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`Food and Drug Administration
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`Silver Spring MD 20993
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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`NDA 206321
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`Reference ID: 3677762
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` NDA APPROVAL
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`
`Novo Nordisk, Inc.
`Attention: Michelle Thompson
`Senior Director, Regulatory Affairs
`P.O. Box 846
`800 Scudders Mill Road
`Plainsboro, NJ 08536
`
`
`Dear Ms. Thompson:
`
`
`Please refer to your New Drug Application (NDA) dated and received December 20, 2013,
`submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA) for
`Saxenda (liraglutide [rDNA origin] injection), 3 mg.
`
`
`We acknowledge receipt of your amendments dated January 10, February 6, 13, and 14,
`March 4 and 21, April 2(3), 11, 15, 18, and 29, May 1, 2(2), 23, and 27, June 6, 16, 18, and 26,
`July 1, 3, 8, 9, 11, 14, and 15(2), August 14(2), 20, 28, and 29, September 24, 26, and 29(2),
`October 1(2), 2, 3(2), 6, 7, 9, 15, 17(2), 18, 20 and 24, November 10(2), 18, and December
`12,16, 17, 18, and 2014.
`
`This new drug application provides for the use of Saxenda (liraglutide [rDNA] injection), as an
`adjunct to a reduced-calorie diet and increased physical activity for chronic weight management
`in adult patients with an initial body mass index (BMI) of 30 kg/m2 or greater (obese), or 27
`kg/m2 or greater (overweight) in the presence of at least one weight-related comorbid condition
`(e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia).
`
`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 labeling text.
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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 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 the enclosed labeling (text for the package insert, medication
`guide, and instructions for use). 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,
`
`

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`NDA 206321
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`Page 2
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`available at
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM072392.pdf.
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`The SPL will be accessible via publicly available labeling repositories.
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`We request that the labeling approved today be available on your website within 10 days of
`receipt of this letter.
`
`
`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 Providing Regulatory Submissions in Electronic Format – Human Pharmaceutical
`Product Applications and Related Submissions Using the eCTD Specifications (June 2008).
`Alternatively, you may submit 12 paper copies, with 6 of the copies individually mounted on
`heavy-weight paper or similar material. For administrative purposes, designate this submission
`“Final Printed Carton and Container Labels for approved NDA 206321.” Approval of this
`submission by FDA is not required before the labeling is used.
`
`Marketing the products with FPL that is not identical to the approved labeling text may render
`the product misbranded and an unapproved new drug.
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`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 indications(s) in pediatric patients unless this requirement is waived,
`deferred, or inapplicable.
`
`We are waiving the pediatric studies requirement for ages 0 to 6 years (inclusive) because
`necessary studies are impossible or highly impracticable. This is because weight maintenance,
`not weight loss, is the clinical goal for obese children 2 to 6 years of age. Weight loss is not
`recommended in children less than 2 years of age because of the requirement for adequate
`growth and development and optimal deposition of lipids in the developing nervous system.
`
`We are deferring submission of your pediatric studies for ages 7 to 17 years (inclusive) for this
`application because this product is ready for approval for use in adults and the pediatric studies
`have not been completed.
`
`Your deferred pediatric studies required by section 505B(a) of the FDCA are required
`postmarketing studies. The status of these postmarketing studies must be reported annually
`according to 21 CFR 314.81 and section 505B(a)(3)(B) of the FDCA. These required studies are
`listed below.
`
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`Reference ID: 3677762
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`

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`NDA 206321
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`Page 3
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`2802-1 A juvenile rat toxicity study with liraglutide treatment from pre-puberty through
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` reproductive maturity.
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`Final Report Submission: December 2014
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`2802-2 A clinical pharmacology study (Trial NN8022-3967) to assess pharmacokinetic
`and pharmacodynamic parameters of Saxenda in obese pediatric patients ages 12
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` to 17 years (inclusive).
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`Final Report Submission: December 2014
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`2802-3 A 56-week randomized, double-blind, placebo-controlled study to evaluate the
`safety and efficacy of Saxenda for the treatment of obesity in pediatric patients
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`ages 12 to 17 (inclusive).
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`Final Protocol Submission August 2015
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`Study Completion:
`August 2019
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`Final Report Submission: August 2020
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`2802-4 A clinical pharmacology study to assess pharmacokinetic and pharmacodynamics
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`parameters of Saxenda in obese pediatric patients ages 7 to 11 years (inclusive).
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`Final Protocol Submission September 2015
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`Study Completion:
`August 2017
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`Final Report Submission:
`February 2018
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`2802-5 A 56-week randomized, double-blind, placebo-controlled study to evaluate the
`safety and efficacy of Saxenda for the treatment of obesity in pediatric patients
`ages 7 to 11 (inclusive). The trial may not be initiated until results from the
`Saxenda adolescent safety and efficacy trial have been submitted to and reviewed
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`by the Agency.
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`Final Protocol Submission April 2020
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`Study Completion:
`October 2023
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`Final Report Submission: August 2024
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`Submit the protocols to your IND 073206, 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 or as a
`supplement to your approved NDA with the proposed labeling changes you believe are
`
`Reference ID: 3677762
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`

`

`NDA 206321
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`Page 4
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`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.
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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
`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 assess a signal of a serious risk
`of medullary thyroid carcinoma associated with Saxenda (liraglutide [rDNA origin] injection).
`
`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 this serious risk.
`
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`Therefore, based on appropriate scientific data, FDA has determined that you are required to
`conduct the following:
`
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`2802-6 A medullary thyroid carcinoma registry-based case series of at least 15 years
`duration to systematically monitor the annual incidence of medullary thyroid
`carcinoma in the United States and to identify any increase related to the
`introduction of Saxenda (liraglutide [rDNA origin] injection) into the
`marketplace. This study will also establish a registry of incident cases of
`medullary thyroid carcinoma and characterize their medical histories related to
`diabetes and use of Saxenda (liraglutide [rDNA origin] injection).
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`
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`The timetable you submitted on December 16, 2014, states that you will conduct this study
`according to the following schedule:
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`Final Protocol Submission:
`Study Completion:
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`Final Report Submission:
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`June 2015
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`September 2030
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`September 2031
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`
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`Finally, we have determined that only a clinical trial (rather than a nonclinical or observational
`study) will be sufficient to assess a signal of a serious risk of breast cancer associated with
`Saxenda (liraglutide [rDNA origin] injection).
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`Therefore, based on appropriate scientific data, FDA has determined that you are required to
`conduct the following:
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`2802-7
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`To assess the risk of breast cancer associated with liraglutide in the LEADER
`(Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular
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`Reference ID: 3677762
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`

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`NDA 206321
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`Page 5
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`2802-8
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`Outcome Results) cardiovascular outcomes trial. To assess this risk, collect
`information on baseline cancer risk and potential confounders for all identified
`cases of breast cancer in the trial, including (but not limited to) prior history of
`breast cancer, family history of breast cancer, BRCA1/BRCA2 status, age at
`menopause, history of radiation to the chest, age at menarche, and current/prior
`use of hormonal therapy.
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`
`
`The timetable you submitted on December 16, 2014, states that you will conduct this trial
`according to the following schedule:
`
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`January 2015
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`Final Protocol Submission:
`September 2015
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`Trial Completion:
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`Final Report Submission: April 2016
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`To assess the risk of breast cancer associated with liraglutide in Trial 1839. To
`assess this risk, collect information on baseline cancer risk and potential
`confounders for all identified cases of breast cancer in the trial, including (but not
`limited to) prior history of breast cancer, family history of breast cancer,
`BRCA1/BRCA2 status, age at menopause, history of radiation to the chest, age at
`menarche, and current/prior use of hormonal therapy.
`
`
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`The timetable you submitted on December 16, 2014, states that you will conduct this trial
`according to the following schedule:
`
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`January 2015
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`Final Protocol Submission:
`March 2015
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`Trial Completion:
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`Final Report Submission: August 2015
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`Submit the protocols to your IND 073206, with a cross-reference letter to this NDA. Submit 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)”.
`
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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 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.
`
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`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
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`Reference ID: 3677762
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`

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`NDA 206321
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`Page 6
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`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.
`
`
`We also remind you that the following requirements under section 505(o)(3) of the FDCA, as
`stated in the approval letter for NDA 022341 for Victoza (liraglutide [rDNA origin] injection)
`dated January 25, 2010, also apply to NDA 206321:
`
`
`1583-9 A randomized, double-blind, controlled trial evaluating the effect of Victoza
`(liraglutide [rDNA origin]) injection on the incidence of major adverse
`cardiovascular events in patients with type 2 diabetes mellitus. This trial must also
`assess adverse events of interest including the long-term effects of Victoza
`(liraglutide [rDNA origin]) injection on potential biomarkers of medullary thyroid
`carcinoma (e.g., serum calcitonin) as well as the long-term effects of Victoza
`(liraglutide [rDNA origin]) injection on pancreatitis, renal safety, serious
`hypoglycemia, immunological reactions, and neoplasms.
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`
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`Final Protocol Submission: March 14, 2010 (completed)
`Trial Completion Date:
`September 14, 2015
`Final Report Submission: April 30, 2016
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`Please cross-reference NDA 206321 when you submit your final report for requirement 1583-9
`to NDA 022341.
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`POSTMARKETING COMMITMENTS SUBJECT TO REPORTING REQUIREMENTS
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`UNDER SECTION 506B
`
`We remind you of your postmarketing commitments:
`
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`2802-9 A study evaluating gallbladder ejection fractions in liraglutide-treated subjects to
`further characterize the effect of liraglutide on gallbladder motility.
`
`
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`The timetable you submitted on December 16, 2014, states that you will conduct this study
`according to the following schedule:
`
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`Final Protocol Submission: September 2015
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`Study Completion:
`January 2017
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`Final Report Submission:
`September 2017
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`
`Reference ID: 3677762
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`

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`NDA 206321
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`Page 7
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`Submit clinical protocols to your IND 073206 for this product. Submit nonclinical and
`chemistry, manufacturing, and controls protocols and all postmarketing final reports to this
`NDA. In addition, under 21 CFR 314.81(b)(2)(vii) and 314.81(b)(2)(viii) you should include a
`status summary of each commitment in your annual report to this NDA. The status summary
`should include expected summary completion and final report submission dates, any changes in
`plans since the last annual report, and, for clinical studies/trials, number of patients entered into
`each study/trial. All submissions, including supplements, relating to these postmarketing
`commitments should be prominently labeled “Postmarketing Commitment Protocol,”
`“Postmarketing Commitment Final Report,” or “Postmarketing Commitment
`Correspondence.”
`
`RISK EVALUATION AND MITIGATION STRATEGY REQUIREMENTS
`
`
`Section 505-1 of the FDCA authorizes FDA to require the submission of a risk evaluation and
`mitigation strategy (REMS), if FDA determines that such a strategy is necessary to ensure that
`
`the benefits of the drug outweigh the risks [section 505-1(a)].
`
`
`In accordance with section 505-1 of FDCA, we have determined that a REMS is necessary for
`Saxenda (liraglutide) to ensure the benefits of the drug outweigh the potential risk of medullary
`thyroid carcinoma and the risk of acute pancreatitis.
`
`We have also determined that a communication plan is necessary to support implementation of
`the REMS.
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`Your proposed REMS, submitted on December 17, 2014, and appended to this letter, is
`approved. The REMS consists of a communication plan and a timetable for submission of
`assessments of the REMS.
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`Your REMS must be fully operational before you introduce Saxenda (liraglutide) into interstate
`commerce.
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`The REMS assessment plan should include but not be limited to the following:
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`a. An evaluation of the implementation of REMS Communication Plan activities:
`
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`i. Product launch date
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`ii. Number of healthcare providers and professional societies targeted by the REMS.
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`iii. REMS Letter: Number of REMS letters sent to healthcare providers and Professional
`Societies via US mail (or email if this method is added) and the dates the letters were
`sent. Number of letters that were undeliverable will be included. Provide a list of
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`names of professional societies with date of confirmed REMS letter receipt, along
`with any actions taken (e.g., posting on societies website, other outreach to members
`regarding REMS letters).
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`iv. REMS Factsheet: number of healthcare providers detailed and provided the REMS
`Factsheet through the detail.
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`Reference ID: 3677762
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`

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`NDA 206321
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`Page 8
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`v. REMS Slides: number of presentations employing the REMS Slides during the
`reporting period and cumulatively and number of attendees (including targeted
`physicians).
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`vi. Scientific meetings: list of scientific meetings where Novo Nordisk Medical
`Information has a presence (e.g., booth) in which the SAXENDA® REMS Factsheet
` was made available.
`
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`vii. REMS website: Date when the REMS website went live and number of unique site
`visits during the assessment period and cumulative.
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`b. Evaluation of healthcare providers’ knowledge:
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`i. An evaluation of healthcare providers’ knowledge of the potential risk for medullary
`thyroid carcinoma and the risk of acute pancreatitis (including necrotizing
`pancreatitis). Stratify results by type of healthcare provider.
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`ii. An evaluation of healthcare providers’ awareness of REMS materials.
`
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`iii. An evaluation of healthcare providers’ sources of knowledge about the risks
`associated with SAXENDA.
`
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`c. Safety Surveillance and Utilization Data for the reporting period and cumulatively:
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`i. SAXENDA total prescription data by healthcare providers target in SAXENDA call
`plan.
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`ii. A summary and analysis of all SAXENDA postmarketing case reports of (a)
`pancreatitis and b) medullary thyroid carcinoma.
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`d. Evaluation of the extent to which the elements of the REMS are meeting the goals and
`objectives of the REMS and whether modifications to the elements or goals and
`objectives are needed.
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`
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`We remind you that in addition to the assessments submitted according to the timetable included
`in the approved REMS, you must submit a REMS assessment and may propose a modification to
`the approved REMS when you submit a supplemental application for a new indication for use as
`described in section 505-1(g)(2)(A) of the FDCA.
`
`If the assessment instruments and methodology for your REMS assessments are not included in
`the REMS supporting document, or if you propose changes to the submitted assessment
`instruments or methodology, you should update the REMS supporting document to include
`specific assessment instrument and methodology information at least 90 days before the
`assessments will be conducted. Updates to the REMS supporting document may be included in a
`new document that references previous REMS supporting document submission(s) for
`unchanged portions. Alternatively, updates may be made by modifying the complete previous
`REMS supporting document, with all changes marked and highlighted. Prominently identify the
`submission containing the assessment instruments and methodology with the following wording
`in bold capital letters at the top of the first page of the submission:
`
`
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`Reference ID: 3677762
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`

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`NDA 206321
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`Page 9
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`NDA 206321 REMS CORRESPONDENCE
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`(insert concise description of content in bold capital letters, e.g.,
`
`UPDATE TO REMS SUPPORTING DOCUMENT - ASSESSMENT
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`METHODOLOGY)
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`
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`Prominently identify the submission containing the REMS assessments or proposed
`modifications with the following wording in bold capital letters at the top of the first page of the
`submission:
`
`
`NDA 206321 REMS ASSESSMENT
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`NEW SUPPLEMENT FOR NDA 206321
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`PROPOSED REMS MODIFICATION
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`NEW SUPPLEMENT (NEW INDICATION FOR USE)
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`FOR NDA 206321
`REMS ASSESSMENT
`PROPOSED REMS MODIFICATION (if included)
`
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`If you do not submit electronically, please send 5 copies of REMS-related submissions.
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`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
`to:
`
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Prescription Drug Promotion
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
`
`
`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.
`
`
`Reference ID: 3677762
`
`

`

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`NDA 206321
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`Page 10
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` METHODS VALIDATION
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`We have not completed validation of the regulatory methods. However, we expect your
`continued cooperation to resolve any problems that may be identified.
`
` REPORTING REQUIREMENTS
`
`We remind you that you must comply with reporting requirements for an approved NDA
`(21 CFR 314.80 and 314.81).
`
`If you have any questions, call Pat Madara, Regulatory Project Manager, at (301) 796-1249.
`
`
`Sincerely,
`
`{See appended electronic signature page}
`
`James P. Smith, M.D., M.S.
`Deputy Director (Acting)
`Division of Metabolism and Endocrinology Products
`Office of Drug Evaluation II
`Center for Drug Evaluation and Research
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`Enclosures:
`Content of Labeling
`Medication Guide
`Instructions for Use
`Carton and Container Labeling
`REMS
`
`Reference ID: 3677762
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`JAMES P SMITH
`12/23/2014
`
`Reference ID: 3677762
`
`