CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`210874Orig1s000
`
`
`OTHER REVIEW(S)
`
`

`

`MEMORANDUM
`REVIEW OF REVISED LABEL AND LABELING
`Division of Medication Error Prevention and Analysis (DMEPA)
`Office of Medication Error Prevention and Risk Management (OMEPRM)
`Office of Surveillance and Epidemiology (OSE)
`Center for Drug Evaluation and Research (CDER)
`
`Date of This Memorandum:
`Requesting Office or Division:
`
`Application Type and Number:
`Product Name and Strength:
`
`Applicant/Sponsor Name:
`FDA Received Date:
`OSE RCM #:
`DMEPA Safety Evaluator:
`DMEPA Team Leader:
`
`May 1, 2019
`Division of Metabolism and Endocrinology Products
`(DMEP)
`NDA 210874
`Qternmet XR (dapagliflozin, saxagliptin, and metformin
`HCl) extended release tablet, 2.5 mg/ mg/1,000 mg,
`5 mg/2.5 mg/1,000 mg, 5 mg/5 mg/1,000 mg, 10 mg/5
`mg/1,000 mg
`AstraZeneca Pharmaceuticals
`May 1, 2019
`2018-1448-2
`Ariane O. Conrad, PharmD, BCACP, CDE
`Hina Mehta, PharmD
`
`PURPOSE OF MEMORANDUM
`1
`Division of Metabolism and Endocrinology Products (DMEP) requested that we review the
`revised trade and sample container and carton labeling for Qternmet XR (Appendix A) to
`determine if they are acceptable from a medication error perspective. The sponsor proposed
`additional revisions to the carton and container to correspond with Agency recommendations
`for the ingredient descriptions in Section 11 Description of the prescribing information. Our
`prior labeling determined that the trade container labels and sample carton labeling for
`Qternmet XR were acceptable. a
`
` CONCLUSION
`2
`The revised trade container labels and sample carton labeling for Qtern are acceptable from a
`medication error perspective. We have no further recommendations at this time.
`
`a DeGraw S. Review of Revised Label and Labeling for Qternmet XR (NDA 210874). Silver Spring (MD): FDA, CDER,
`OSE, DMEPA (US); 2019 April 23. RCM No.: 2018-1448-1.
`
`1
`
`Reference ID: 4427055
`
`4 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`(b)
`(4)
`
`

`

`Signature Page 1 of 1
`--------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically. Following this are manifestations of any and all
`electronic signatures for this electronic record.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
`
`ARIANE O CONRAD
`05/01/2019 03:53:42 PM
`
`HINA S MEHTA
`05/01/2019 05:25:30 PM
`
`Reference ID: 4427055
`
`

`

`MEMORANDUM
`REVIEW OF REVISED LABEL AND LABELING
`Division of Medication Error Prevention and Analysis (DMEPA)
`Office of Medication Error Prevention and Risk Management (OMEPRM)
`Office of Surveillance and Epidemiology (OSE)
`Center for Drug Evaluation and Research (CDER)
`
`Date of This Memorandum:
`Requesting Office or Division:
`Application Type and Number:
`Product Name and Strength:
`
`Applicant/Sponsor Name:
`FDA Received Date:
`OSE RCM #:
`DMEPA Safety Evaluator:
`DMEPA Team Leader:
`
`April 23, 2019
`Division of Metabolism and Endocrinology Products (DMEP)
`NDA 210874
`Qternmet XR (dapagliflozin, saxagliptin, and metformin HCl)
`extended-release tablets
`2.5 mg/ mg/1,000 mg
`5 mg/2.5 mg/1,000 mg
`5 mg/5 mg/1,000 mg
`10 mg/5 mg/1,000 mg
`AstraZeneca
`April 18, 2019
`2018-1448-1
`Stephanie DeGraw, PharmD
`Hina Mehta, PharmD
`
`PURPOSE OF MEMORANDUM
`1
`The Division of Metabolism and Endocrinology Products requested we review the revised container
`labels for Qternmet XR (Appendix A) to determine if they are acceptable from a medication error
`perspective. The revisions are in response to recommendations that we made during a previous
`label and labeling reviewa and an information request sent on April 9, 2019.b
`
` CONCLUSION
`2
`We note our recommendation of adding a comma to all numbers greater than or equal to 1,000 in
`our previous review. AstraZeneca responded with their preference to display 1000 without a
`comma to avoid potential confusion when both a comma and decimal point are included within the
`same strength statement and visual field. In addition, the proposal to display 1000 without a
`
`a DeGraw, S. Label and Labeling Review for Qternmet (dapagliflozin-saxagliptin-metformin) NDA 210874. Silver Spring (MD):
`FDA, CDER, OSE, DMEPA (US); 2019 JAN 23. RCM No.: 2018-1448.
`b https://darrts.fda.gov//darrts/faces/ViewDocument?documentId=090140af804eb815& afrRedirect=1801611992296345
`1
`
`Reference ID: 4422869
`
`(b
`)
`
`(
`
`

`

`comma for all dosage strengths provides for consistency across dose presentations. We note the
`exclusion of the comma would not likely lead to confusion as there are three parts to the strength
`presentation as the product contains three separate components.
`
`The revised container labels are acceptable from a medication error perspective. We have no
`additional recommendations at this time.
`
`Reference ID: 4422869
`
`2
`
`4 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`

`

`Signature Page 1 of 1
`--------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically. Following this are manifestations of any and all
`electronic signatures for this electronic record.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
`
`STEPHANIE L DEGRAW
`04/23/2019 11:01:54 AM
`
`HINA S MEHTA
`04/24/2019 12:29:59 PM
`
`Reference ID: 4422869
`
`

`

`
`Date:
`
`To:
`
`
`Through:
`
`
`From:
`
`Subject:
`Drug Name (established
`name):
`
`Department of Health and Human Services
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Medical Policy Initiatives
`Division of Medical Policy Programs
`
`PATIENT LABELING REVIEW
`
`April 16, 2019
`
`Lisa Yanoff, M.D.
`Acting Director
`Division of Metabolism and Endocrinology Products
`(DMEP)
`
`LaShawn Griffiths, MSHS-PH, BSN, RN
`Associate Director for Patient Labeling
`Division of Medical Policy Programs (DMPP)
`
`Marcia Williams, PhD
`Team Leader, Patient Labeling
`Division of Medical Policy Programs (DMPP)
`
`Nyedra W. Booker, PharmD, MPH
`Patient Labeling Reviewer
`Division of Medical Policy Programs (DMPP)
`Meena Savani, PharmD
`Regulatory Review Officer
`Office of Prescription Drug Promotion (OPDP)
`Review of Patient Labeling: Medication Guide (MG)
`QTERNMET XR (dapagliflozin, saxagliptin, and metformin
`hydrochloride)
`
`Dosage Form and Route: extended-release tablets, for oral use
`Application
`NDA 210874
`Type/Number:
`
`AstraZeneca
`
`
`Applicant:
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4420048
`
`

`

`INTRODUCTION
`On July 2, 2018, AstraZeneca submitted for the Agency’s review a New Drug
`Application (NDA) 210874 for QTERNMET XR (dapagliflozin, saxagliptin, and
`metformin hydrochloride) extended-release tablets, for oral use. The proposed
`indication for QTERNMET XR (dapagliflozin, saxagliptin, and metformin
`hydrochloride) extended-release tablets, for oral use is as an adjunct to diet and
`exercise to improve glycemic control in adults with type 2 diabetes mellitus (T2DM)
`
`This review is written by the Division of Medical Policy Programs (DMPP) and the
`Office of Prescription Drug Promotion (OPDP) in response to a request by the
`Division of Metabolism and Endocrinology Products (DMEP) on July 9, 2018 for
`DMPP and OPDP to review the Applicant’s proposed Medication Guide (MG) for
`QTERNMET XR (dapagliflozin, saxagliptin, and metformin hydrochloride)
`extended-release tablets, for oral use.
`
`1
`
` 2
`
` MATERIAL REVIEWED
`• Draft QTERNMET XR (dapagliflozin, saxagliptin, and metformin hydrochloride)
`extended-release tablets, for oral use MG received on July 2, 2018, revised by the
`Review Division throughout the review cycle, and received by DMPP on April 2,
`2019.
`• Draft QTERNMET XR (dapagliflozin, saxagliptin, and metformin hydrochloride)
`extended-release tablets, for oral use MG received on July 2, 2018, revised by the
`Review Division throughout the review cycle, and received by OPDP on April 2,
`2019.
`• Draft QTERNMET XR (dapagliflozin, saxagliptin, and metformin hydrochloride)
`extended-release tablets, for oral use Prescribing Information (PI) received on
`July 2, 2017, revised by the review division throughout the review cycle, and
`received by DMPP on April 2, 2019.
`• Draft QTERNMET XR (dapagliflozin, saxagliptin, and metformin hydrochloride)
`extended-release tablets, for oral use Prescribing Information (PI) received on
`July 2, 2017, revised by the review division throughout the review cycle, and
`received by OPDP on April 2, 2019.
`
`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.
`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
`
`
`
`
`
`
`
`Reference ID: 4420048
`
`(b) (4)
`
`

`

`accessible for patients with vision loss. We have reformatted the MG document
`using the Arial font, size 10.
`In our collaborative review of the MG we have:
`• simplified wording and clarified concepts where possible
`• ensured that the MG is consistent with the Prescribing Information (PI)
`• removed unnecessary or redundant information
`• ensured that the MG is free of promotional language or suggested revisions to
`ensure that it is free of promotional language
`• ensured that the MG meets the Regulations as specified in 21 CFR 208.20
`• ensured that the MG meets the criteria as specified in FDA’s Guidance for Useful
`Written Consumer Medication Information (published July 2006)
`
` 4
`
` 5
`
` CONCLUSIONS
`The MG is acceptable with our recommended changes.
`
` RECOMMENDATIONS
`• Please send these comments to the Applicant and copy DMPP and OPDP on the
`correspondence.
`• Our collaborative review of the MG is appended to this memorandum. Consult
`DMPP and OPDP regarding any additional revisions made to the PI to determine
`if corresponding revisions need to be made to the MG.
` Please let us know if you have any questions.
`
`
`
`
`
`
`
`Reference ID: 4420048
`
`10 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`

`

`Signature Page 1 of 1
`--------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically. Following this are manifestations of any and all
`electronic signatures for this electronic record.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
`
`NYEDRA W BOOKER
`04/16/2019 01:10:18 PM
`
`MEENA R SAVANI
`04/16/2019 01:28:49 PM
`
`MARCIA B WILLIAMS
`04/16/2019 01:36:59 PM
`
`LASHAWN M GRIFFITHS
`04/16/2019 02:54:35 PM
`
`Reference ID: 4420048
`
`

`

`FOOD AND DRUG ADMINISTRATION
`Center for Drug Evaluation and Research
`Office of Prescription Drug Promotion
`****Pre-decisional Agency Information****
`
`
`
`
`Memorandum
`
`Date:
`April 11, 2019
`
`
`To:
`
`
`Richard Whitehead, Regulatory Project Manager
`Division of Metabolism and Endocrinology Products (DMEP)
`
`
`
`
`
`
`From:
`
`
`
`CC:
`
`Subject:
`
`
`NDAs:
`
`
`
`Monika Houstoun, Associate Director for Labeling, DMEP
`
`Meena Savani, Regulatory Review Officer
`Office of Prescription Drug Promotion (OPDP)
`
`Melinda McLawhorn, Team Leader, OPDP
`
`OPDP Labeling Comments for QTERNMET (dapagliflozin and saxagliptin)
`and QTERNMET XR (dapagliflozin, saxagliptin, and metformin HCl)
`
`209091/Supplement 002
`210874
`
`
`
`In response to DMEP’s consult request dated July 9, 2018, OPDP has reviewed the proposed
`product labeling (PI) for the original NDA 210874 for QTERNMET XR and for NDA
`209091/S002 for QTERN. The supplement (S002) proposes to expand the QTERN indication
`to include concomitant use of QTERN with background metformin and provides for the addition
`of studies (NCT02681094, NCT016060007,
` to Section 14
`of the PI.
`
`PIs and Medication Guides: OPDP’s comments on the proposed labeling are based on the
`draft PIs received by electronic mail from DMEP on April 2, 2019 and are provided below.
`
` A
`
` combined OPDP and Division of Medical Policy Programs (DMPP) review will be completed,
`and comments on the proposed Medication Guides will be sent under separate cover.
`
`Carton and Container Labeling: OPDP has reviewed the attached proposed carton and
`container labeling for QTERNMET XR submitted by the Sponsor to the electronic document
`room on April 8, 2019, and we do not have any comments.
`
`Thank you for your consult. If you have any questions, please contact Meena Savani at (240)
`402-1348 or Meena.Savani@fda.hhs.gov.
`
`
`
`
`Reference ID: 4418417
`
`1
`
`118 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`(b) (4)
`
`

`

`Signature Page 1 of 1
`--------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically. Following this are manifestations of any and all
`electronic signatures for this electronic record.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
`
`MEENA R SAVANI
`04/11/2019 07:09:08 PM
`
`Reference ID: 4418417
`
`

`

`Clinical Inspection Sunnnary
`NDA 209091/ 3002 and NDA 210874
`
`Addendum to Clinical Inspection Summary
`3/25/2019
`
`Cynthia F. Kleppinger, M.D., Senior Medical Officer
`Kassa Ayalew, M.D., M.P.H., Branch Chief
`Good Clinical Practice Assessment Branch (GCPAB)
`Division of Clinical Compliance Evaluation (DCCE)
`Office of Scientific Investi ations OSI
`
`Frank Pucino, Phann. D., M.P.H., Clinical Reviewer
`
`Patrick Archdeacon, M.D., M.Phil., Clinical Team Leader
`Richard Whitehead, M.S., Regulatory Project Manager
`Division of Metabolism and Endocrinolo 3
`
`NDA
`209091/s002 and 210874
`
`A n nlicant
`
`AstraZeneca AB
`
`Da n a ' liflozin/Saxa ' tin Fixed Combination Dru Product
`
`No
`
`
`
`Therapeutic
`Classification
`
`Proposed
`
`Antidiabetic Agents, Non-Insulin (3031400)
`
`.
`.
`Treatment of type 2 diabetes melhtus
`
`Consultation
`7/24/2018
`Request Date
`Summary
`Goal Date
`
`3/28/2019; addendum added 4/01/2019
`
`Date
`
`PDUFA Date
`
`5/2/2019
`
`I. OVERALL ASSESSNIENT OF FINDINGS AND RECONIMENDATIONS
`
`The inspection for this new drug application (NDA) and supplemental new drug application
`(sNDA) consisted of three domestic clinical sites. In general, based on the inspections of the three
`clinical sites, the inspectional findings support validity of data as reported by the sponsor under
`this NDA.
`
`The compliance classification for Dr. Altamirano is Voluntary Action Indicated (VAI). Although
`regulatory violations were noted (as described below), they are unlikely to significantly impact
`primary safety and efficacy analyses. Data from this site is acceptable for use in support of the
`indication for this application. The full Establishment Inspection Report was submitted for review.
`
`The compliance classification for Drs. Bueso and Dennis is No Action Indicated (NAI). Data from
`these sites is considered reliable based on the available information. The full Establishment
`
`Inspection Reports were submitted for review.
`
`Reference ID: 4412619
`
`

`

` Clinical Inspection Summary
`
` NDA 209091/ s002 and NDA 210874
`
`All classifications are considered preliminary until the final communication letter is sent to the
`inspected entity.
`
`ADDENDUM INFORMATION:
`
`In addition to FDA inspections done by the Office of Regulatory Affairs, the European Medicines
`Agency (EMA) has currently in house a marketing application for
`Dapagliflozin/Saxagliptin/Metformin (EU reference number EMEA/H/C/004910) and shared with
`the Office of Scientific Investigations (OSI) their Integrated Inspection Report dated March 1,
`2019 of Study CV181-168 “A Multicenter, Randomized, Double-Blind, Placebo-Controlled,
`Parallel Group, Phase 3 Trial to Evaluate the Safety and Efficacy of Triple Therapy with
`Saxagliptin added to Dapagliflozin in Combination with Metformin compared to Therapy with
`Placebo added to Dapagliflozin in combination with Metformin in Subjects with Type 2 Diabetes
`who have Inadequate Glycemic Control on Metformin and Dapagliflozin)”. The study included
`315 subject
`
`Reference ID: 4412619
`
`2
`
`Information under Confidentiality Agreement
`
`Information under Confidentiality
`Agreement
`
`

`

`Clinical Inspection Summary
`NDA 209091/ $002 and NDA 210874
`
`
`
`reviewer was in agreement with the assessment.
`
`After full review of the inspectional reports, the OSI
`
`Refelenoe ID: 4412619
`
`

`

`Clinical Inspection Summary
`NDA 209091/ $002 and NDA 210874
`
`H. BACKGROUND
`
`The sponsor AstraZeneca Pharmaceuticals LP (AstraZeneca) has submitted a new drug application
`(NDA 210874) for QTERNIVIET XRTM (dapagliflozin, saxagliptin, and metformin hydrochloride)
`extended release tablet for oral use. The proposed indication for QTERNMET XRTM is as an
`adjlmct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus
`(T2DM)
`(our
`
`At the same time, AstraZeneca has submitted a supplement to their new drug application (sNDA
`209091/3002) seeking marketing approval to expand the QTERN® (dapagliflozin and saxagliptin)
`indication to include concomitant use of QTERNQ on a background of metformin and to provide a
`low dose (dapagliflozin 5 mg/saxagliptin 5 mg) of QTERNQ.
`
`QTERNO was approved February 28, 2017 as an adjunct to diet and exercise to improve glycemic
`control in adults with TZDM
`W4)
`
`Dapagliflozin (FARXIGA‘E’), saxagliptin (ONGLYZAU), and metformin
`(GLUCOPHAGEO XR) are all FDA-approved oral antidiabetic drugs.
`
`NDA 210874 and sNDA 209091/$002 are supported by two pivotal Phase 3 studies (Study
`D 1683C00005 and Study CV181 169).
`
`Studv CV181169 was previouslv submitted to NDA 209091
`
`“3‘20
`
`(but) were
`Five domestic clinical sites and the contract research organization
`inspected under
`(no); there were no significant inspectional findings. For NDA 209091,
`OSI was not re—consulted with a request to conduct additional audits/site inspections.
`
`Inspections were requested for Study D1683C00005 entitled “A Multi-Center, Randomized,
`Double—Blind, Active-Controlled, Parallel Group, Phase III Trial to Evaluate the Safety and
`Efficacy of Saxagliptin 5 mg Co-administered with Dapagliflozin 5 mg compared to Saxagliptin
`5 mg or Dapagliflozin 5 mg all given as Add-on therapy to Metformin in Patients with Type 2
`Diabetes who have Inadequate Glycemic Control on Metformin Alone”.
`
`Subjects were randomized at 119 sites in six countries, including 47 sites in the United States
`(US). A total of 1058 subjects were enrolled into this study. There were 883 subjects randomized
`and 832 subjects completed the study. The primary endpoint was the change from baseline HbAlc
`to Week 24.
`
`Reference ID: 4412619
`
`

`

` Clinical Inspection Summary
`
` NDA 209091/ s002 and NDA 210874
`
`III. RESULTS (by Site):
`
`# of Subjects
`Randomized
`
`Inspection
`Date
`
`Classification
`
`28 subjects
`
`09/17 –
`09/21/ 2018
`
`Voluntary Action
`Indicated (VAI)
`
`Name of CI/ Address
`Site#
`Dario D. Altamirano, D.O.
`AGA Clinical Trials
`900 West 49th Street, Suite 430
`Hialeah, FL 33012
`Site 7819
`Patrick Dennis, M.D.
`DelRicht Research
`3525 Prytania Street, Suite 321
`New Orleans, LA 70115-8131
`Site 7826
`Gerardo Bueso, M.D.
`Endocrine Associates
`5711 Almeda Road
`Houston, TX 77004-7303
`Site 7822
`Key to Compliance Classifications
`NAI = No deviation from regulations
`VAI = Deviation(s) from regulations
`OAI = Significant deviations from regulations; data unreliable.
`*Pending = Preliminary classification based on information in 483 (if applicable) and preliminary
` communication with the field; final classification is pending letter to site.
`
`12 subjects
`
`10/01 –
`10/04/2018
`
`No Action Indicated
`(NAI)
`
`21 subjects
`
`11/05 –
`11/09/2019
`
`No Action Indicated
`(NAI)
`
`NOTE: Site inspections focused on review of informed consent documents (ICDs), institutional
`review board (IRB)/ ethics committee (EC) correspondences, 1572s/investigator agreements,
`financial disclosures, training records, CVs and licenses, delegation of duties, monitoring logs and
`reports, inclusion/exclusion criteria, enrollment logs, subject source documents including medical
`history records, drug accountability, concomitant medication records, and adverse event reports.
`Source records were compared to the sponsor’s data line listings.
`
`Reference ID: 4412619
`
`5
`
`

`

`Clinical Inspection Summary
`NDA 209091/ 5002 and NBA 210874
`
`1. Dario Altamirano] Site 7819
`
`There were 53 subjects screened and 28 subjects enrolled into the study; 26 subjects
`completed the study (two subjects withdrew consent). There were 53 subject records
`reviewed.
`
`The site is
`
`W" AGA Clinical Trials,
`(h) (4)
`
`Dr. Altamirano has been working for the
`organization since the beginning. All subjects were screened and treated at this location.
`Dr. Altamirano has a private practice in the same building and floor and divides his time
`equally between research and private practice.
`
`The institutional review board ORB) of record was
`
`(we)
`
`The source documents were legible and contemporaneous. Of note, the subject records
`were identified with the randomization number (as is typical), yet some had source
`documents identifying them with their screening number, often for Visit 0 and/or Visit 1.
`The source records were compared to the sponsor data line listings. There was no under-
`reporting of adverse events. The primary eflicacy endpoint was verifiable.
`
`At the conclusion of the inspection, a Form FDA-483, Inspectional Observations, was
`issued for:
`
`1. Failure to inform subjects of new unanticipated risks to subjects or others for 28 out of
`28 randomized subjects.
`0S1 Reviewer Comment: On 7/8/16, the IRB sent communication to Dr. Altamirano
`regarding an FDA Drug Safety Communication “Unanticipated Problem Involving
`Risks to Subjects or Others " strengthening kidney warningsfor canagliflozin and
`dapagliflozin, requesting him to inform subjects about the unanticipated risks and to
`document this action in research records but hefailed tofollow through with the [RB
`request. All subject records were reviewed and, although this was a human subject
`protection deviation, there was no reported renalfailure either during the study or at
`the endfor any subject.
`2. Failure to re-consent five out of 10 randomized subjects to the most current IRB
`approved informed consent form (ICF).
`0S1 Reviewer Comment: Dr. Altamiranofailed to reconsentfive out of 10 subjects that
`needed to be reconsented to version 2.0 ofthe ICF, which included additional
`information regarding unanticipated risks ofrenal injurv. This was an oversight ofthe
`stafl
`3. Failure to meet protocol specific windows for rescue therapy safety lab retest.
`0S1 Reviewer Comment: Protocol section 4.4 "Rescue Ilierapy, ” states, “Patients with
`a
`(I'm FPG value meeting the lack ofglycemic control criterion at a pre-
`specified visit will be scheduledfor afollow-up visit (within 3 to 5 days) to obtain a
`second
`(m4) FPG value...
`Subject (I'm was brought backfor retest on
`
`Reference ID: 4412619
`
`

`

`Clinical Inspection Summary
`NDA 209091/ 5002 and NDA 210874
`
`@(6)
`
`(5)“)
`
`, one day out ofthe protocol window, and the labs were reviewed on
`Subject MO was brought backfor a retest on
`(me), six davs out oftheprotocol
`window, and the labs were reviewed on
`(ma)- Subject (bmwas brought backfor a
`retest on
`(I’m), our days out ofthe protocol window, and the labs were reviewed on
`0M). Subject @ was brought backfor a retest on
`(mo, 34 days out of
`(me)
`the protocol window, and the labs were reviewed on
`a”). 0nly one subject
`was significantly out ofwindow. Dr. Altamirano was able to produce copies oftext
`messagesfrom staflto subjects requesting that they call/follow-up with the site.
`4. Failure to print, review, and maintain safety labs for three out of 28 randomized
`sub'ects.
`05!]Reviewer Comment: Subject M0 had missing hematologvpanel, chemistrypanel,
`and FPG safety labsfor Visit 4 and missing safety retest labsfor the unscheduled visit
`conducted on
`(me) Subject ”(shad missing FPG labsfor Visit 3. Subject m6) had
`missing all safety labsfor Visit 4. Dr. Altamirano was able to contact the
`(m4)
`and request reprints ofthe missing laboratory testing. There were no significant
`abnormalities.
`
`Although regulatory violations were noted as described above, they are unlikely to significantly
`impact primary safety and efficacy analyses. Data from this site appear acceptable.
`
`2. Patrick Dennis] Site 7826
`
`There were 40 subjects pre-screened,l6 subjects enrolled into the study and 12 subjects
`randomized; six subjects completed the study (six withdrew consent, two were withdrawn
`for prohibited medications, one was lost to follow-up, and one died, which was not related
`to test article). There were 40 subject records reviewed.
`
`Dr. Dennis has been conducting clinical studies as a clinical investigator since September
`of 2015. All the subject screenings and subject visits were conducted at Dr. Dennis’s
`practice.
`
`The IRB of record was
`
`(m4)
`
`The source records were well organized and complete. Source records were compared to
`the sponsor data line listings and there were no discrepancies. There was no under-
`reporting of adverse events. The primary eflicacy endpoint was verifiable.
`
`The inspection revealed adequate adherence to the regulations and the investigational plan.
`There were no objectionable conditions noted and no Form FDA-483, Inspectional
`Observations, issued.
`
`3. Gerardo Bueso/ Site 7822
`
`There were 28 subjects screened and 21 subjects enrolled into the study; 15 subjects
`
`Reference ID: 4412619
`
`

`

` Clinical Inspection Summary
`
` NDA 209091/ s002 and NDA 210874
`
`completed the study. There were 21 subject records reviewed.
`
`Dr. Bueso has been conducting clinical research since 2003.
`
`The IRB of record was
`
`The records were organized and available. The source records were compared to the
`sponsor data line listings. There were no discrepancies. There was no under-reporting of
`adverse events. The primary efficacy endpoint was verifiable.
`
`The inspection revealed adequate adherence to the regulations and the investigational plan.
`There were no objectionable conditions noted and no Form FDA-483, Inspectional
`Observations, issued.
`
`{See appended electronic signature page}
`
`Cynthia F. Kleppinger, M.D.
`Good Clinical Practice Assessment Branch
`Division of Clinical Compliance Evaluation
`Office of Scientific Investigations
`
`CONCURRENCE:
`
`{See appended electronic signature page}
`
`Kassa Ayalew, M.D., M.P.H
`Branch Chief
`Good Clinical Practice Assessment Branch
`Division of Clinical Compliance Evaluation
`Office of Scientific Investigations
`
`cc:
`
`Central Doc. Rm./ NDA 209091 and NDA 210874
`DMEP/Division Director/ Lisa Yanoff
`DMEP /Deputy Director/William Chong
`DMEP/Team Lead/ Patrick Archdeacon
`DMEP/Clinical Reviewer/ Frank Pucino
`DMEP /Regulatory Project Manager/Rich Whitehead
`OSI/DCCE/Division Director/Ni Aye Khin
`OSI/DCCE/GCPAB/Branch Chief/Kassa Ayalew
`OSI/DCCE/GCPAB/Acting Team Leader/Min Lu
`OSI/DCCE/GCPAB Reviewer/Cynthia Kleppinger
`OSI/DCCE/GCPAB/Program Analyst/Yolanda Patague
`OSI/DCCE/Database Project Manager/Dana Walters
`
`Reference ID: 4412619
`
`8
`
`(b) (4)
`
`

`

`Signature Page 1 of 1
`--------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically. Following this are manifestations of any and all
`electronic signatures for this electronic record.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
`
`CYNTHIA F KLEPPINGER
`04/01/2019 02:33:11 PM
`
`KASSA AYALEW
`04/01/2019 05:03:50 PM
`
`Reference ID: 4412619
`
`

`

`M E M O R A N D U M
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`DATE:
`
`March 29, 2019
`
`TO:
`
`Lisa Yanoff, M.D.
`Director (Acting)
`Division of Metabolism and Endocrinology Products
`(DMEP)
`
`Office of Drug Evaluation II
`Office of New Drugs
`
`Norman Stockbridge, M.D.
`Director
`
`Division of Cardiovascular and Renal Products (DCRP)
`Office of Drug Evaluation I
`Office of New Drugs
`
`FROM:
`
`Srinivas R. Chennamaneni, Ph.D.
`Staff Fellow
`
`Division of New Drug Bioequivalence Evaluation (DNDBE)
`Office of Study Integrity and Surveillance (OSIS)
`
`THROUGH: Charles R. Bonapace, Pharm.D.
`Director
`
`Division of New Drug Bioequivalence Evaluation (DNDBE)
`Office of Study Integrity and Surveillance (OSIS)
`(It) (4)
`
`SUBJECT: Surveillance inspection
`
`mm
`
`1. Inspection Summary
`
`OSIS inspected the analytical portion of studies D168AC00001
`(NDA 210874, Qternment XR — Saxagliptin, Dapagliflozin &
`Metformin),
`mm conducted at
`
`”W
`ow
`
`I did not observe objectionable conditions and did not issue
`Form FDA 483 at the inspection close—out. The final inspection
`classification is No Action Indicated (NAI).
`
`1.1. Recommendation
`
`mmmmwnxmnwu
`
`

`

`Page 2 – Surveillance inspection
`
`
`
`
`
`
`
`
`
`Based on my review of the inspectional findings, I conclude the
`data from the audited studies are reliable.
`
`
`2. Inspected Studies
`
`Study D168AC00001 (NDA 210874)
`“A Randomized, 3-period, 3-treatment, Single-dose, Open-label,
`Single-center, Crossover Study to Assess the Fed-state
`Bioequivalence of a Triple Fixed-combination Drug Product of 2.5
`mg Saxagliptin/5 mg Dapagliflozin/1000 mg Metformin XR and 5 mg
`Saxagliptin/10 mg Dapagliflozin/1000 mg Metformin XR Relative to
`Individual Components (ONGLYZA® and XIGDUO® XR) Co-administered
`to Healthy Subjects”
`
`Sample Analysis Period: 6/29/2017 – 9/19/2017
`
`
`
`2.1. Studies not yet associated with an application
`
`Reference ID: 4411841
`
`
`
`V. 2.3 Last Revised Date 1-9-2019
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Page 3 – Surveillance inspection
`
`
`
`
`
`
`
`
`
`3. Scope of Inspection
`OSIS scientist Srinivas R. Chennamaneni, Ph.D. audited the
`bioanalytical portion of the above studies at
`
`
`
`
`
`
`
`
`
` was conducted in
`The previous FDA inspection of
` and classified as NAI. At the conclusion of the inspection,
`no deficiencies were observed, and no Form FDA 483 was issued.
`
`The current inspection included a thorough examination of study
`records, facilities, laboratory equipment, method validation,
`and sample analysis, and interviews with the firm’s management
`and staff. In addition, Standard Operating Procedures (SOPs),
`employee training records, laboratory notebooks, audit trails.
`
`To assess the firm’s current bioanalytical operations, I
`examined method validation and study sample analysis of ongoing
`study
`
`
`
`
`4. Inspectional Findings
`
`At the conclusion of the inspection, I did not observe
`objectionable conditions and I did not issue Form FDA 483 to
`
`
`
`Study D168AC00001:
`
`Study sample analysis for triple fixed-combination drug product
`of saxagliptin, dapagliflozin (DAPA), and metformin was
`conducted
`
`
`
`
`5. Conclusion
`
`After review of the inspectional findings, I conclude that data
`from the audited studies are reliable. In addition, data from
`studies not audited but submitted to pending applications
`(Attachment 1) are reliable for Agency review.
`
`
`
`
`V. 2.3 Last Revised Date 1-9-2019
`
`Reference ID: 4411841
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Page 4 – Surveillance inspection
`
`
`
`
`
`
`
`
`
`Studies using similar methods conducted between the previous
`inspection
` and the end of the current surveillance
`interval should be considered reliable without an