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` NDA 213051
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` NDA APPROVAL
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`Novo Nordisk Inc.
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`Attention: Stephanie DeChiaro
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`Senior Director, Regulatory Affairs
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`800 Scudders Mill Rd.
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`P.O. Box 846
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`Plainsboro, NJ 08536
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`Dear Ms. DeChiaro:
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`Please refer to your new drug application (NDA) dated and received March 20, 2019,
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`and your amendments, submitted under section 505(b) of the Federal Food, Drug, and
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`Cosmetic Act (FDCA) for Rybelsus (semaglutide) tablets.
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`This new drug application provides for the use of Rybelsus (semaglutide) tablets as an
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`adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes
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`mellitus.
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`APPROVAL & LABELING
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`We have completed our review of this application, as amended. It is approved, effective
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`on the date of this letter, for use as recommended in the enclosed agreed-upon
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`labeling.
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`WAIVER OF ½ PAGE LENGTH REQUIREMENT FOR HIGHLIGHTS
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`We are waiving the requirements of 21 CFR 201.57(d)(8) regarding the length of
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`Highlights of Prescribing Information. This waiver applies to all future supplements
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`containing revised labeling unless we notify you otherwise.
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`CONTENT OF LABELING
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`As soon as possible, but no later than 14 days from the date of this letter, submit the
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`content of labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using
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`the FDA automated drug registration and listing system (eLIST), as described at
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`FDA.gov.1 Content of labeling must be identical to the enclosed labeling (text for the
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`Prescribing Information and Medication Guide) as well as annual reportable changes
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`not included in the enclosed labeling. Information on submitting SPL files using eLIST
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` 1 http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm
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`Reference ID: 4494169
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` NDA 213051
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`Page 2
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` may be found in the guidance for industry SPL Standard for Content of Labeling
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` Technical Qs and As.2
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`The SPL will be accessible via publicly available labeling repositories.
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`CARTON AND CONTAINER LABELING
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`Submit final printed carton and container labeling that are identical to the enclosed
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`carton and container labeling as soon as they are available, but no more than 30 days
`after they are printed. Please submit these labeling electronically according to the
` guidance for industry Providing Regulatory Submissions in Electronic Format — Certain
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` Human Pharmaceutical Product Applications and Related Submissions Using the eCTD
`Specifications. For administrative purposes, designate this submission “Final Printed
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` Carton and Container Labeling for approved NDA 213051.” Approval of this
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` submission by FDA is not required before the labeling is used.
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` REQUIRED PEDIATRIC ASSESSMENTS
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`Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for
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`new active ingredients (which includes new salts and new fixed combinations), new
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`indications, new dosage forms, new dosing regimens, or new routes of administration
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`are required to contain an assessment of the safety and effectiveness of the product for
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`the claimed indication in pediatric patients unless this requirement is waived, deferred,
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`or inapplicable.
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`We are waiving the pediatric study requirement for ages 0 through 9 years (inclusive)
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`because necessary studies are impossible or highly impracticable. This is because
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`there are too few children in this age range with type 2 diabetes mellitus to study.
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`We are deferring submission of your pediatric study for ages 10 to 17 years (inclusive)
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`for this application because this product is ready for approval for use in adults and the
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`pediatric study has not been completed.
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`Your deferred pediatric study required under section 505B(a) of the FDCA is a required
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`postmarketing study. The status of this postmarketing study must be reported annually
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`according to 21 CFR 314.81 and section 505B(a)(3)(C) of the FDCA. This required
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`study is listed below.
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`3692-1 Conduct a 52-week, randomized, double-blind, placebo-controlled parallel
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`group study of the safety and efficacy of Rybelsus (semaglutide) tablets
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`for the treatment of type 2 diabetes mellitus in pediatric patients ages 10
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` 2 We update guidances periodically. For the most recent version of a guidance, check the FDA Guidance
` Documents Database https://www.fda.gov/RegulatoryInformation/Guidances/default.htm.
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`U.S. Food and Drug Administration
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`Silver Spring, MD 20993
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`www.fda.gov
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`Reference ID: 4494169
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` NDA 213051
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`Page 3
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` to 17 years (inclusive). Background therapy will consist of either
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` metformin, insulin, or metformin plus insulin.
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`Draft Protocol Submission: November 2019
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`Final Protocol Submission: May 2020
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`December 2026
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`Study Completion:
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`Final Report Submission: June 2027
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`Submit the protocol to your IND 114464, with a cross-reference letter to this NDA.
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`Reports of this required pediatric postmarketing study must be submitted as a new drug
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`application (NDA) or as a supplement to your approved NDA with the proposed labeling
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`changes you believe are warranted based on the data derived from these studies.
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`When submitting the reports, please clearly mark your submission "SUBMISSION OF
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`REQUIRED PEDIATRIC ASSESSMENTS" in large font, bolded type at the beginning of
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`the cover letter of the submission.
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`POSTMARKETING REQUIREMENTS UNDER 505(o)
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`Section 505(o)(3) of the FDCA authorizes FDA to require holders of approved drug and
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`biological product applications to conduct postmarketing studies and clinical trials for
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`certain purposes, if FDA makes certain findings required by the statute.
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`We have determined that an analysis of spontaneous postmarketing adverse events
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`reported under subsection 505(k)(1) of the FDCA will not be sufficient to assess a signal
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`of a serious risk of medullary thyroid carcinoma associated with Rybelsus
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`(semaglutide), and to assess the nonclinical signal of a risk of concentration of
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`semaglutide and salcaprozate sodium in breast milk.
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`Furthermore, the new pharmacovigilance system that FDA is required to establish under
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`section 505(k)(3) of the FDCA will not be sufficient to assess these serious risks.
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`Therefore, based on appropriate scientific data, FDA has determined that you are
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`required to conduct the following:
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`3692-2 Conduct a medullary thyroid carcinoma registry-based case series of at
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`least 15 years duration to systematically monitor the annual incidence of
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`medullary thyroid carcinoma in the United States and to identify any
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`increase related to the introduction of Rybelsus (semaglutide) tablets into
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`the marketplace. This study will also establish a registry of incident cases
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`U.S. Food and Drug Administration
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`Silver Spring, MD 20993
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`www.fda.gov
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`Reference ID: 4494169
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`NDA 213051
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`Page 4
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`of medullary thyroid carcinoma and characterize their medical histories
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`related to diabetes and use of Rybelsus (semaglutide) tablets.
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`The timetable you submitted on September 13, 2019, states that you will conduct this
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`study according to the following schedule:
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`Draft Protocol Submission:
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`Final Protocol Submission:
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`Interim Report Submissions:
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`May 2020
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`November 2020
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`March 2021
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`March 2022
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`March 2023
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`March 2024
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`March 2025
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`March 2026
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`March 2027
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`March 2028
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`March 2029
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`March 2030
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`March 2031
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`March 2032
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`March 2033
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`March 2034
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`March 2035
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`February 2036
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`February 2037
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`Study Completion:
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`Final Report Submission:
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`3692-3 Conduct a milk-only lactation study in lactating women who have received
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`Rybelsus (semaglutide) tablets therapeutically to assess concentrations of
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`semaglutide and salcaprozate sodium (SNAC) in breast milk using a
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`validated assay.
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`The timetable you submitted on September 13, 2019, states that you will conduct this
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`study according to the following schedule:
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`Final Protocol Submission: December 2020
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`December 2022
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`Study Completion:
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`Final Report Submission: December 2023
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`Submit clinical protocols to your IND 114464 with a cross-reference letter to this NDA.
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`Submit nonclinical and chemistry, manufacturing, and controls protocols and all final
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`report(s) to your NDA. Prominently identify the submission with the following wording in
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`bold capital letters at the top of the first page of the submission, as appropriate:
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`Required Postmarketing Protocol Under 505(o), Required Postmarketing Final
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`Report Under 505(o), Required Postmarketing Correspondence Under 505(o).
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`U.S. Food and Drug Administration
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`Silver Spring, MD 20993
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`www.fda.gov
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`Reference ID: 4494169
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` NDA 213051
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`Page 5
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` Submission of the protocols for required postmarketing observational studies to your
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` IND is for purposes of administrative tracking only. These studies do not constitute
`clinical investigations pursuant to 21 CFR 312.3(b) and therefore are not subject to the
`IND requirements under 21 CFR part 312 or FDA’s regulations under 21 CFR parts 50
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`(Protection of Human Subjects) and 56 (Institutional Review Boards).
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` 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
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`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
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`314.81(b)(2)(vii) requires you to report annually on the status of any postmarketing
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`commitments or required studies or clinical trials.
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` FDA will consider the submission of your annual report under section 506B and
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` 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
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` 21 CFR 314.81(b)(2)(vii). We remind you that to comply with 505(o), your annual report
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` undertaken to investigate a safety issue. Failure to submit an annual report for studies
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` or clinical trials required under 505(o) on the date required will be considered a violation
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` of FDCA section 505(o)(3)(E)(ii) and could result in enforcement action.
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` POSTMARKETING COMMITMENTS SUBJECT TO REPORTING REQUIREMENTS
`UNDER SECTION 506B
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`We remind you of your postmarketing commitments:
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`3692-4 Develop a sensitive assay to assess the neutralizing activity of anti­
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`semaglutide antibodies and its cross-neutralizing effect on native GLP-1.
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`The timetable you submitted on September 13, 2019, states that you will conduct this
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`study according to the following schedule:
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`October 2020
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`Study Completion:
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`Final Report Submission: December 2020
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`3692-5 Assess the incidence of neutralizing antibodies to semaglutide and GLP-1
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`in subjects treated with Rybelsus (semaglutide) tablets. The samples can
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`be derived from pre-existing clinical studies, but a plan to select the
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`samples should be agreed upon with the Agency.
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`The timetable you submitted on September 13, 2019, states that you will conduct this
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`study according to the following schedule:
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`U.S. Food and Drug Administration
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`Silver Spring, MD 20993
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`www.fda.gov
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`Reference ID: 4494169
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` NDA 213051
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`Page 6
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` May 2021
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` Study Completion:
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` Final Report Submission: June 2021
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` PROMOTIONAL MATERIALS
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` You may request advisory comments on proposed introductory advertising and
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` 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,
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` and the Prescribing Information, Medication Guide, and Patient Package Insert (as
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` applicable) to:
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`OPDP Regulatory Project Manager
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`Food and Drug Administration
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`Center for Drug Evaluation and Research
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`Office of Prescription Drug Promotion
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`5901-B Ammendale Road
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`Beltsville, MD 20705-1266
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`Alternatively, you may submit a request for advisory comments electronically in eCTD
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`format. For more information about submitting promotional materials in eCTD format,
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`see the draft guidance for industry Providing Regulatory Submissions in Electronic and
`Non-Electronic Format—Promotional Labeling and Advertising Materials for Human
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`Prescription Drugs.3
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`As required under 21 CFR 314.81(b)(3)(i), you must submit final promotional materials,
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`and the Prescribing Information, at the time of initial dissemination or publication,
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`accompanied by a Form FDA 2253. Form FDA 2253 is available at FDA.gov.4
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`Information and Instructions for completing the form can be found at FDA.gov.5 For
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`more information about submission of promotional materials to the Office of Prescription
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`Drug Promotion (OPDP), see FDA.gov.6
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`REPORTING REQUIREMENTS
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` We remind you that you must comply with reporting requirements for an approved NDA
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` (21 CFR 314.80 and 314.81).
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` 3 When final, this guidance will represent the FDA’s current thinking on this topic. For the most recent
` version of a guidance, check the FDA guidance web page at
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` https://www.fda.gov/RegulatoryInformation/Guidances/default.htm.
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` 4 http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM083570.pdf
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` 5 http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM375154.pdf
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` 6 http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm
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`U.S. Food and Drug Administration
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`Silver Spring, MD 20993
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`www.fda.gov
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`Reference ID: 4494169
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`

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`NDA 213051
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`Page 7
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`If you have any questions, call Peter Franks, Regulatory Project Manager, at
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`(240) 402-4197.
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`Sincerely,
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`{See appended electronic signature page}
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`Lisa B. Yanoff, M.D.
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`Director (Acting)
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`Division of Metabolism and Endocrinology Products
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`Office of Drug Evaluation II
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`Center for Drug Evaluation and Research
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`ENCLOSURES:
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`• Content of Labeling
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`o Prescribing Information
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`o Medication Guide
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`• Carton and Container Labeling
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`U.S. Food and Drug Administration
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`Silver Spring, MD 20993
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`www.fda.gov
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`Reference ID: 4494169
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`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/
`------------------------------------------------------------
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`LISA B YANOFF
`09/20/2019 07:33:44 AM
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`Reference ID: 4494169
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`