CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`206073Orig1s000
`
`MEDICAL REVIEW(S)
`
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`
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`
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`
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`(b
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`CLINICAL FILING CHECKLIST FOR NDA/BLA or Supplement
`
`NDA/BLA Number: 206073
`
`Drug Name:
`Empagliflozin/Linagliptin Fixed
`Dose Combination
`
`Applicant: Boehringer
`Ingelheim
`NDA/BLA Type: NME
`
`On initial overview of the NDA/BLA application for filing:
`
`Stamp Date: January 30, 2014
`
`Content Parameter
`FORMAT/ORGANIZATION/LEGIBILITY
`1.
`Identify the general format that has been used for this
`application, e.g. electronic CTD.
`2. On its face, is the clinical section organized in a manner to
`allow substantive review to begin?
`
`3.
`
`4.
`
`Is the clinical section indexed (using a table of contents)
`and paginated in a manner to allow substantive review to
`begin?
`For an electronic submission, is it possible to navigate the
`application in order to allow a substantive review to begin
`(e.g., are the bookmarks adequate)?
`5. Are all documents submitted in English or are English
`translations provided when necessary?
`Is the clinical section legible so that substantive review can
`begin?
`LABELING
`7. Has the applicant submitted the design of the development
`package and draft labeling in electronic format consistent
`with current regulation, divisional, and Center policies?
`SUMMARIES
`8. Has the applicant submitted all the required discipline
`summaries (i.e., Module 2 summaries)?
`
`6.
`
`9. Has the applicant submitted the integrated summary of
`safety (ISS)?
`
`10. Has the applicant submitted the integrated summary of
`efficacy (ISE)?
`
`11. Has the applicant submitted a benefit-risk analysis for the
`product?
`12. Indicate if the Application is a 505(b)(1) or a 505(b)(2). If
`Application is a 505(b)(2) and if appropriate, what is the
`reference drug?
`DOSE
`
`Yes No NA
`
`Comment
`
`x
`
`x
`
`x
`
`x
`
`x
`
`x
`
`x
`
`x
`
`x
`
`x
`
`eCTD
`
`Clinical section is
`composed of a single
`study report
`
`Clinical summaries are
`not submitted, but are
`not necessary as
`clinical data comes
`from a single study
`Summaries are not
`submitted, but are not
`necessary as clinical
`data comes from a
`single study
`Summaries are not
`submitted, but are not
`necessary as clinical
`data comes from a
`single study
`
`505(b)(1)
`
`File name: 5_Clinical Filing Checklist for NDA_BLA or Supplement 010908
`1
`
`Reference ID: 3478437
`
`

`

`CLINICAL FILING CHECKLIST FOR NDA/BLA or Supplement
`
`Content Parameter
`13. If needed, has the applicant made an appropriate attempt to
`determine the correct dosage and schedule for this product
`(i.e., appropriately designed dose-ranging studies)?
`Study Number:
` Study Title:
` Sample Size: Arms:
`Location in submission:
`EFFICACY
`14. Do there appear to be the requisite number of adequate and
`well-controlled studies in the application?
`
`Pivotal Study #1
`Study 1275.1: A phase 3, randomized, double-blind,
`parallel group study to evaluate the efficacy and safety of
`once daily oral administration of BI 10773 25
`mg/linaglipitin 5 mg and BI 10773 10 mg and linaglipitin 5
`mg fixed dose combination tablets compared with the
`individual components (BI 10773 25 mg, BI 10773 10 mg,
`and linaglipitin 5 mg) for 52 weeks in treatment naïve and
`metformin treated patients with type 2 diabetes mellitus and
`insufficient glycemic control
`15. Do all pivotal efficacy studies appear to be adequate and
`well-controlled within current divisional policies (or to the
`extent agreed to previously with the applicant by the
`Division) for approvability of this product based on
`proposed draft labeling?
`16. Do the endpoints in the pivotal studies conform to previous
`Agency commitments/agreements? Indicate if there were
`not previous Agency agreements regarding
`primary/secondary endpoints.
`17. Has the application submitted a rationale for assuming the
`applicability of foreign data to U.S. population/practice of
`medicine in the submission?
`SAFETY
`18. Has the applicant presented the safety data in a manner
`consistent with Center guidelines and/or in a manner
`previously requested by the Division?
`19. Has the applicant submitted adequate information to assess
`the arythmogenic potential of the product (e.g., QT interval
`studies, if needed)?
`
`Yes No NA
`x
`
`Comment
`Dose selection is
`based on the doses for
`the individual
`components
`
`x
`
`x
`
`x
`
`x
`
`x
`
`Though this is a single
`clinical study protocol,
`there are two studies
`encompassed: (1) a
`study in treatment
`naïve patients, and (2)
`a study as add-on to
`metformin
`
`x
`
`References QT studies
`for the individual
`components
`
`File name: 5_Clinical Filing Checklist for NDA_BLA or Supplement 010908
`2
`
`Reference ID: 3478437
`
`

`

`CLINICAL FILING CHECKLIST FOR NDA/BLA or Supplement
`
`Content Parameter
`20. Has the applicant presented a safety assessment based on all
`current worldwide knowledge regarding this product?
`
`Yes No NA
`x
`
`21. For chronically administered drugs, have an adequate
`number of patients (based on ICH guidelines for exposure1)
`been exposed at the dose (or dose range) believed to be
`efficacious?
`
`x
`
`x
`
`22. For drugs not chronically administered (intermittent or
`short course), have the requisite number of patients been
`exposed as requested by the Division?
`23. Has the applicant submitted the coding dictionary2 used for
`mapping investigator verbatim terms to preferred terms?
`24. Has the applicant adequately evaluated the safety issues that
`are known to occur with the drugs in the class to which the
`new drug belongs?
`25. Have narrative summaries been submitted for all deaths and
`adverse dropouts (and serious adverse events if requested
`by the Division)?
`
`x
`
`x
`
`x
`
`Comment
`The FDC product has
`only been used in
`clinical trials.
`Though the number of
`patients studied for the
`FDC does not meet the
`ICH guidelines, the
`numbers studied in the
`individual component
`development programs
`satisfies the
`guidelines.
`
`MedDRA v16.0
`
`x
`
`x
`
`x
`
`OTHER STUDIES
`26. Has the applicant submitted all special studies/data
`requested by the Division during pre-submission
`discussions?
`27. For Rx-to-OTC switch and direct-to-OTC applications, are
`the necessary consumer behavioral studies included (e.g.,
`label comprehension, self selection and/or actual use)?
`PEDIATRIC USE
`28. Has the applicant submitted the pediatric assessment, or
`provided documentation for a waiver and/or deferral?
`ABUSE LIABILITY
`29. If relevant, has the applicant submitted information to
`assess the abuse liability of the product?
`FOREIGN STUDIES
`30. Has the applicant submitted a rationale for assuming the
`applicability of foreign data in the submission to the U.S.
`population?
`DATASETS
`31. Has the applicant submitted datasets in a format to allow
`reasonable review of the patient data?
`
`1 For chronically administered drugs, the ICH guidelines recommend 1500 patients overall, 300-600
`patients for six months, and 100 patients for one year. These exposures MUST occur at the dose or dose
`range believed to be efficacious.
`2 The “coding dictionary” consists of a list of all investigator verbatim terms and the preferred terms to
`which they were mapped. It is most helpful if this comes in as a SAS transport file so that it can be sorted
`as needed; however, if it is submitted as a PDF document, it should be submitted in both directions
`(verbatim -> preferred and preferred -> verbatim).
`File name: 5_Clinical Filing Checklist for NDA_BLA or Supplement 010908
`3
`
`x
`
`x
`
`x
`
`Reference ID: 3478437
`
`

`

`CLINICAL FILING CHECKLIST FOR NDA/BLA or Supplement
`
`Content Parameter
`32. Has the applicant submitted datasets in the format agreed to
`previously by the Division?
`33. Are all datasets for pivotal efficacy studies available and
`complete for all indications requested?
`34. Are all datasets to support the critical safety analyses
`available and complete?
`35. For the major derived or composite endpoints, are all of the
`raw data needed to derive these endpoints included?
`CASE REPORT FORMS
`36. Has the applicant submitted all required Case Report Forms
`in a legible format (deaths, serious adverse events, and
`adverse dropouts)?
`37. Has the applicant submitted all additional Case Report
`Forms (beyond deaths, serious adverse events, and adverse
`drop-outs) as previously requested by the Division?
`FINANCIAL DISCLOSURE
`38. Has the applicant submitted the required Financial
`Disclosure information?
`GOOD CLINICAL PRACTICE
`39. Is there a statement of Good Clinical Practice; that all
`clinical studies were conducted under the supervision of an
`IRB and with adequate informed consent procedures?
`
`Yes No NA
`x
`
`Comment
`
`x
`
`x
`
`x
`
`x
`
`x
`
`x
`
`x
`
`IS THE CLINICAL SECTION OF THE APPLICATION FILEABLE? _Yes_
`
`The clinical section of this NDA appears to be complete and ready for review.
`
`File name: 5_Clinical Filing Checklist for NDA_BLA or Supplement 010908
`4
`
`Reference ID: 3478437
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`

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`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`WILLIAM H CHONG
`03/27/2014
`
`Reference ID: 3478437
`
`