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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`Food and Drug Administration
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`Silver Spring MD 20993
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`NDA 22334/S-32
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`NDA 203985/S-10
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`SUPPLEMENT APPROVAL
`FULFILLMENT OF POSTMARKETING
`REQUIREMENTS
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`Novartis Pharmaceuticals Corporation
`Attention: Rose Gao
`Director, Oncology Drug Regulatory Affairs
`One Health Plaza
`Building 315, 4th Floor
`East Hanover, NJ 07936
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`Dear Ms. Gao:
`
`Please refer to your supplemental New Drug Applications (sNDAs) dated March 31, 2015,
`received March 31, 2015, and your amendments, submitted under section 505(b) of the Federal
`Food, Drug, and Cosmetic Act (FDCA), for AFINITOR® (everolimus) tablets for oral
`administration and AFINITOR® DISPERZ (everolimus tablets for oral suspension).
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` These Prior Approval supplemental new drug applications confirm the clinical benefit of
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`AFINITOR and AFINITOR DISPERZ for the treatment of pediatric and adult patients with
`tuberous sclerosis complex (TSC) who have subependymal giant cell astrocytoma (SEGA) that
`requires therapeutic intervention but cannot be curatively resected, approved on October 29,
`2010, for AFINITOR and approved on August 29, 2012, for AFINITOR DISPERZ under the
`provisions of 21 CFR 314.510. The INDICATIONS AND USAGE, Subependymal Giant Cell
`Astrocytoma (SEGA) with Tuberous Sclerosis Complex (TSC) subsection has been revised to
`remove the following language (italicized): The effectiveness of AFINITOR Tablets and
`AFINITOR DISPERZ is based on demonstration of durable objective response, as evidenced by
`reduction in SEGA tumor volume. Improvement in disease-related symptoms and overall survival
`in patients with SEGA and TSC has not been demonstrated. In addition, the ADVERSE
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`REACTIONS, USE IN SPECIFC POPULATIONS, Pediatric Use, and CLINICAL STUDIES
`sections of labeling have been revised with the results of the clinical trial verifying the clinical
`benefit of AFINITOR and AFINITOR DISPERZ in this population.
`
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`APPROVAL & LABELING
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`We have completed our review of these supplemental applications, as amended. They are
`approved, effective on the date of this letter, for use as recommended in the enclosed, agreed-
`upon labeling text.
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`Reference ID: 3879270
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`NDA 22334/S-32
`NDA 203985/S-10
`Page 2
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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 and text for the
`patient 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 these NDAs, 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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`We request that the labeling approved today be available on your website within 10 days of
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`receipt of this letter.
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`SUBPART H FULFILLED
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`We approved NDA 22334/S-6 and NDA 203985 under the regulations at 21 CFR 314 Subpart H
`for accelerated approval of new drugs for serious or life-threatening illnesses. Approval of NDA
`22334/S-32 and NDA 203985/S-10 fulfills the below post marketing requirement
`(PMR #1700-1) made under 21 CFR 314.510:
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`Reference ID: 3879270
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`NDA 22334/S-32
`NDA 203985/S-10
`Page 3
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`PMR 1700-1:
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`Submit the final report (at least 4 years of follow-up) and datasets from M2301, a randomized,
`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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`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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`FULFILLMENT OF POSTMARKETING REQUIREMENTS
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`We have also received your submissions dated March 31, 2015, containing the final reports for
`the following postmarketing requirement listed in the October 29, 2010, approval letter for
`NDA 22334/S-6 and the August 29, 2012, approval letter for NDA 203985.
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`PMR 1700-3:
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`To evaluate the potential for serious risk of adverse long-term effects of Afinitor (everolimus) on
`growth for pediatric patients, submit long-term follow-up data on patients enrolled on M2301, a
`randomized, double-blind, placebo-controlled, multi-center phase 3 trial evaluating treatment
`with Afinitor (everolimus) versus placebo in patients with subependymal giant cell astrocytoma
`(SEGA) associated with tuberous sclerosis (TS).
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`
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`We have reviewed your submission and conclude that the above requirement was fulfilled. You
`are no longer required to report on this requirement.
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`We remind you that there are postmarketing requirements listed in the April 26, 2012, and
`July 20, 2012, approval letters that are still open.
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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
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`Reference ID: 3879270
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`NDA 22334/S-32
`NDA 203985/S-10
`Page 4
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`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
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`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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`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}
`
`
`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: 3879270
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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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`JOSEPH E GOOTENBERG on behalf of PATRICIA KEEGAN
`01/29/2016
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`Reference ID: 3879270
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