CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`APPLICATION NUMBER:
`
`209803Orig1s000
`
`
` Steglatro tablets, 5 mg and 15 mg.
`
`ertugliflozin
`
`
`
`Trade Name:
`
`Generic or Proper
`Name:
`
`Sponsor:
`
`
`
`
`Approval Date:
`
`
`Indication:
`
`
`Merck Sharp & Dohme Corp.
`
`December 19, 2017
`
`For the use of Steglatro (ertugliflozin) tablets as an
`adjunct to diet and exercise to improve glycemic control
`in adults with type 2 diabetes mellitus..
`
`

`

`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`209803Orig1s000
`
`CONTENTS
`
`Reviews / Information Included in this NDA Review.
`
`
`
`Approval Letter
`Other Action Letters
`Labeling
`REMS
`Summary Review
`Officer/Employee List
`Office Director Memo
`Cross Discipline Team Leader Review
`Clinical Review(s)
`Product Quality Review(s)
`Non-Clinical Review(s)
`Statistical Review(s)
`Clinical Microbiology / Virology Review(s)
`Clinical Pharmacology Review(s)
`Other Reviews
`Risk Assessment and Risk Mitigation Review(s)
`Proprietary Name Review(s)
`Administrative/Correspondence Document(s)
`
`
`X
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`X
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`X
`X
`
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`X
`X
`X
`X
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`X
`X
`X
`X
`X
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`

`

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`
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`209803Orig1s000
`
`
`APPROVAL LETTER
`
`

`

`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`NDA 209803
`
`Merck Sharp & Dohme Corp.
`Attention: Vivian Fuh, M.D., F.A.C.P.
`Executive Director, Global Regulatory Affairs
`126 E. Lincoln Avenue, P.O. Box 2000
`Mail Drop: RY34-B188
`Rahway, NJ 07065
`
`Dear Dr. Fuh:
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`NDA APPROVAL
`
`Please refer to your New Drug Application (NDA) dated and received December 19, 2016, and
`your amendments, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act
`(FDCA) for Steglatro (ertugliflozin) tablets, 5 mg and 15 mg.
`
`This new drug application provides for the use of Steglatro (ertugliflozin) tablets as an adjunct to
`diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
`
`We have completed our review of this application, as amended. It is approved, effective on the
`date of this letter, for use as recommended in the agreed-upon labeling text.
`
`WAIVER OF HIGHLIGHTS SECTION
`
`We are waiving the requirements of 21 CFR 201.57(d)(8) regarding the length of Highlights of
`prescribing information. This waiver applies to all future supplements containing revised
`labeling unless we notify you otherwise.
`
`CONTENT OF LABELING
`
`As soon as possible, but no later than 14 days from the date of this letter, submit the content of
`labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using the FDA
`automated drug registration and listing system (eLIST), as described
`at http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm.
`Content of labeling must be identical to, except with the revisions indicated, the enclosed
`labeling (text for the prescribing information and Medication Guide). Information on submitting
`SPL files using eLIST may be found in the guidance for industry SPL Standard for Content of
`Labeling Technical Qs and As, available
`at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances
`/UCM072392.pdf.
`
`Reference ID: 4197746
`
`

`

`NDA 209803
`Page 2
`
`The SPL will be accessible via publicly available labeling repositories.
`
`CARTON AND IMMEDIATE CONTAINER LABELS
`
`Submit final printed carton and immediate container labels that are identical to the enclosed
`carton and immediate container labels as soon as they are available, but no more than 30 days
`after they are printed. Please submit these labels electronically according to the guidance for
`industry titled Providing Regulatory Submissions in Electronic Format — Certain Human
`Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications
`(May 2015, Revision 3). For administrative purposes, designate this submission “Final Printed
`Carton and Container Labels for approved NDA 209803.” Approval of this submission by
`FDA is not required before the labeling is used.
`
`ADVISORY COMMITTEE
`
`Your application for ertugliflozin was not referred to an FDA advisory committee because this
`drug is not the first in its class.
`
`REQUIRED PEDIATRIC ASSESSMENTS
`
`Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new
`active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of
`administration are required to contain an assessment of the safety and effectiveness of the
`product for the claimed indication(s) in pediatric patients unless this requirement is waived,
`deferred, or inapplicable.
`
`We are waiving the pediatric study requirement for ages 0 through 9 years (inclusive) because
`necessary studies are impossible or highly impracticable. This is because there are too few
`children in this age range with type 2 diabetes mellitus to study.
`
`We are deferring submission of your pediatric study for ages 10 to 17 years (inclusive) for this
`application because this product is ready for approval for use in adults and the pediatric study has
`not been completed.
`
`Your deferred pediatric study required by section 505B(a) of the FDCA is a required
`postmarketing study. The status of this postmarketing study must be reported annually according
`to 21 CFR 314.81 and section 505B(a)(3)(C) of the FDCA. This required study is listed below.
`
`3311-1
`
`Conduct a 24-week, randomized, double-blind, placebo-controlled, parallel group
`study of the safety, efficacy, and pharmacokinetics (PK) of ertugliflozin as add-on
`to metformin background therapy for the treatment of type 2 diabetes mellitus in
`pediatric patients ages 10 to 17 years (inclusive), followed by a 30-week double-
`blind, controlled extension. Patients will be randomized to receive one of two
`doses of ertugliflozin or placebo once daily. The ertugliflozin doses will be
`determined using a population PK model derived from the Phase 3 program (in
`
`Reference ID: 4197746
`
`

`

`NDA 209803
`Page 3
`
`adult subjects) for ertugliflozin. As part of the pediatric study, sparse blood
`samples for population PK and exposures-response analysis will be collected. An
`interim analysis of the PK data will be performed during this study to confirm
`acceptable exposure to ertugliflozin with the selected doses.
`
`Final Protocol Submission: October 2018
`Study Completion:
`March 2026
`Final Report Submission:
`September 2026
`
`Submit the protocol to your IND 106447, with a cross-reference letter to this NDA.
`
`Reports of this required pediatric postmarketing study must be submitted as a new drug
`application (NDA) or as a supplement to your approved NDA with the proposed labeling
`changes you believe are warranted based on the data derived from these studies. When
`submitting the reports, please clearly mark your submission "SUBMISSION OF REQUIRED
`PEDIATRIC ASSESSMENTS" in large font, bolded type at the beginning of the cover letter of
`the submission.
`
`POSTMARKETING REQUIREMENTS UNDER 505(o)
`
`Section 505(o)(3) of the FDCA authorizes FDA to require holders of approved drug and
`biological product applications to conduct postmarketing studies and clinical trials for certain
`purposes, if FDA makes certain findings required by the statute.
`
`We have determined that an analysis of spontaneous postmarketing adverse events reported
`under subsection 505(k)(1) of the FDCA will not be sufficient to:
`
`(cid:120) Assess signals of a serious risk of major adverse cardiovascular events (MACE) with
`Steglatro (ertugliflozin). There have been signals of a serious risk of cardiovascular
`events with some other medications developed for the treatment of type 2 diabetes
`mellitus and available data have not definitively excluded the potential for this serious
`risk with Steglatro (ertugliflozin).
`
`(cid:120) Assess signals of the serious risks of amputations, ketoacidosis, complicated genital
`infections, complicated urinary tract infections, fractures, pancreatitis, serious
`hypersensitivity events, malignancies, and worsening renal function.
`
`Furthermore, the new pharmacovigilance system that FDA is required to establish under section
`505(k)(3) of the FDCA will not be sufficient to assess these serious risks.
`
`Finally, we have determined that only a clinical trial (rather than a nonclinical or observational
`study) will be sufficient to assess these serious risks.
`
`Therefore, based on appropriate scientific data, FDA has determined that you are required to
`conduct the following trials:
`
`Reference ID: 4197746
`
`

`

`NDA 209803
`Page 4
`
`3311-2
`
`Conduct a randomized, double blind, placebo-controlled trial evaluating the effect
`of ertugliflozin on the incidence of major adverse cardiovascular events (MACE)
`in subjects with type 2 diabetes mellitus. The primary objective of the trial should
`be to demonstrate that the upper bound of the 2-sided 95% confidence interval for
`the estimated risk ratio comparing the incidence of MACE (non-fatal myocardial
`infarction, non-fatal stroke, cardiovascular death) observed with ertugliflozin to
`that observed in the placebo group is less than 1.3. This trial must also assess
`pregnancy outcomes and the following adverse events: amputations,
`ketoacidosis, complicated genital infections, complicated urinary tract infections,
`fractures, pancreatitis, serious hypersensitivity events, and malignancies. The
`estimated glomerular filtration rate (eGFR) should also be monitored over time to
`assess effects on renal function.
`
`The timetable you submitted on November 21, 2017, states that you will conduct this trial
`according to the following schedule:
`
`Trial Completion:
`Final Report Submission:
`
`October 2019
`December 2020
`
`Submit clinical protocols to your IND 106447 with a cross-reference letter to this NDA. Submit
`nonclinical and chemistry, manufacturing, and controls protocols and all final reports to your
`NDA. Prominently identify the submission with the following wording in bold capital letters at
`the top of the first page of the submission, as appropriate: Required Postmarketing Protocol
`Under 505(o), Required Postmarketing Final Report Under 505(o), Required
`Postmarketing Correspondence Under 505(o).
`
`Section 505(o)(3)(E)(ii) of the FDCA requires you to report periodically on the status of any
`study or clinical trial required under this section. This section also requires you to periodically
`report to FDA on the status of any study or clinical trial otherwise undertaken to investigate a
`safety issue. Section 506B of the FDCA, as well as 21 CFR 314.81(b)(2)(vii) requires you to
`report annually on the status of any postmarketing commitments or required studies or clinical
`trials.
`
`FDA will consider the submission of your annual report under section 506B and
`21 CFR 314.81(b)(2)(vii) to satisfy the periodic reporting requirement under section
`505(o)(3)(E)(ii) provided that you include the elements listed in 505(o) and
`21 CFR 314.81(b)(2)(vii). We remind you that to comply with 505(o), your annual report must
`also include a report on the status of any study or clinical trial otherwise undertaken to
`investigate a safety issue. Failure to submit an annual report for studies or clinical trials required
`under 505(o) on the date required will be considered a violation of FDCA section
`505(o)(3)(E)(ii) and could result in enforcement action.
`
`Reference ID: 4197746
`
`

`

`NDA 209803
`Page 5
`
`PROMOTIONAL MATERIALS
`
`You may request advisory comments on proposed introductory advertising and promotional
`labeling. To do so, submit, in triplicate, a cover letter requesting advisory comments, the
`proposed materials in draft or mock-up form with annotated references, and the package insert,
`Medication Guide, and patient PI (as applicable) to:
`
`OPDP Regulatory Project Manager
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Prescription Drug Promotion
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
`
`Alternatively, you may submit a request for advisory comments electronically in eCTD format.
`For more information about submitting promotional materials in eCTD format, see the draft
`Guidance for Industry (available
`at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidan
`ces/UCM443702.pdf ).
`
`As required under 21 CFR 314.81(b)(3)(i), you must submit final promotional materials, and the
`package insert, at the time of initial dissemination or publication, accompanied by a Form FDA
`2253. Form FDA 2253 is available
`at http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM083570.pdf.
`Information and Instructions for completing the form can be found
`at http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM375154.pdf.
`For more information about submission of promotional materials to the Office of Prescription
`Drug Promotion (OPDP),
`see http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm.
`
`REPORTING REQUIREMENTS
`
`We remind you that you must comply with reporting requirements for an approved NDA
`(21 CFR 314.80 and 314.81).
`
`We request that for a period of 5 years from the U.S. approval date, you submit all cases of
`ketoacidosis reported with Steglatro (ertugliflozin) tablets as 15-day Alert reports (as described
`under 21 CFR 314.80(c)(1)), and that you provide detailed analyses of events of ketoacidosis
`reported from clinical study and post-marketing reports in your periodic safety report (i.e., the
`Periodic Adverse Drug Experience Report [PADER] required under 21 CFR 314.80(c)(2) or the
`ICH E2C Periodic Benefit-Risk Evaluation Report [PBRER] format). These analyses should
`show cumulative data relative to the date of approval of Steglatro (ertugliflozin) tablets as well
`as relative to prior periodic safety reports. Medical literature reviews for case reports/case series
`of ketoacidosis reported with Steglatro (ertugliflozin) tablets should also be provided in the
`periodic safety report.
`
`Reference ID: 4197746
`
`

`

`NDA 209803
`Page 6
`
`MEDWATCH-TO-MANUFACTURER PROGRAM
`
`The MedWatch-to-Manufacturer Program provides manufacturers with copies of serious adverse
`event reports that are received directly by the FDA. New molecular entities and important new
`biologics qualify for inclusion for three years after approval. Your firm is eligible to receive
`copies of reports for this product. To participate in the program, please see the enrollment
`instructions and program description details
`at http://www.fda.gov/Safety/MedWatch/HowToReport/ucm166910.htm.
`
`POST APPROVAL FEEDBACK MEETING
`
`New molecular entities and new biologics qualify for a post approval feedback meeting. Such
`meetings are used to discuss the quality of the application and to evaluate the communication
`process during drug development and marketing application review. The purpose is to learn
`from successful aspects of the review process and to identify areas that could benefit from
`improvement. If you would like to have such a meeting with us, call the Regulatory Project
`Manager for this application.
`
`If you have any questions, call Liz Godwin, Regulatory Project Manager, at (240) 402-3438.
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Mary T. Thanh Hai, M.D.
`Deputy Director
`Office of Drug Evaluation II
`Office of New Drugs
`Center for Drug Evaluation and Research
`
`Enclosures:
`Content of Labeling
`Carton and Container Labeling
`
`Reference ID: 4197746
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`MARY T THANH HAI
`12/19/2017
`
`Reference ID: 4197746
`
`(
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