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` NDA APPROVAL
`
`Sibylle R. Jennings, Ph.D.
`Senior Associate Director, Drug Regulatory Affairs
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`DEPARTMENT OF HEALTH & HUMAN SERVICES
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`Public Health Service
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`Food and Drug Administration
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`Rockville, MD 20857
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`NDA 22-334
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`Novartis Pharmaceuticals Corporation
`One Health Plaza
`East Hanover, NJ 07936-1080
`
`Attention:
`
`
`
`Dear Dr. Jennings:
`
`
`Please refer to your new drug application (NDA) dated June 27, 2008, received June 30, 2008,
`submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA) for
`Afinitor® (everolimus) tablets 5 mg and 10 mg.
`
`We acknowledge receipt of your submissions dated July 29, August 4, 20, 21 (2), 26, 29,
`September 5 (2), 9, 11, 25 (2), 29 (2), 30 (2), October 14, 17, 20, 21, 24, 28, 31, November 11,
`19, 26, December 5, 10, 22, 2008, January 12, 20, 30, February 5, 10, 17, 18, 20, 23 (2), 25, 26,
`27, March 3, 10, 11, 12, 20, 25, and 27, 2009.
`
`This new drug application provides for the use of Afinitor® (everolimus) tablets for the treatment
`of patients with advanced renal cell carcinoma after failure of treatment with sunitinib or
`sorafenib.
`
`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.
`
`An expiration dating period of 24 months is granted when stored as recommended in the
`approved product labeling. You may extend the expiration dating based on accrual of real-time
`stability data and report this in an annual report for this NDA.
`
`This application was not taken to a meeting of the Oncologic Drugs Advisory Committee
`(ODAC) because the application is based on a trial demonstrating a clinically and statistically
`significant improvement in progression-free survival with an acceptable benefit/risk ratio.
`Progression-free survival has previously been used as the basis for approval of drugs for the
`treatment of advanced renal cell carcinoma and the safety profile is similar to that of other drugs
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`approved for this indication.
`
`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
`
`
`

`

`NDA 22-334
`Page 2
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`product for the claimed indication(s) in pediatric patients unless this requirement is waived,
`deferred, or inapplicable.
`
`We are waiving the pediatric study requirement for this application because necessary studies are
`impossible or highly impracticable since this disease does not occur in the pediatric population.
`
`POSTMARKETING REQUIREMENTS UNDER 505 (o)
`
`
`Title IX, Subtitle A, Section 901 of the Food and Drug Administration Amendments Act of 2007
`(FDAAA) amends the FDCA to authorize 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 (section 505(o)(3)(A), 21 U.S.C.
`355(o)(3)(A)). This provision took effect on March 25, 2008.
`
`Trial A2303 evaluated everolimus in patients with moderate hepatic impairment (Child Pugh
`Class B) and due to increases in everolimus exposure, a dose reduction is needed in these
`patients. No exposure data are available for patients with severe hepatic impairment and
`current labeling recommends that Afinitor® (everolimus) should not be used in these
`patients.
`
`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 identify an unexpected serious
`risk of increased drug exposure when Afinitor® (everolimus) is administered to patients with
`severe hepatic impairment.
`
`Furthermore, the new pharmacovigilance system that FDA is required to establish under section
`505(k)(3) of the FDCA has not yet been established and is not sufficient to assess these serious
`risks.
`
`
`Finally, we have determined that only a clinical trial (rather than a nonclinical or
`observational study) will be sufficient to assess the unexpected serious risk of increased drug
`exposure when Afinitor® (everolimus) is administered to patients with severe hepatic
`impairment.
`
`Therefore, based on appropriate scientific data, FDA has determined that you are required,
`pursuant to section 505(o)(3) of the FDCA, to complete the following postmarketing clinical
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`trial:
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`1. Conduct a trial in patients with severe hepatic impairment (Child Pugh Class C). This
`trial need not be conducted in patients with cancer and a single dose evaluation will be
`appropriate. The protocol should be submitted prior to initiation for review and
`concurrence.
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`The timetable you submitted on March 3, 2009 states that you will conduct this trial
`according to the following timetable:
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`Final Protocol Submission:
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`Trial Start Date:
`Final Report Submission:
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`
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`May 14, 2009
`October 14, 2009
`April 14, 2011
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`

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`NDA 22-334
`Page 3
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`
`Submit protocols to your IND 66,279, with a cross-reference letter to this NDA 22-334. Submit
`all final report(s) to your NDA. Use the following designators to prominently label all
`submissions, including supplements, relating to this postmarketing requirement as appropriate:
`
`
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`• Required Postmarketing Protocol under 505(o)
`
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`• Required Postmarketing Final Report under 505(o)
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`• Required Postmarketing Correspondence under 505(o)
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`
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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.
`
`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.
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`POSTMARKETING COMMITMENTS
`
`
`We remind you of your postmarketing commitments in your submission dated March 27, 2009.
`These commitments are listed below.
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`2. Submit the final, per-protocol overall survival analysis of protocol C2240 which was to
`be conducted 2 years after randomization of the last patient.
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`
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`Protocol Submission:
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`Trial Start Date:
`Final Report Submission:
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`July 27, 2006
`December 6, 2006
`June 2010
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`3.
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`Protocol Submission Date: May 14, 2009
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`Final Report Submission:
`January 14, 2010
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`(b) (4)
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`

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`NDA 22-334
`Page 4
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`Submit clinical protocols to your IND for this product. Submit nonclinical and chemistry,
`manufacturing, and controls protocols and all 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 trials number of patients entered into each 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.”
`
`CONTENT OF LABELING
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`
`
`As soon as possible, but no later than 14 days from the date of this letter, please submit the
`content of labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format as described
`at http://www.fda.gov/oc/datacouncil/spl.html that is identical to the enclosed labeling (text for
`the package insert and patient package insert). Upon receipt, we will transmit that version to the
`National Library of Medicine for public dissemination. For administrative purposes, please
`designate this submission, “SPL for approved NDA 22-334.”
`
`CARTON AND IMMEDIATE CONTAINER LABELS
`
`
`Submit final printed carton and 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 titled
`Providing Regulatory Submissions in Electronic Format – Human Pharmaceutical Product
`Applications and Related Submissions Using the eCTD Specifications (October 2005).
`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 22-334.” Approval of this
`submission by FDA is not required before the labeling is used.
`
`Marketing the product(s) 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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`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(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
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`
`
`

`

`NDA 22-334
`Page 5
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`As required under 21 CFR 314.81(b)(3)(i), you must submit final promotional materials, and the
`package insert(s), at the time of initial dissemination or publication, accompanied by a Form
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`FDA 2253. For instruction on completing the Form FDA 2253, see page 2 of the Form. For
`more information about submission of promotional materials to the Division of Drug Marketing,
`Advertising, and Communications (DDMAC), see www.fda.gov/cder/ddmac.
`
`METHODS VALIDATION
`
`
`We have not completed validation of the regulatory methods. However, we expect your
`continued cooperation to resolve any problems that may be identified.
`
`LETTERS TO HEALTH CARE PROFESSIONALS
`
`
`If you issue a letter communicating important safety related information about this drug product
`(i.e., a “Dear Health Care Professional” letter), we request that you submit an electronic copy of
`the letter to both this NDA and to the following address:
`
`
`
`MedWatch
`
`Food and Drug Administration
`
`Suite 12B05
`
`5600 Fishers Lane
`
`Rockville, MD 20857
`
`
`REPORTING REQUIREMENTS
`
`
`We remind you that you must comply with reporting requirements for an approved NDA (21
`CFR 314.80 and 314.81).
`
`MEDWATCH-TO-MANUFACTURER PROGRAM
`
`
`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 www.fda.gov/medwatch/report/mmp.htm.
`
`
`If you have any questions, call Christy Cottrell, Regulatory Project Manager, at (301) 796-4256.
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`
`
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`Sincerely,
`
` {See appended electronic signature page}
`
`Richard Pazdur, M.D.
`
`Director
`Office of Oncology Drug Products
`Center for Drug Evaluation and Research
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`
`
`Enclosure
`
`

`

`---------------------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`---------------------------------------------------------------------------------------------------------------------
`/s/
`
`---------------------
`Richard Pazdur
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`3/30/2009 01:00:32 PM
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`
`