 19, 2016. Metformin (brand name Glucophage) has been previously approved for
`treatment of T2DM and is considered a first line therapy. The proposed indication for E + M is
`as an adjunct to diet and exercise to improve glycemic control in adults with T2DM
`
`
`
`Brief Overview of Clinical Studies
`
`This efficacy statistical review encompasses four confirmatory safety and efficacy trials,
`including two active-controlled studies (P005 and P002) and two placebo-controlled studies
`(P006 and P007). All these studies had a background that included metformin. Change in HbA1c
`(%) from baseline was the primary efficacy endpoint for all four studies. In all these studies, two
`doses of ertugliflozin were used: ertugliflozin 5 mg (E5) and ertugliflozin 15 mg (E15). More
`detail on study design including sample size and background medication can be found in this
`section of the Statistical Review for NDA 209803 dated August 25, 2017 and in Table 1 of the
`same review.
`
`Statistical Issues
`
`Statistical issues concerning missing data, dropouts, and rescue rates are described in Section
`3.2.2.3 in the statistical review for NDA 209803, and Section 5.1 in this review. Sensitivity
`analyses used to address these issues did not alter our conclusions.
`
`Conclusions and Recommendations
`
`The primary endpoint for all three studies used to support this NDA is reduction in HbA1c (%).
`Three of the four studies demonstrate the statistical superiority of the combination therapy
`compared to individual component (E+M vs M) and added contribution of the individual
`component of E vs. a background that includes M. Non-inferiority study P002 demonstrated the
`non-inferiority of E15 compared to glimepiride (E15+M vs. glimepiride +M). The contribution
`of M to E+M (E+M vs. E) was not assessed statistically. Please refer to Sections 3.2.4 in the
`statistical review for NDA 209803, and Section 5 in this review for further details. This
`statistical review supports the use of ertugliflozin as add-on therapy to metformin.
`
`2
`
`INTRODUCTION
`
`2.1
`
`Overview
`
`This submission included four confirmatory safety and efficacy trials. The primary endpoint for
`each of these is HbA1c (%) change from baseline. The sponsor is seeking approval for efficacy
`and safety of FDC ertugliflozin and metformin tablets (E+M) to improve glycemic control in
`adults with T2DM.
`
`3
`
`Reference ID: 4145183
`
`(b) (4)
`
`

`

`Refer to Table 1, Section 2.1.3 of the Statistical Review for NDA 209803 for further details of
`study design for studies P005, P002, P006, and P007, including background medication and
`sample size for each of the four studies.
`
`2.1.1 Class and Indication
`
`FDC ertugliflozin and metformin tablets (E+M - proposed proprietary name Segluromet) is a
`combination of an oral sodium glucose co-transporter 2 (SGLT2) inhibitor with metformin, a
`biguanide. Examples of approved FDC drugs combining an SGLT2 inhibitor with metformin
`include:
`1)
`2)
`3)
`
`Synjardy (empagliflozin +metformin).
`Invokamet (canagliflozin + metformin)
`Xiduo (dapagliflozin + metformin)
`
`SGLT2 inhibitors prevent kidneys from reabsorbing glucose back into the blood. The excess
`glucose in the blood is then removed from the body via urine. Metformin decreases high blood
`sugar, primarily by suppressing liver glucose production. The proposed indication for E+M is to
`improve glycemic control in adults with T2DM.
`
`2.1.2 Select Submission History and Communication to Sponsor
`
`Refer to Statistical Review of NDA 209803 for submission and communication history,
`including select history of IND submissions and comments concerning preventing and
`addressing missing data.
`
`2.1.3 Specific Studies Reviewed
`
`Four of the seven studies in Table 1 of the Statistical Review of NDA 209803 (ertugliflozin - E)
`are used to support this review for E+M. These are the factorial study (P005), the non-inferiority
`study (P002), and placebo studies P007 and P006. Efficacy results of all four of these studies are
`included
` in Section 14 of the draft label for this NDA.
`
`2.2 Data Sources
`
`The data and final study report for NDA 209806 were submitted electronically as an eCTD
`submission. The submission, organized as an .enx file, is archived at the following link.
`
`\\CDSESUB1\EVSPROD\NDA209806\209806.enx
`
`3 STATISTICAL EVALUATION
`
`3.1 Data and Analysis Quality
`
`The SDTM and ADaM data sets are located in the proper sections of the submission, and
`analysis reviewer guides are provided which define variables and their locations.
`
`4
`
`Reference ID: 4145183
`
`(b) (4)
`
`

`

`3.2
`
`Evaluation of Efficacy
`
`3.2.1 Study Design and Endpoints
`
`The primary and secondary efficacy endpoints for the four studies are shown in Table 2 of the
`Statistical Review for NDA 209803. Secondary endpoints typically include Fasting Plasma
`Glucose (FPG), HbA1c < 7%, Body Weight, and Systolic Blood Pressure (SBP). Study P007
`includes the secondary endpoint of Diastolic Blood Pressure (DBP).
`
`Refer to this section in the Statistical Review for NDA 209803 for further details.
`
`3.2.2 Statistical Methodologies
`
`Refer to this Section in the Statistical review for NDA 209803 for details on the sponsor’s and
`statistical reviewer’s analyses approach, and issues we have with missing values and retrieve
`dropouts.
`
`3.2.3 Patient Disposition, Demographic and Baseline Characteristics
`
`Refer to this section in the Statistical Review for NDA 209803.
`
`3.2.4 Results and Conclusions
`
`Refer to this section in the Statistical Review for NDA 209803 for analyses results for all four
`studies: P002, P005, P006 and P007, and my conclusions.
`
`3.3 Evaluation of Safety
`
`Please see the clinical review of Dr. Frank Pucino for NDA 209803 for the evaluation of safety.
`
`4 FINDINGS IN SPECIAL/SUBGROUP POPULATIONS
`
`4.1
`
`Sex, Race, Age, and Geographic Region
`
`Please see this section in the Statistical Review for NDA 209803 for all four studies.
`
`5 SUMMARY AND CONCLUSIONS
`
`5.1
`
`Statistical issues
`
`The following statistical issues were identified in this application. Sensitivity analyses used to
`address these issues did not alter our conclusion that efficacy was demonstrated.
`
`5
`
`Reference ID: 4145183
`
`

`

` Missing data, which ranged from 5% to 20% across the arms in the four studies, were
`strongly associated with treatment discontinuation.
` There were very few retrieved dropouts.
` The sponsor’s primary analysis treated observations after initiation of rescue therapy as
`missing.
` Data after treatment discontinuation were completely excluded (i.e. not included in the
`analysis set) in the sponsor’s initially submitted primary and sensitivity analyses.
`
`5.2 Collective Evidence
`
`The primary efficacy endpoint was change from baseline in HbA1c (%) in the four studies
`reviewed for this NDA. The primary endpoint analysis for study P007 demonstrated superiority
`of the combination therapy (E+M vs. M) and added contribution of the individual component of
`E against a background of M. Placebo study P006 demonstrated the superiority of the
`combination therapy (E+M+S vs. M+S) and added contribution of E against a background of M
`and Sitagliptin 100 mg. Active control study P005 also demonstrated the superiority of E+M+S
`vs. M+S. The primary endpoint analysis for active control study P002 demonstrated the non-
`inferiority of E compared to glimepiride (G) (non-inferiority of E+M vs. G+M) for glycemic
`control among patients receiving background therapy of M; These findings were consistent using
`the sponsor’s primary analysis, and also across our sensitivity analyses which addressed possible
`shortcomings in the primary analyses.
`
`Each of these four studies demonstrated the efficacy contribution of the component E to the
`combination of E+M. The combination drug law in CFR 21 Section 300.50 requires that each
`component of an FDC combination drug be demonstrated. The contribution of the component M
`to E+M was not assessed statistically in this submission in any of the studies. It should be noted
`that in at least two other approved combination drugs involving an SGLT2 inhibitor and
`metformin, a factorial study was used to demonstrate the statistically significant contribution of
`each component. See for example NDA 204353, S014 (Invokamet – Canagliflozin XR and
`Metformin,
`Table
`9
`in
`the
`label
`–
`https://www.accessdata.fda.gov/drugsatfda docs/label/2017/204353s014lbl.pdf)
`and NDA
`206111, S009 (Synjardy – Empagliflozin and Metformin, Table 8
`in
`the
`label -
`https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/206111s009lbl.pdf). A similar factorial study
`was not found for the combination drug Xiduo (NDA 205649 - dapagliflozin and metformin).
`
`5.3 Conclusions and Recommendations
`
`In my view, the collective evidence from this statistical review supports the use of ertugliflozin
`as an add-on therapy to metformin to improve glycemic control in adults with T2DM. This
`NDA is approvable from the statistical point of view with this claim.
`
`5.4 Labeling Recommendations
`
`Please see this section in the Statistical Review for NDA 209803 for the three studies.
`
`6
`
`Reference ID: 4145183
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`ALEXANDER CAMBON
`08/28/2017
`
`MARK D ROTHMANN
`08/28/2017
`Signing for Yun Wang
`
`Reference ID: 4145183
`
`

`

`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Translational Sciences
`Office of Biostatistics
`
`S T A T I S T I C A L R E V I E W A N D E V A L U A T I O N
`CLINICAL STUDIES
`
`NDA#:
`
`NDA 209803
`
`Drug Name:
`Indication(s):
`
`Applicant:
`Date(s):
`
`Ertugliflozin
`As an adjunct to diet and exercise to improve glycemic control in
`adults with Type 2 Diabetes Mellitus
`Merck Sharp and Dohme Corporation
`Submitted Date: 12/19/2016
`PDUFA Goal Date: 12/19/2017
`Primary Review Completion Date: 08/25/2017
`
`Review Priority:
`
`Standard
`
`Biometrics Division:
`II
`Statistical Reviewer:
`Alexander Cambon
`Concurring Reviewers: Yun Wang, Acting Team Leader
`
`Medical Division:
`Clinical Team:
`Project Manager:
`
`Division of Metabolism and Endocrinology Products
`Frank Pucino/William Chong
`Elizabeth Godwin
`
`Keywords: active control/non-inferiority, analysis of covariance, sensitivity analyses,
`missing data, drop-outs, jump to reference, return to baseline
`
`
`
`Reference ID: 4144831
`
`

`

`Table of Contents
`EXECUTIVE SUMMARY ..................................................................................................................................5
`BRIEF OVERVIEW OF CLINICAL STUDIES.....................................................................................................................5
`STATISTICAL ISSUES ....................................................................................................................................................5
`CONCLUSIONS AND RECOMMENDATIONS....................................................................................................................5
`INTRODUCTION ................................................................................................................................................5
`2.1
`OVERVIEW.......................................................................................................................................................5
`2.1.1
`Class and Indication ...............................................................................................................................6
`2.1.2
`Select Submission History and Communication to Sponsor...................................................................6
`2.1.3
`Specific Studies Reviewed.......................................................................................................................8
`2.2
`DATA SOURCES ...............................................................................................................................................9
`STATISTICAL EVALUATION .......................................................................................................................10
`3.1
`DATA AND ANALYSIS QUALITY.....................................................................................................................10
`3.2
`EVALUATION OF EFFICACY..............