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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`NDA 208700
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`Food and Drug Administration
`Silver Spring MD 20993
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`NDA APPROVAL
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`Advanced Accelerator Applications USA, Inc.
`Attention: Victor Paulus, Ph.D.
`Global Head, Regulatory Affairs
`350 Fifth Avenue, Suite 6902
`New York, NY 10118
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`Dear Dr. Paulus:
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`Please refer to your New Drug Application (NDA) submitted and received April 28, 2016, and
`your amendments, submitted under section 505(b)(1) of the Federal Food, Drug, and Cosmetic
`Act for Lutathera (lutetium Lu 177 dotatate), injection for intravenous use, 370 MBq/mL. We
`also refer to our December 19, 2016, action letter regarding the application.
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`We acknowledge receipt of your amendment dated July 26, 2017, which constituted a complete
`response to our December 19, 2016, action letter.
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`This new drug application provides for the use of Lutathera (lutetium Lu 177 dotatate) injection
`for intravenous use, 370 MBq/mL for the treatment of somatostatin receptor positive GEP-NETs
`including foregut, midgut, and hindgut neuroendocrine tumors in adults.
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`APPROVAL
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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 labeling text.
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`WAIVER OF HIGHLIGHTS SECTION
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`We are waiving the requirements of 21 CFR 201.57(d)(8) regarding the length of Highlights of
`prescribing information. This waiver applies to all future supplements containing revised
`labeling unless we notify you otherwise.
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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 prescribing information,
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`Reference ID: 4212675
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`

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`NDA 208700
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`Page 2
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`Information on submitting SPL files using eLIST may be found in the guidance for industry SPL
`Standardfor Content ofLabeling Technical Qs and As, available at
`hm; ://www.fda . gov/downloads/Drugs/GuidanceComplianceRegulatOQInformation/Guidances/U
`CM072392 .pdf.
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`The SPL will be accessible via publicly available labeling repositories.
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`CARTON AND INIMEDIATE CONTAINER LABELS
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`Submit final printed carton and immediate container labels that are identical to the carton and
`immediate container labels submitted on January 22, 2018, as soon as they are available, but no
`more than 30 days after they are printed. Please submit these labels electronically according to
`the guidance for industry titled Providing Regulatory Submissions in Electronic Format —
`Certain Human Pharmaceutical Product Applications and Related Submissions Using the eCTD
`Specifications (May 2015, Revision 3). For administrative purposes, designate this submission
`“Final Printed Carton and Container Labels for approved NDA 208700.” Approval of this
`submission by FDA is not required before the labeling is used.
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`DATING PERIOD
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`The dating period for Lutathera shall be 72 hours post calibration, defined as
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`(we)
`when stored below
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`25 °C (77°C).
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`ADVISORY CONINIITTEE
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`Your application for lutetium Lu 177 dotatate was not referred to an FDA advisory committee
`because there were no public health issues raised that would benefit from a public discussion or
`that required the expert opinions of the Committee. In addition, the safety profile of the drug is
`deemed acceptable for the indicated population of patients.
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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 new
`active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of
`administration are required to contain an assessment of the safety and effectiveness of the
`product for the claimed indication(s) in pediatric patients unless this requirement is waived,
`deferred, or inapplicable.
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`Because this drug product for this indication has an orphan drug designation, you are exempt
`from this requirement.
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`Reference ID: 421 2675
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`NDA 208700
`Page 3
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`POSTMARKETING REQUIREMENTS UNDER 505(o)
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`Section 505(o)(3) of the Federal Food, Drug, and Cosmetic Act (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.
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`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 known serious risks of
`renal failure, myelodysplastic syndrome, and acute leukemia.
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`Furthermore, the new pharmacovigilance system that FDA is required to establish under section
`505(k)(3) of the FDCA will not be sufficient to assess these serious risks.
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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 these known serious risks.
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`Therefore, based on appropriate scientific data, FDA has determined that you are required to
`conduct the following trials:
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`3326-01
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`Submit cumulative, integrated safety analyses after 5 and after 10 years of follow-
`up from an adequate number of patients enrolled in clinical trials to identify and
`characterize the risk of renal failure with Lutathera; include incidence rates, time
`to onset, predisposing factors and outcomes. These safety evaluations should be
`adequate to inform labeling of patient populations at highest risk and to provide
`evidence-based dose modifications and monitoring recommendations.
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`The timetable you submitted on December 21, 2017, states that you will conduct
`this trial according to the following schedule:
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`Final Analysis Plan Submission:
`Interim Safety Report Submission:
`Final Report Submission:
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`June 2018
`September 2021
`December 2025
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`Submit cumulative, integrated safety analyses after 5 and after 10 years of follow-
`up from an adequate number of patients enrolled in clinical trials to identify and
`characterize the risks of myelodysplastic syndrome and acute leukemia with
`Lutathera; include incidence rates, time to onset, predisposing factors and
`outcomes. These safety evaluations should be adequate to inform labeling of
`patient populations at highest risk and to provide evidence-based dose
`modifications and monitoring recommendations.
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`The timetable you submitted on December 21, 2017, states that you will conduct
`this trial according to the following schedule:
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`3326-02
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`Reference ID: 4212675
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`

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`NDA 208700
`Page 4
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`Final Analysis Plan Submission:
`Interim Safety Report Submission:
`Final Report Submission:
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`June 2018
`September 2021
`December 2025
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`Submit Safety Reports to your IND 077219 with a cross-reference letter to this 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
`safety analyses required under this section. This section also requires you to periodically report
`to FDA on the status of any safety evaluations 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 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 safety analysis otherwise undertaken to investigate a
`safety issue. Failure to submit an annual report for safety analyses 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.
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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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`3326-03
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`Submit the final clinical report and datasets at the time of the final analysis for
`overall survival (OS) for Trial NETTER-1, entitled “A Multicentre, stratified,
`open, randomized, comparator-controlled, parallel-group phase III study
`comparing treatment with 177 Lu-DOTA0-Tyr3-Octreotate to Octreotide LAR in
`Patients with Inoperable, Progressive, Somatostin Receptor Positive, Midgut
`Carcinoid Tumors”, to revise product labeling with mature OS data.
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`The timetable you submitted on January 11, 2018, states that you will conduct this
`trial according to the following schedule:
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`Final Report Submission: May 2021
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`Reference ID: 4212675
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`NDA 208700
`Page 5
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`Submit clinical protocols to your IND 077219 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.”
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`PROMOTIONAL MATERIALS
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`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 prescribing
`information, Medication Guide, and patient PI (as applicable) to:
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`OPDP Regulatory Project Manager
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Prescription Drug Promotion
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
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`Alternatively, you may submit a request for advisory comments electronically in eCTD format.
`For more information about submitting promotional materials in eCTD format, see the draft
`Guidance for Industry (available at:
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM443702.pdf).
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`As required under 21 CFR 314.81(b)(3)(i), you must submit final promotional materials, and the
`prescribing information, 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.
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`REPORTING REQUIREMENTS
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`We remind you that you must comply with reporting requirements for an approved NDA
`(21 CFR 314.80 and 314.81).
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`Reference ID: 4212675
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`

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`NDA 208700
`Page 6
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`MEDWATCH-TO-MANUFACTURER PROGRAM
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`The MedWatch-to-Manufacturer Program provides manufacturers with copies of serious adverse
`event reports that are received directly by the FDA. New molecular entities and important new
`biologics qualify for inclusion for three years after approval. Your firm is eligible to receive
`copies of reports for this product. To participate in the program, please see the enrollment
`instructions and program description details at
`http://www.fda.gov/Safety/MedWatch/HowToReport/ucm166910.htm.
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`POST APPROVAL FEEDBACK MEETING
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`New molecular entities and new biologics qualify for a post approval feedback meeting. Such
`meetings are used to discuss the quality of the application and to evaluate the communication
`process during drug development and marketing application review. The purpose is to learn from
`successful aspects of the review process and to identify areas that could benefit from
`improvement. If you would like to have such a meeting with us, call the Regulatory Project
`Manager for this application.
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`If you have any questions, call Nataliya Fesenko, Regulatory Health Project Manager, at
`(240) 402-6376.
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`Sincerely,
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`{See appended electronic signature page}
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`Richard Pazdur, M.D.
`Director
`Office of Hematology and Oncology Products
`Center for Drug Evaluation and Research
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`Enclosures:
`Content of Labeling
`Carton and Container Labeling
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`Reference ID: 4212675
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`

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`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
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`RICHARD PAZDUR
`01/26/2018
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`Reference ID: 4212675
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