`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
` NDA 022334/S-009/S-010
`
`
`
`
`
`
`
`
`
`Food and Drug Administration
`
`Silver Spring MD 20993
`
`
`SUPPLEMENT APPROVAL
`
`
`Lincy Thomas, Pharm.D.
`Senior Associate Director
`
`Novartis Pharmaceuticals Corporation
`One Health Plaza
`East Hanover, New Jersey 07936-1080
`
`Attention:
`
`
`
`Dear Dr. Thomas:
`
`Please refer to your Supplemental New Drug Applications (sNDAs) dated November 4 and
`December 23, 2010, received November 5 and December 27, 2010, respectively, submitted
`under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA) for Afinitor®
`
`(everolimus) Tablets, 2.5 mg, 5 mg, and 10 mg.
`
`We acknowledge receipt of your amendments dated December 14 (2), 15, 20, 22 (2), 2010,
`January 6 (2), 17, 21 (2), 27, 31, February 2 (2), 3, 4 (2), 11 (2), 15, 17, 18, 23, March 2, 8, 9, 10,
`15, 18, 24, 25, 30, April 4 (2), 25, and May 4, 2011.
`
`“Prior Approval” supplemental new drug application S-009 provides for a new indication in
`patients with progressive neuroendocrine tumors of pancreatic origin (PNET) that are
`unresectable, locally advanced, or metastatic.
`
`“Prior Approval” supplemental new drug application S-010 provides for the addition of safety
`information to the prescribing information for Afinitor® (everolimus). Specifically, the changes
`
`include the addition of language to the label regarding renal failure and urinary protein
`monitoring to the Warnings and Precautions section, and the addition of pulmonary embolism to
`the Adverse Reactions section.
`
`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.
`
`
`CONTENT OF LABELING
`
`
`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, text for the
`
`Reference ID: 2942958
`
`

`

`
`
` NDA 022334/S-009/S-010
`Page 2
`
`
` 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.
`
`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.
`
`The SPL will be accessible from publicly available labeling repositories.
`
`Also within 14 days, amend all pending supplemental applications 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).
`
`We request that the labeling approved today be available on your website within 10 days of
`receipt of this letter.
`
`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 indication in pediatric patients unless this requirement is waived,
`deferred, or inapplicable.
`
`Because this drug product for these indications has an orphan drug designation, you are exempt
`from this requirement.
`
`
`POSTMARKETING REQUIREMENTS UNDER 505(o)
`
`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.
`
`Since Afinitor® (everolimus) Tablets were approved on March 30, 2009, we have become aware
`of two trials in which information on overall survival has not been reported. A decrease in
`overall survival of patients treated with Afinitor® (everolimus) Tablets would change the safety
`profile of this drug for this indication. We consider this information to be “new safety
`information” as defined in section 505-1(b)(3) of the FDCA.
`
`
`Reference ID: 2942958
`
`

`

`
`
` NDA 022334/S-009/S-010
`Page 3
`
`
`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 the signal of a serious
`risk of a decrease in overall survival of patients treated with Afinitor® (everolimus) Tablets.
`
`Furthermore, the new pharmacovigilance system that FDA is required to establish under section
`505(k)(3) of the FDCA is not yet sufficient to assess this serious risk.
`
`Finally, we have determined that only a clinical trial (rather than a nonclinical or observational
`study) will be sufficient to assess the signal of a serious risk of a decrease in overall survival of
`patients treated with Afinitor® (everolimus) Tablets.
`
`Therefore, based on appropriate scientific data, FDA has determined that you are required to
`conduct the following:
`
`
`1756-1
`
`
`Submit the results of the final analysis of overall survival data from
`
`
`RAD001C2324 to further characterize the safety and efficacy profile of
`
`everolimus in pancreatic neuroendocrine tumors.
`
`
`
`
`The timetable you submitted on May 4, 2011, states that you will conduct this trial according to
`the following schedule:
`
` Trial Completion:
`
`
`Final Report Submission:
`
` Submit the results of the final analysis of overall survival data from
`
`
`RAD001C2325 to further characterize the safety and efficacy profile of
`
`everolimus in carcinoid tumors.
`
`
`October 2013
`
`July 2014
`
`
`1756-2
`
`
`
`The timetable you submitted on May 4, 2011, states that you will conduct this trial according to
`the following schedule:
`
`
`October 2011
`
`July 2012
`
`
`
`
`Trial Completion:
`Final Report Submission:
`
`Submit all updates and final reports 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)”.
`
`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.
`
`
`Reference ID: 2942958
`
`

`

`
`
` NDA 022334/S-009/S-010
`Page 4
`
`
`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 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.
`
`
`PROMOTIONAL MATERIALS
`
`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:
`
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Division of Drug Marketing, Advertising, and Communications
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
`
`
`
`You must submit final promotional materials and package insert(s), accompanied by a Form
`
`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/opacom/morechoices/fdaforms/cder.html;
`instructions are provided on page 2 of the form. For more information about submission of
`promotional materials to the Division of Drug Marketing, Advertising, and Communications
`(DDMAC), see http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm.
`
`
`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 Christy Cottrell, Regulatory Project Manager, at (301) 796-4256.
`
`
`Sincerely,
`
`
`{See appended electronic signature page}
`
`Robert L. Justice, M.D., M.S.
`
`Director
`Division of Drug Oncology Products
`Office of Oncology Drug Products
`Center for Drug Evaluation and Research
`
`
`
`Reference ID: 2942958
`
`

`

`
`
` NDA 022334/S-009/S-010
`Page 5
`
`
`ENCLOSURE:
`Content of Labeling
`
`
`
`
`
`Reference ID: 2942958
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`ROBERT L JUSTICE
`05/05/2011
`
`Reference ID: 2942958
`
`