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` NDA 217806
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` NDA APPROVAL
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`Eli Lilly and Company
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`Attention: Ingrid Hensley, PhD
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`Senior Director, Global Regulatory Affairs- North America
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`Lilly Corporate Center
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`Drop Code 2543
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`Indianapolis, IN 46285
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`
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`Dear Dr. Hensley:
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`Please refer to your new drug application (NDA) dated and received May 8, 2023, and
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`your amendments, submitted under section 505(b) of the Federal Food, Drug, and
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`Cosmetic Act (FDCA) for Zepbound (tirzepatide) injection.
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`This NDA provides for the use of Zepbound (tirzepatide) injection as an adjunct to a
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`reduced-calorie diet and increased physical activity for chronic weight management in
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`adults with an initial body mass index (BMI) of:
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`• 30 kg/m2 or greater (obesity) or
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`• 27 kg/m2 or greater (overweight) in the presence of at least one weight-related
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`comorbid condition (e.g., hypertension, dyslipidemia, type 2 diabetes mellitus,
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`obstructive sleep apnea, or cardiovascular disease).
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`APPROVAL & LABELING
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`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 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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`Reference ID: 5274616
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`

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` NDA 217806
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`Page 2
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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, Instructions for Use, and Medication Guide) as well as annual
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`reportable changes not included in the enclosed labeling. Information on submitting SPL
`files using eLIST may be found in the guidance for industry SPL Standard for Content of
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`Labeling 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
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`after they are printed. Please submit these labeling electronically according to the
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`guidance for industry SPL Standard for Content of Labeling Technical Qs & As. For
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`administrative purposes, designate this submission “Final Printed Carton and
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`Container Labeling for approved NDA 217806.” Approval of this submission by FDA
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`is not required before the labeling is used.
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`DATING PERIOD
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`Based on the stability data submitted to date, the expiry dating period for Zepbound
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`(tirzepatide) injection shall be 24 months from the date of manufacture when stored at
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`2oC to 8oC (36oF to 46oF).
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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 studies requirement for ages 0 to 5 years inclusive,
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` because the product does not represent a meaningful therapeutic benefit over existing
`therapies for pediatric patients in this age group and is not likely to be used in a
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` substantial number of pediatric patients in this group. FDA proposes that studies of
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` weight management products be conducted in children who are 7 years or older, while
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` the European Medicines Agency (EMA) guideline on the clinical evaluation of medicinal
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` products used in weight management in children recommends enrollment of children
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`1 http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm
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`2 We update guidances periodically. For the most recent version of a guidance, check the FDA Guidance
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`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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`
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`Reference ID: 5274616
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`

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`NDA 217806
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`Page 3
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`aged 6 years and older in clinical trials. As the pediatric study plan is a global program,
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`the EMA guideline will be applied.
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`We are deferring submission of your pediatric studies for ages 6 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 studies have not been completed.
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` Your deferred pediatric studies required by section 505B(a) of the FDCA are required
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` postmarketing studies. The status of these postmarketing studies must be reported
`annually according to 21 CFR 314.81 and section 505B(a)(4)(C) of the FDCA. These
`required studies are listed below.
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` 4534-1 Conduct a 72-week, randomized, double-blind, placebo-controlled,
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` multicenter, parallel-arm study to evaluate the safety and efficacy of
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` Zepbound (tirzepatide) as an adjunct to lifestyle intervention for chronic
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` weight management in pediatric patients aged 12 to 17 years (inclusive)
` with obesity.
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` Study Completion:
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` Final Report Submission:
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` February 2027
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` August 2027
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` 4534-2 Conduct a safety, tolerability, pharmacokinetic, and pharmacodynamic
` study of Zepbound (tirzepatide) administered subcutaneously in pediatric
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` patients aged 6 to 11 years (inclusive) with obesity. Data from this study
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` should be considered when choosing dose(s) for the safety and efficacy
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` trial in this pediatric population.
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` Study Completion:
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` Final Report Submission:
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` May 2025
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` October 2025
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` 4534-3 Conduct a 72-week, randomized, double-blind, placebo-controlled,
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` multicenter, parallel-arm study to evaluate the safety and efficacy of
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` Zepbound (tirzepatide) as an adjunct to lifestyle intervention for chronic
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` weight management in pediatric patients aged 6 to 11 years (inclusive)
` with obesity.
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`Draft Protocol Submission:
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`Final Protocol Submission:
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`Study Completion:
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`Final Report Submission:
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`October 2025
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`April 2026
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`December 2029
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`June 2030
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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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`
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`Reference ID: 5274616
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`

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` NDA 217806
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`Page 4
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` FDA considers the term final to mean that the applicant has submitted a protocol, the
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` FDA review team has sent comments to the applicant, and the protocol has been
` revised as needed to meet the goal of the study or clinical trial.3
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`Submit the protocols to your IND 139721, with a cross-reference letter to this NDA.
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`Reports of these required pediatric postmarketing studies must be submitted as an NDA
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`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
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`PEDIATRIC ASSESSMENTS" in large font, bolded type at the beginning of the cover
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`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 or to identify an unexpected serious risk
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`of maternal and fetal adverse reactions.
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`Furthermore, the active postmarket risk identification and analysis system as available
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`under 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 studies:
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`4534-4 Collect global data from a prospective pregnancy exposure registry,
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`preferably a disease-based multi-product pregnancy registry, using a
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`registry-based cohort study to compare the maternal, fetal, and infant
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`outcomes of women exposed to Zepbound (tirzepatide) for chronic weight
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`management during pregnancy with unexposed comparator population(s).
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`Align the study protocol with protocol(s) outside the United States to reach
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`the target sample size. The registry will identify and record pregnancy
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`complications, major and minor congenital malformations, spontaneous
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`abortions, stillbirths, elective terminations, preterm births, small-for-
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`gestational-age births, and any other adverse outcomes, including
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`postnatal growth and development. These outcomes will be assessed
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`throughout pregnancy. Infant outcomes, including effects on postnatal
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`3 See the guidance for Industry Postmarketing Studies and Clinical Trials—Implementation of Section
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`505(o)(3) of the Federal Food, Drug, and Cosmetic Act (October 2019).
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`https://www.fda.gov/RegulatoryInformation/Guidances/default.htm.
`
`U.S. Food and Drug Administration
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`
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`Silver Spring, MD 20993
`www.fda.gov
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`Reference ID: 5274616
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`

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` NDA 217806
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`Page 5
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` growth and development, will be assessed through at least the first year of
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` life.
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`The timetable you submitted on November 6, 2023, states that you will conduct this
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`study according to the following schedule:
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`June 2024
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`June 2025
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`June 2026
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`June 2028
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`June 2030
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`June 2032
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`June 2034
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`June 2035
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`June 2036
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`Draft Protocol Submission:
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`Final Protocol Submission:
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`Interim Report Submission:
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`Study Completion:
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`Final Report Submission:
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`4534-5 Conduct an additional pregnancy study that uses a different design from
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`the pregnancy exposure registry (for example a cohort study using claims
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`or electronic medical record data) to compare the risks and prevalence of
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`pregnancy and infant outcomes (including but not limited to major
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`congenital malformations, spontaneous abortions, stillbirths, small-for-
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`gestational-age births, preterm births, and postnatal growth and
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`development) between women exposed to Zepbound (tirzepatide) for
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`chronic weight management during pregnancy and unexposed comparator
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`population(s).
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`The timetable you submitted on November 6, 2023, 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 Submission:
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`Study Completion:
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`Final Report Submission:
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`September 2024
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`September 2025
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`September 2026
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`September 2028
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`September 2030
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`September 2031
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`September 2032
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`4534-6 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 Zepbound (tirzepatide) for the
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`treatment of overweight and obesity into the marketplace. This study will
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`also establish a registry of incident cases of medullary thyroid carcinoma
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`and characterize their medical histories related to the use of Zepbound
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`(tirzepatide) for the treatment of obesity/overweight.
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`
`U.S. Food and Drug Administration
`
`Silver Spring, MD 20993
`
`www.fda.gov
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`
`
`Reference ID: 5274616
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`

`

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` NDA 217806
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`Page 6
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` The timetable you submitted on November 1, 2023, states that you will conduct this
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` study according to the following schedule:
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`May 2024
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`May 2025
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`May 2026
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`May 2027
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`May 2028
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`May 2029
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`May 2030
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`May 2031
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`May 2032
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`May 2033
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`May 2034
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`May 2035
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`May 2036
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`May 2037
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`May 2038
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`May 2039
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`May 2040
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`August 2040
`August 2041
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`Draft Protocol Submission:
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`Final Protocol Submission:
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`Interim Report Submission:
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`Study Completion:
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`Final Report Submission:
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`FDA considers the term final to mean that the applicant has submitted a protocol, the
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`FDA review team has sent comments to the applicant, and the protocol has been
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`revised as needed to meet the goal of the study or clinical trial.4
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`Submit clinical protocol(s) to your IND 139721 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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`Submission of the protocol(s) for required postmarketing observational studies to your
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`IND is for purposes of administrative tracking only. These studies do not constitute
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`clinical investigations pursuant to 21 CFR 312.3(b) and therefore are not subject to the
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`IND requirements under 21 CFR part 312.
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`Section 505(o)(3)(E)(ii) of the FDCA requires you to report periodically on the status of
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`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
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`4 See the guidance for Industry Postmarketing Studies and Clinical Trials—Implementation of Section
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`
`
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`505(o)(3) of the Federal Food, Drug, and Cosmetic Act (October 2019).
`https://www.fda.gov/RegulatoryInformation/Guidances/default.htm.
`
`U.S. Food and Drug Administration
`
`
`
`Silver Spring, MD 20993
`www.fda.gov
`
`
`
`
`Reference ID: 5274616
`
`

`

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` NDA 217806
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`Page 7
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` undertaken to investigate a safety issue. Section 506B(a)(1) of the FDCA, as well as
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` 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.
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`FDA will consider the submission of your annual report under section 506B(a)(1) 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
` must also include a report on the status of any study or clinical trial otherwise
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` 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
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` of FDCA section 505(o)(3)(E)(ii) and could result in enforcement action.
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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. For information about submitting promotional materials, see the
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`final guidance for industry Providing Regulatory Submissions in Electronic and Non-
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`Electronic Format—Promotional Labeling and Advertising Materials for Human
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`Prescription Drugs.5
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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.6
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`Information and Instructions for completing the form can be found at FDA.gov.7
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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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`Your product is a Part 3 combination product (21 CFR 3.2(e)); therefore, you must also
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`comply with postmarketing safety reporting requirements for an approved combination
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`product (21 CFR 4, Subpart B). Additional information on combination product
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`postmarketing safety reporting is available at FDA.gov.8
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`COMPENDIAL STANDARDS
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`A drug with a name recognized in the official United States Pharmacopeia or official
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`National Formulary (USP-NF) generally must comply with the compendial standards for
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`5 For the most recent version of a guidance, check the FDA guidance web page at
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`https://www.fda.gov/media/128163/download.
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`6 http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM083570.pdf
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`7 http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM375154.pdf
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`8 https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safety-
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`reporting-combination-products
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`
`U.S. Food and Drug Administration
`
`Silver Spring, MD 20993
`
`www.fda.gov
`
`
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`Reference ID: 5274616
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`

`

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` NDA 217806
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`Page 8
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` strength, quality, and purity, unless the difference in strength, quality, or purity is plainly
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`stated on its label (see FD&C Act § 501(b), 21 USC 351(b)). FDA typically cannot share
`application-specific information contained in submitted regulatory filings with third
`parties, which includes USP-NF. To help ensure that a drug continues to comply with
`compendial standards, application holders may work directly with USP-NF to revise
`official USP monographs. More information on the USP-NF is available on USP’s
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`website9.
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`
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`If you have any questions, call Arati B. Kamath, Ph.D., Regulatory Project Manager, at
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`(301) 796-3159.
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`
`
`Sincerely,
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`
`
`{See appended electronic signature page}
`
`
`
`John Sharretts, M.D.
`
`Director
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`
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`Division of Diabetes, Lipid Disorders, and Obesity
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`Office of Cardiology, Hematology, Endocrinology, and
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`Nephrology
`
`Office of New Drugs
`
`
`Center for Drug Evaluation and Research
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`ENCLOSURES:
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`• Content of Labeling
`
`
`o Prescribing Information
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`
`o Medication Guide
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`Instructions for Use
`o
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`• Carton and Container Labeling
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`
`
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`9 https://www.uspnf.com/
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`
`U.S. Food and Drug Administration
`
`
`Silver Spring, MD 20993
`www.fda.gov
`
`
`
`
`Reference ID: 5274616
`
`

`

`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/
`------------------------------------------------------------
`
`JOHN M SHARRETTS
`11/08/2023 11:03:27 AM
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`Reference ID: 5274616
`
`