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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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` NDA 22334/S-31
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`Food and Drug Administration
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`Silver Spring MD 20993
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`SUPPLEMENT APPROVAL
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`Novartis Pharmaceuticals Corporation
`Attention: Joseph V. Posluszny, Ph.D.
`Executive Director, Regulatory Affairs
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`One Health Plaza
`East Hanover, NJ 07936
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`Dear Dr. Posluszny:
`
`Please refer to your Supplemental New Drug Application (sNDA) dated November 20, 2014,
`received November 20, 2014, submitted under section 505(b) of the Federal Food, Drug, and
`Cosmetic Act (FDCA) for Afinitor (everolimus).
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`We acknowledge receipt of your amendments dated April 29, June 5, and September 9, 2015.
`We also refer to your submission of November 20, 2014, containing a postmarketing
`requirement (PMR) report for Study CRAD001C2485, entitled “Everolimus (RAD001) Therapy
`of Giant Cell Astrocytomas in Patients with Tuberous Sclerosis Complex,” and to our
`September 18, 2015, letter stating that PMRs 1700-2 and 1700-4 have been fulfilled.
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`This “Prior Approval” supplemental new drug application revises the CLINICAL STUDIES,
`Subependymal Giant Cell Astrocytoma with Tuberous Sclerosis Complex (14.5) subsection of
`the package insert to provide five-year long term efficacy data results for Study
`CRAD001C2485.
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`The indication for the use of Afinitor for the treatment of patients with subependymal giant cell
`astrocytoma associated with tuberous sclerosis who require therapeutic intervention but are not
`candidates for curative surgical resection was approved under the provisions of accelerated
`approval regulations (21 CFR 314.500) on October 29, 2010. Marketing of this drug product and
`related activities must adhere to the substance and procedures of the referenced accelerated
`approval regulations.
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`We remind you of your postmarketing requirement specified in October 29, 2010, approval letter
`for NDA 22334/S-06. This requirement, along with required completion dates, is listed below.
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`PMR 1700-1:
`Submit the final report (at least 4 years of follow-up) and datasets from M2301, a randomized,
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`double-blind, placebo-controlled, multi-center phase 3 trial evaluating treatment with everolimus
`versus placebo in patients with subependymal giant cell astrocytoma (SEGA) associated with
`tuberous sclerosis (TS).
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`Reference ID: 3822070
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`

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`Final Protocol Submission:
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` Trial Completion:
`Final Report and Dataset Submission:
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`January 2011
`September 2014
`March 2015
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`NDA 22334/S-31
`Page 2
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`The timetable you submitted on October 26, 2010, states that you will conduct this trial
`according to the following schedule:
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`APPROVAL & LABELING
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`We have completed our review of this supplemental 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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`Please note that we have previously granted a waiver of the requirements of 21 CFR
`201.57(d)(8) regarding the length of Highlights of prescribing information.
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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, with the
`addition of any labeling changes in pending “Changes Being Effected” (CBE) supplements, as
`well as annual reportable changes not included in the enclosed labeling.
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`Information on submitting SPL files using eList may be found in the guidance for industry titled
`“SPL Standard for Content of Labeling Technical Qs and As at
`http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/U
`CM072392.pdf.
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`The SPL will be accessible from publicly available labeling repositories.
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`Also within 14 days, amend all pending supplemental applications that includes labeling changes
`for this NDA, including CBE supplements for which FDA has not yet issued an action letter,
`with the content of labeling [21 CFR 314.50(l)(1)(i)] in MS Word format, that includes the
`changes approved in this supplemental application, as well as annual reportable changes and
`annotate each change. To facilitate review of your submission, provide a highlighted or marked-
`up copy that shows all changes, as well as a clean Microsoft Word version. The marked-up copy
`should provide appropriate annotations, including supplement number(s) and annual report
`date(s).
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`Reference ID: 3822070
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`NDA 22334/S-31
`Page 3
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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 none of these criteria apply to your application, you are exempt from this requirement.
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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 the following, in triplicate, (1) a cover letter requesting advisory
`comments, (2) the proposed materials in draft or mock-up form with annotated references, and
`(3) the package insert(s) to:
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`OPDP Regulatory Project Manager
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Prescription Drug Promotion (OPDP)
`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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`You must submit final promotional materials and package insert(s), accompanied by a Form
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`FDA 2253, at the time of initial dissemination or publication [21 CFR 314.81(b)(3)(i)]. 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: 3822070
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`

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`NDA 22334/S-31
`Page 4
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`If you have any questions, please call Ms. Sharon Sickafuse, Senior Regulatory Health Project
`Manager, at (301) 796-2320.
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`Sincerely,
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`{See appended electronic signature page}
`
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`Patricia Keegan, M.D.
`Director
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`Division of Oncology Products 2
`Office of Hematology and Oncology Products
`Center for Drug Evaluation and Research
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`ENCLOSURE:
`Content of Labeling
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`Reference ID: 3822070
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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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`PATRICIA KEEGAN
`09/18/2015
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`Reference ID: 3822070
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