CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`209091Orig1s000
`
`ADMINISTRATIVE and CORRESPONDENCE
`DOCUMENTS
`
`
`
`
`

`

`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
`
`
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`
`
`AstraZeneca
`Attention: Barbara J. Blandin
`Director, Regulatory Affairs
`1800 Concord Pike
`P O Box 8355
`Wilmington, DE 19803-8355
`
`
`Dear Ms. Blandin:
`
`
`Please refer to your Pre-Investigational New Drug Application (PIND) file for saxagliptin and
`dapagliflozin tablets.
`
`We also refer to the meeting between representatives of your firm and the FDA on
`June 23, 2014. The purpose of the meeting was to discuss the format and content of your
`planned NDA.
`
` A
`
` copy of the official minutes of the meeting is enclosed for your information. Please notify us
`of any significant differences in understanding regarding the meeting outcomes.
`
`If you have any questions, call Abolade (Bola) Adeolu, Regulatory Project Manager at
`(301) 796-4264.
`
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Jean-Marc Guettier, MD
`Director
`Division of Metabolism & Endocrinology Products
`Office of Drug Evaluation II
`Center for Drug Evaluation and Research
`
`
`
`Enclosure:
` Meeting Minutes
`
`Reference ID: 3597864
`
`
`
`

`

`
`
`
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`
`
`
`
`MEMORANDUM OF MEETING MINUTES
`
`
`Type B
`Pre-NDA
`
`Meeting Type:
`Meeting Category:
`
`Meeting Date and Time:
`Meeting Location:
`
`
`June 23, 2014, from 12:00 to 1:30 PM
`10903 New Hampshire Avenue
`White Oak Building 22; Conference Room # 1311
`Silver Spring, MD 20903
`
`Jean-Marc Guettier, MD
`Abolade (Bola) Adeolu, RPh, MS, MBA
`
`
`Application Number:
`IND 118840
`Product Name:
`saxagliptin and dapagliflozin tablets
`Indication:
`Treatment of adults with Type 2 Diabetes Mellitus (T2DM)
`Sponsor/Applicant Name: AstraZeneca AB
`
`Meeting Chair:
`Meeting Recorder:
`
`FDA ATTENDEES
`Jean-Marc Guettier, MD – Director, DMEP
`William Chong, MD – Clinical Team Lead (Acting)/Clinical Reviewer
`Fred Alavi, PhD - Nonclinical Reviewer
`Vikram Sinha, PhD – Director, Division of Pharmacometrics, Office of Clinical Pharmacology
`Nitin Mehrotra, PhD – Team Lead, Division of Pharmacometrics
`Lokesh Jain, PhD - Clinical Pharmacology Team Lead
`Johnny Lau, PhD - Clinical Pharmacology Reviewer
`Brad McEvoy, PhD- Statistical Reviewer, Division of Biometrics II (DBII)
`Anna Kettermann, PhD - Statistical Reviewer, DBII
`Assadollah Noory, PhD- Biopharmaceutics Reviewer
`Cynthia Kleppinger, MD- Senior Medical Officer, Office of Scientific Investigations
`Rosemary Addy, MS – Supervisory Consumer Safety Officer, Pediatric and Maternal Health
` Staff (PMHS)
`Cynthia Kleppinger, MD- Senior Medical Officer,
`Carolyn Yancey, MD- Medical Officer, Division of Risk Management, Office of Surveillance
` and Epidemiology (OSE)
`Julie Marchick, MPH- Chief, Project Management Staff
`Abolade (Bola) Adeolu, RPh, MS, MBA
`
`EASTERN RESEARCH GROUP ATTENDEES
`So Hyun Kim- Independent Assessor
`
`
`
`
`
`Reference ID: 3597864
`
`

`

`IND 118840
`Page 2
`
`SPONSOR ATTENDEES
`AstraZeneca
`
`Elisabeth Björk, MD, PhD, VP, Head of CVMD, Global Medicines Development (via telecom)
`Barbara Blandin, Regulatory Affairs Director
`Sandy Fitt, Director, Clinical Delivery
`Boaz Hirshberg, MD, Executive Director, Clinical Research
`Ian Hunt, VP, Global Regulatory Affairs, CV/GI TA
`John Monyak, Principal Statistician
`Artist Parker, MD, Senior Safety Medical Director
`Briggs Morrison, EVP Global Medicines Development & Chief Medical Officer
`Gerard O’Malley, Global Product VP
`Artist Parker, MD, Senior Safety Medical Director
`Frank Senk , Programming Team Leader
`Donald Stanski, Global Head Quantitative Clinical Pharmacology
` Statistical Consultant to AstraZeneca
`
`
`Bristol-Myers Squibb
`Anne Marie Apanovitch, Ph.D, Associate Director, Global Biometric Sciences
`David W. Boulton, PhD, Group Director, Clinical Pharmacology & Pharmacometrics
`Nayyar Iqbal, MD, Executive Director, Global Clinical Research
`Sekayi Mushonga, Pharm.D, Director, Global Regulatory Sciences
`
`1.0
`
`BACKGROUND
`
` A
`
`DISCUSSION
`
` type B meeting request for saxagliptin and dapagliflozin tablets was submitted on
`April 25, 2014. A teleconference meeting was initially granted and then changed to a face-to-
`face meeting scheduled for June 23, 2014. AstraZeneca AB is requesting feedback on the format
`and content of their planned NDA application.
`
`
`2.0
`
` Your questions are repeated below followed by our initial responses in bold regular font, then
`the meeting discussion in italics. Post meeting comments are in underlined regular font
`Nonclinical Questions
`Question 1
`The nonclinical profiles of saxagliptin and dapagliflozin have been previously established in a
`comprehensive development program
`that
`included studies of
`in vitro and
`in vivo
`pharmacodynamics (PD), including core safety pharmacology, pharmacokinetics (PK) and
`metabolism, and toxicity and toxicokinetics (saxagliptin, NDA 22-350 and dapagliflozin, NDA
`202-293). In support of the saxagliptin/dapagliflozin FDC product (BMS-986098), an additional
`3-month repeated-dose oral combination toxicity study with saxagliptin and dapagliflozin was
`conducted in rats, and will be included in the NDA. In addition, Modules 2.4, 2.6 and 2.7 will be
`
`
`
`Reference ID: 3597864
`
`(b) (4)
`
`

`

`IND 118840
`
`Page 2
`
`submitted in the NDA. No additional nonclinical studies are ongoing or planned to support the
`
`saxagliptin/dapagliflozin NDA.
`
`Does the Agency agree that the combination toxicology study is sufficient to support the filing
`
`andpotential approval of the saxagliptin/dapagliflozin FDC NDA?
`
`FDA Response:
`
`We agree that the 3-month combination toxicology study is sufficient to support the filing
`
`and review of the nonclinical components of the NDA.
`
`Meeting Discussion: There was no discussion on this question at the meeting.
`
`BiopharmaceuticsICIinical Pharmacology Questions
`
`Question 2
`
`An ongoing bioequivalence (BE) study (CV181341) comparing the EMS—986098 FDC 0”“)
`5-mg/10-mg EMS-986098 FDC tablets with the respective strengths of saxagliptin
`and dapagliflozin concomitantly administered in fasted healthy adults will be completed and
`submitted as part of the NDA.
`In the Agency’s written response to the Sponsor’s pre-IND
`Meeting request (correspondence dated 5-Aug—2013), the Agency had agreed to the Sponsor’s
`proposal
`(5)“)
`The NDA
`
`application will include the biowaiver request and the complete information supporting the BE
`waiver request.
`In addition, supportive of the coadministration of saxagliptin and dapagliflozin
`in a fixed-dose form is a completed drug-drug interaction study (CV181191) to assess the efl'ect
`of either agent on the PK of the other agent.
`
`Does the Agency agree that the Clinical Pharmacology DDI study and the Biopharmaceutics
`
`the filing and potential
`support
`to
`BE study are sufficient
`saxagliptin/dapagliflozin FDC NDA (See Section 7.1)?
`
`approval of the
`
`FDA Response:
`
`You proposed to study the bioequivalence of the
`
`(m4)
`
`strength
`
`(5 mg saxagliptin/10 mg dapagliflozin fixed dose combination tablet versus 5 mg
`saxagliptin individually coadministered with 10 mg dapagliflozin under fasting condition)
`as well as the high-fat—meal—effect studies for
`(m4)
`5 mg saxagliptin/10 mg dapagliflozin fixed dose
`combination tablet. Your proposed program appears sufficient to support the
`Biopharmaceutics aspect of a New Drug Application (NDA) for
`
`(b) (4)
`
`dapagliflozin) fixed dose combination tablets. See the “Biowaiver” response below for the
`
`remaining strengths of the saxagliptin/dapagliflozin fixed dose combination tablets.
`
`5 mg saxagliptin/l0 mg
`
`Reference ID: 3597864
`
`

`

`IND 118840
`
`Page 3
`
`Since the efficacy and safety studies supporting the use of the saxagliptin/dapagliflozin
`fixed dose combination tablets are being conducted as add-on to other existing therapy
`such as metformin, in your NDA submission you need to address the potential mutual
`
`interactions among the existing therapy, saxagliptin, and dapagliflozin.
`
`Sponsor Response to Preliminarv Comments:
`On June 20, 2014, the sponsor sent thefollowing response by email, regarding the statement,
`“Since the efficacy and safety studies supporting the use ofthe saxagliptin/dapagliflozinfixed
`dose combination tablets are being conducted as add-on to other existing therapy such as
`mejormin, in your NDA submission you need to address the potential mutual interactions among
`the existing therapy, saxagliptin, and dapagliflozin
`
`In the Summary of Clinical Pharmacology to be included in the saxaglmtin/dapagliflozin
`FDC NDA submission, AZ willplan to provide a summary ofresultsfrom in vitro and in
`vivo studies conducted with each component ofthe saxagliptin/dapagliflozin FDC to
`assess the potentialfor drug-drug interactions with other anti-diabetics. Does FDA agree
`that this will satisfiI their requestfor an assessment ofpotential mutual interactions
`amongst the existing therapy, saxagliptin and dapagliflozin?
`
`FDA ’s Response Dated June .20l 2014:
`The sponsor needs to consider resultsfrom the available drug-drug interaction studies and
`providejustification supporting no significant nmtual interactions amongst the existing therapy,
`saxagliptin and dapagliflozin. The proposed data is suflicient to address this question.
`
`Meeting Discussion: There was no discussion on this question at the meeting.
`
`Biowaiver:
`Based on the demonstration of BE of the
`
`(m4)
`
`strength
`
`(5 mg saxagliptin/10 mg dapagliflozin fixed dose combination tablet versus 5 mg
`saxagliptin individually coadministered with 10 mg dapagliflozin under fastiggncondifion),
`
`When requesting for biowaivers, you need to provide formulation
`
`composition for all the strengths of your FDC products along with dissolution profiles
`comparison and fZ-values using 12 units of each dosage strength and using the final
`dissolution method.
`
`(5)“)
`
`Of note, biowaiver will be granted only during
`
`NDA review.
`
`Reference ID: 3597864
`
`

`

`IND 118840
`Page 4
`
`We assume that at this point, your dissolution method is under development. We request
`that you develop a dissolution method for both analytes of your drug product, and submit
`the following dissolution information:
`
`
`1. Dissolution Test: Include the dissolution method report supporting the selection of
`the proposed dissolution test. The dissolution report should include the following
`information:
`
`a. Solubility data for the drug substance covering the pH range;
`
`
`
`b. Detailed description of the dissolution test being proposed for the evaluation of
`your product and the developmental parameters (i.e., selection of the
`equipment/apparatus, in vitro dissolution/release media, agitation/rotation speed,
`pH, assay, sink conditions, etc.) used to select the proposed dissolution method as
`the optimal test for your product. If a surfactant was used, include the data
`supporting the selection of the type and amount of surfactant. The testing
`conditions used for each test should be clearly specified. The dissolution profile
`should be complete and cover at least % of drug release of the label amount
`or whenever a plateau (i.e., no increase over 3 consecutive time-points) is
`reached. We recommend use of at least twelve samples per testing variable;
`c. Provide the complete dissolution profile data (individual, mean, SD, profiles) for
`your product. The dissolution data should be reported as the cumulative
`percentage of drug dissolved with time (the percentage is based on the product’s
`label claim);
`d. Data to support the discriminating ability of the selected dissolution method. In
`general, the testing conducted to demonstrate the discriminating ability of the
`selected dissolution method should compare the dissolution profiles of the
`reference (target) product and the test products that are intentionally
`manufactured with meaningful variations for the most relevant critical
`manufacturing variables (i.e., ±
`% change to the specification-ranges of
`these variables);
`e. Supportive validation data for the dissolution method (i.e., method robustness,
`etc.) and analytical method (precision, accuracy, linearity, stability, etc.).
`
`
`2. Dissolution Acceptance Criterion: For the selection of the dissolution acceptance
`criterion of your product, the following points should be considered:
`
`a. The dissolution profile data from the pivotal clinical batches and primary
`(registration) stability batches should be used for the setting of the dissolution
`acceptance criterion of your product (i.e., specification-sampling time point and
`specification value).
`b. The in vitro dissolution profile should encompass the timeframe over which at
`least % of the drug is dissolved or where the plateau of drug dissolved is
`reached, if incomplete dissolution is occurring.
`c. For immediate release product the selection of the specification time point
`should be where Q= % dissolution occurs.
`
`
`
`Reference ID: 3597864
`
`(b)
`(4)
`
`(b) (4)
`
`(b)
`(4)
`
`(b) (4)
`
`

`

`IND 118840
`
`Page 5
`
`Note that the final determination on the acceptability of the dissolution method is a review
`issue that can be determined during the IND or NDA. However, the acceptability of the
`proposed dissolution criterion for your product will be made during the NDA review
`
`process based on the totality of the provided dissolution data.
`
`Meeting Discussion: There was no discussion on this question at the meeting.
`
`Clinical Program Questions
`
`Question 3
`
`There are three Phase 3 clinical studies (CV181169, CV181168, and MB102129) being
`conducted under the saxagliptin or dapagliflozin INDs to evaluate the safety and efficacy of the
`saxagliptin and dapagliflozin combination in subjects with T2DM. Based on Agency feedback
`relative to the review of the study synopsis (Agency correspondence received on 10-Apr-2012),
`Study CV181169 (24 weeks, N = 534), which utilizes a dual add-on to metfomlin XR strategy
`with saxagliptin + dapagliflozin, is intended to provide the substantial evidence to support the
`review and approval of the NDA for the saxagliptin and dapagliflozin FDC product. The other
`two studies (24 weeks plus long-term (LT) extension to 52 weeks) are being conducted as
`sequential add—on studies for both saxagliptin (in dapagliflozin/metfonnin immediate release (IR)
`failures [CV181168, planned N = 280]) and for dapagliflozin (in saxagliptin/metformin
`Wextended release OR) failures [MB]02129, planned N = 280]). The sequential add—on
`studies are intended to support the safety evaluation of the saxagliptin/dapagliflozin FDC product
`(hm)
`
`Does the Agency agree
`
`FDA Response:
`
`We do not agree
`
`(m4)
`
`(m4)
`
`Efficacy data from all studies submitted as part of the
`initial NDA submission should be included.
`"’""
`
`Based on your
`
`Reference ID: 3597864
`
`

`

`IND 118840
`
`Page 6
`
`subsequent questions, you appear to be aware that this may be an issue. Our concerns with
`
`regard to this will be addressed under the appropriate questions.
`
`Meeting Discussion:
`
`AstraZeneca requested clarification on the reasoning for requestng 52 week exposures now
`compared to the advice received in 2012 which stated 24 weeks exposure would be adequate.
`The FDA stated that our previous experience withfixed dose combinations have typically been in
`combination with metformin. Since combination with meyormin is usually studied extensively in
`the development program of the individual component,
`there is generally suflicient safety
`information to evaluate. With the proposed combination product,
`the experience is limited
`making safety of the combination a concern.
`(mm
`
`The FDA stated that further review of
`this study with internal discussion would be needed to assess whether this study provides
`suflicient data to satisflz the safety concerns and to allow for evaluation of eflicacy only to
`support thefixed dose combination.
`
`Post-meeting Comments:
`
`We have reviewed the clinical study smopsis provided for study D1690C00010. We note that
`
`with regard to safet_v_1
`
`the swopsis focuses primarily on adverse events of concern with
`
`dapagliflozin. We were unable to identifl any discussion on the impact of combining these two
`(1111
`roducts on the adverse events of concern for DPP-4 inhibitors i.e. sita
`' tin . Without
`
`this information, we cannot agee to rely on this study to support the safeg profile of combining
`
`an SGLTZ inhibitor with a DPP-4 inhibitor
`i.e. the
`to osed combination of saxa i tin and
`
`dapagliflozin 1.
`
`Question 4
`Does the Agency agree
`
`‘\‘J
`
`FDA Response:
`
`See our response above.
`
`09(4)
`
`4
`0””
`
`Meeting Discussion: There was no discussion on this question at the meeting.
`
`uestion 5
`Does the Agency agree
`
`mm
`
`Reference ID: 3597864
`
`

`

`IND 118840
`
`Page 7
`
`FDA Response:
`
`We will expect there to be data covering 52 weeks of exposure to support the safety of the
`FDC. As you will likely need to submit data from multiple studies to provide this exposure,
`we will expect an integrated summary of safety and an integrated summary of efficacy.
`
`Meeting Discussion: There was no discussion on this question at the meeting.
`
`Question 6
`
`Study CV181169 included a lO-mg dose of dapagliflozin. According to the approved US
`Prescribing Information (USPI) for Farxiga (dapagliflozin) tablets, the recommended starting
`dose of dapagliflozin is 5-mg once daily (QD), which can be increased to lO—mg QB in patients
`tolerating dapagliflozin 5-mg QD who require additional glycemic control.
`It is file Sponsor’s
`position that because CV181169 confirmed the safe
`of the use of saxa- 'tin S-m and
`
`dawa lfozm 10 m in combination,
`
`
`
`
`
`
`
`FDA Response:
`
`
`
`
`Reference ID: 3597864
`
`

`

`IND 118840
`Page 8
`
`Meeting Discussion:
`
`Question 7
`Does the Agency agree that summaries in Module 2 (to include Biopharmaceutics, Clinical
`Pharmacology, Efficacy, Safety, and a Clinical Overview), as well as a
`
`report in Module 5.3.5.3 will be sufficient for filing of the saxagliptin/dapagliflozin FDC
`NDA?
`FDA Response:
`See our responses above. We are uncertain whether your proposal for the contents of the
`initial NDA submission are adequate to demonstrate safety and efficacy. A decision on
`whether the application is sufficient for filing would be made at the time of filing and
`would involve many review disciplines.
`
`Meeting Discussion: There was no discussion on this question at the meeting.
`
`
`
`Reference ID: 3597864
`
`(b) (4)
`
`(b) (4)
`
`

`

`IND 1 18840
`
`Page 9
`
`4-Month Safety Update (4MSU) Questions
`
`Question 8
`
`In the 4MSU,
`
`(m4) safety data
`
`will be included.
`
`(no)
`"’W
`
`The Sponsor proposes to submit completed clinical study reports and data
`
`(m4)
`
`Does the Agency agree with the proposal to provide
`
`(5) (4)
`
`the safety data
`
`(b)
`(4)
`
`in the 4MSU, along with
`
`updated Modules 2. 7.4 and 2.5?
`
`FDA Response:
`
`We do not agree. See our responses above. We expect that the information from study
`CV181168 and/or study MB102129 will be submitted in the initial NBA and integrated
`with the data from CV181169 at the time of NDA submission. This should include the
`
`completed data from CV181168 and/or M310219 which will provide information
`
`onexposure to 52 weeks.
`If both of the studies are not included in the initial NDA
`submission, the integrated safety data will need to include the available long-term data
`from the study that was not included. Updating the Summary of Clinical Safety and the
`
`Clinical Overview is acceptable. If one of the sequential add-on studies is not included in
`the initial submission, all of the updated safety information should be included
`(m4)
`
`Meeting Discussion: There was no discussion on this question at the meeting.
`
`Question 9
`
`Does the Agency agree with the proposal
`
`(we)
`
`?
`
`FDA Response:
`
`We do not agree. See our responses above. Data from study CV181168 and/or study
`MB102129 should be submitted with your initial NBA, and should be complete. The 24
`week data from CV181169
`(m4) and safety
`data for 52 weeks of exposure will need to be submitted.
`If you do not submit both
`
`CV181168 and MB102129 with the initial NDA submission, any additional safety
`
`Reference ID: 3597864
`
`

`

`IND 118840
`Page 10
`
`information submitted in the 4 month safety update should be complete and integrated
`with the initially submitted data to allow for easy comparison of the initial safety data to
`the updated safety data (separate and integrated with the initial).
`
`Meeting Discussion: There was no discussion on this question at the meeting.
`
`Pediatric Plan Question
`Question 10
`The Sponsor has requested a deferral of the requirement to submit pediatric assessment of the
`saxagliptin/dapagliflozin FDC at the time of the NDA submission. On 16-Apr-2014, an initial
`pediatric study plan (PSP) was submitted to IND 118840 for the saxagliptin/dapagliflozin FDC
`product (Sequence No. 0013).
`
`
`The Sponsor is currently targeting submission of the saxagliptin/dapagliflozin FDC NDA
` Since the initial PSP was submitted on 16-Apr-2014, this allows for at least
`210 calendar days (per the PSP guidance) to obtain confirmation of Agency agreement with the
`initial PSP by the time the NDA is submitted.
`
`In the event the Agency has not confirmed agreement with the initial PSP by the time the NDA
`is submitted, is there a mechanism for allowing the PSP review to continue in parallel to the
`submission and review of the saxagliptin/dapagliflozin FDC NDA?
`
`FDA Response:
`We plan to provide written comments to you on your iPSP no later than 90 calendar days
`from the date of receipt of the iPSP, i.e, no later than 90 calendar days from April 16, 2014.
`You will then have 90 calendar days to submit an Agreed iPSP to the IND. It is incumbent
`upon you during this 90-day period to make every effort to develop an Agreed iPSP to
`which FDA will agree. We therefore strongly encourage you to communicate frequently
`with the review division during this time.
`
`Once you submit an Agreed iPSP, we plan to take no longer than 30 calendar days to
`provide written comments to you indicating whether we agree with AstraZeneca’s
`Agreed iPSP.
`
`If we have not confirmed agreement with your Agreed iPSP by the time you submit an
`NDA for the saxagliptin/dapagliflozin FDC proposed product, we will determine whether
`or not to continue the iPSP review process, depending upon the reasons that agreement
`was not reached. However, we could decide to refuse to file the NDA, again depending
`upon the facts and circumstances for non-agreement.
`
`We refer you to the draft guidance entitled “Guidance for Industry, Pediatric
`Study Plans: Content of and Process for Submitting Initial Pediatric Study Plans and
`Amended Pediatric Study Plans,” published July 2013.
`
`
`
`
`Reference ID: 3597864
`
`(b)
`(4)
`
`

`

`IND 118840
`Page 11
`
`Meeting Discussion: There was no discussion on this question at the meeting.
`
`Electronic Submission of the Common Technical Document Question
`Question 11
`The Sponsor plans to submit this NDA in eCTD format. This application will be submitted
`following the eCTD structure specified in ICH M2 EWG, Electronic Common Technical
`Document Specification v.3.2.2 dated July 2008, and utilizing the recommendations in the FDA
`Guidance for Industry entitled Providing Regulatory Submissions in Electronic Format - Human
`Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications
`dated June 2008 and FDA Implementation of Study Tagging File v.2.6.1 dated June 2008.
`
`Is the proposed format and content of the saxagliptin/dapagliflozin FDC NDA as described
`above acceptable to the Agency?
`
`FDA Response:
`The proposed electronic format is acceptable to the Agency as eCTD is our preferred
`format for electronic submissions.
`
`You should reference the updated draft FDA Guidance for Industry entitled Providing
`Regulatory Submissions
`in Electronic Format - Human Pharmaceutical Product
`Applications and Related Submissions Using the eCTD Specifications dated January 2013
`for our latest recommendations on eCTD issues.
`
`Meeting Discussion: There was no discussion on this question at the meeting.
`
`Case Report Forms Question
`QUESTION 12
`Case report forms (CRFs) will be submitted electronically in PDF format as specified in the
`guidance. CRFs for all deaths, serious adverse events (SAEs), and discontinuations due to AEs
`occurring within 30 days of the last dose of study medication will be provided for the new
`clinical studies included with this NDA.
`
`Does the Agency agree with the proposed plans for inclusion of CRFs in the NDA?
`
`FDA Response:
`We agree with the proposed CRFs to be included in the NDA. If additional safety concerns
`arise during the review, we may request additional CRFs.
`
`Meeting Discussion: There was no discussion on this question at the meeting.
`
`
`
`
`Reference ID: 3597864
`
`

`

`IND 118840
`
`Page 12
`
`Datasets Question
`
`Question 13
`
`In the initial NDA, clinical study reports and related datasets will be submitted for the Phase 1
`bioequivalence study (CV181341),
`the clinical pharmacology drug-drug interaction study
`(CV181191), and the dual add—on safety and efficacy study (CV181169). Also, in the initial
`NDA, collected data and derived analysis data will be provided
`(m4)
`
`In the 4MSU,
`
`(no) will be submitted
`
`(hm)
`
`For
`
`M“)
`
`the 4MSU, the Sponsor plans
`
`(hm)
`
`Does the Agency agree with the proposed plans for inclusion of datasets in the NBA and the
`4MSU?
`
`FDA Response:
`We do not agree with the proposed plan. As discussed above, we will expect data from at
`least 52 weeks of exposure to the combination of saxagliptin plus dapagliflozin to support
`
`safety for the FDC product. We expect that the initial NDA will include data from the
`
`completed CV181169, and from CV181168 and/or MB102129. Datasets for all of the
`studies included in the initial NDA submission should be submitted. For the 4 month safety
`update, all additional safety data should be presented and integrated,
`(m4)
`
`For the analysis datasets, we have the following general comments:
`
`0 Each analysis dataset should include the treatment assignments, baseline
`
`assessments, and key demographic variables. The analysis datasets should include
`all variables needed for conducting all primary, secondary, and sensitivity analyses
`
`included in the study report. For endpoints that include imputations, both observed
`
`and imputed variables should be included and clearly identified.
`0 The analysis dataset documentation (Define.pdf) should include sufficient detail,
`such as definitions or descriptions of each variable in the dataset, algorithms for
`derived variables (including source variable used), and descriptions for the code
`used in factor variables.
`
`0 The SAS programs that are used to create the derived datasets for the efficacy
`endpoints and the SAS programs that are used for efficacy data analysis should be
`included in the NDA submission.
`
`Reference ID: 3597864
`
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`
`• Please provide the location of the SAS dataset, the names of the variables used and
`the programs used to get every new value that will be appearing in the label.
`In addition to the electronic datasets, you should submit study protocols including
`the statistical analysis plan, all protocol amendments (with dates), generated
`treatment assignment lists, and the actual treatment allocations (along with the date
`of enrollment).
`
`
`The Office of Scientific Investigations (OSI) requests that the following items be provided
`to facilitate development of clinical investigator and sponsor/monitor/contract research
`organization (CRO) inspection assignments, and the background packages that are sent
`with those assignments to the FDA field investigators who conduct those inspections (Items
`I and II). This information is requested for all major trials used to support safety and
`efficacy in the application (i.e., phase 2/3 pivotal trials). Please note that if the requested
`items are provided elsewhere in the submission in the format described, the Applicant can
`identify the location(s) and/or provide link(s) to the requested information.
`
`The dataset that is requested in Item III below is for use in a clinical site selection model
`that is being piloted in CDER. Electronic submission of the site level dataset is voluntary
`and is intended to facilitate the timely selection of appropriate clinical sites for FDA
`inspection as part of the application and/or supplement review process.
`
`This request also provides instructions for where OSI requested items should be placed
`within an eCTD submission (Technical Instructions: Submitting Bioresearch Monitoring
`[BIMO] Clinical Data in eCTD Format).
`
`I. Request for general study related information and comprehensive clinical investigator
`information (if items are provided elsewhere in the submission, describe the location or
`provide a link to the requested information).
`
`
`
`1. Please include the following information in a tabular format in the original
`NDA/BLA for each of the completed pivotal clinical trials:
`a. Site number
`b. Principal Investigator
`c. Site Location: Address (e.g. Street, City, State, Country) and contact
`information (i.e., phone, fax, email)
`d. Location of Principal Investigator: Address (e.g. Street, City, State, and
`Country) and contact information (i.e., phone, fax, email). If the Applicant is
`aware of changes to a clinical investigator’s site address or contact information
`since the time of the clinical investigator’s participation in the study, we request
`that this updated information also be provided.
`
`
`2. Please include the following information in a tabular format, by site, in the original
`NDA/BLA for each of the completed pivotal clinical trials:
`
`a. Number of subjects screened at each site
`b. Number of subjects randomized at each site
`
`
`
`Reference ID: 3597864
`
`

`

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`c. Number of subjects treated who prematurely discontinued at each site
`
`
`3. Please include the following information in a tabular format in the NDA/BLA for
`each of the completed pivotal clinical trials:
`
`a. Location at which sponsor trial documentation is maintained (e.g., monitoring
`plans and reports, training records, data management plans, drug accountability
`records, IND safety reports, or other sponsor records as described in ICH E6,
`Section 8). This is the actual physical site(s) where documents are maintained
`and would be available for inspection
`b. Name, address and contact information of all contract research organizations
`(CROs) used in the conduct of the clinical trials and brief statement of trial
`related functions transferred to them. If this information has been submitted in
`eCTD format previously (e.g., as an addendum to a Form FDA 1571) you may
`identify the location(s) and/or provide link(s) to information previously
`provided.
`c. The location at which trial documentation and records generated by the CROs
`with respect to their roles and responsibilities in conduct of respective studies is
`maintained. As above, this is the actual physical site where documents would be
`available for inspection.
`
`
`4. For each pivotal trial, provide a sample annotated case report form (or identify the
`location and/or provide a link if provided elsewhere in the submission).
`
`5. For each pivotal trial, provide the original protocol and all amendments (or identify
`the location and/or provide a link if provided elsewhere in the submission).
`
`
`II. Request for Subject Level Data Listings by Site
`
`1. For each pivotal trial: Site-specific individual subject data listings (hereafter
`referred to as “line listings”). For each site, provide:
`a. Listing for each subject consented/enrolled; for subjects who were not
`randomized to treatment and/or treated with study therapy, include reason not
`randomized and/or treated
`b. Subject listing for treatment assignment (randomization)
`c. Listing of subjects that discontinued from study treatment and subjects that
`discontinued from the study completely (i.e., withdrew consent) with date and
`reason discontinued
`d. Listing of per-protocol subjects/ non per-protocol subjects and reason not per-
`protocol
`e. By subject, listing of eligibility determination (i.e., inclusion and exclusion
`criteria)
`f. By subject, listing of AEs, SAEs, deaths and dates
`g. By subject, listing of protocol violations and/or deviations reported in the
`NDA/BLA, including a description of the deviation/violation
`
`
`
`Reference ID: 3597864
`
`

`

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`
`h. By subject, listing of the primary and secondary endpoint efficacy parameters or
`events. F