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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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` NDA 202570/S-014
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`Food and Drug Administration
`Silver Spring MD 20993
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`SUPPLEMENT APPROVAL/
`FULFILLMENT OF POSTMARKETING COMMITMENT
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` PF PRISM C.V.
`c/o Pfizer, Inc.
`Attention: J. Nicole Earnhardt, Ph.D., RAC
`Manager, Worldwide Safety & Regulatory
`10646 Science Center Drive
`San Diego, CA 92121
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`Dear Dr. Earnhardt:
`
`Please refer to your Supplemental New Drug Application (sNDA) dated November 14, 2014,
`received November 14, 2014, submitted under section 505(b) of the Federal Food, Drug, and
`Cosmetic Act (FDCA) for XALKORI (crizotinib).
`
`We acknowledge receipt of your amendments dated February 13 (2), February 23, March 11,
`March 20, May 22, June 1, June 19, June 29, July 13, July 29, September 1, September 4,
`September 9, September 10, September 11, and September 14 (3), 2015.
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`This Prior Approval supplemental new drug application provides for inclusion of data from
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`Study A8081014 (Study 1) in the Adverse Reactions and Clinical Studies sections, inclusion of
`updated safety information across multiple clinical studies in the Warnings and Precautions
`section (5.1, 5.2, 5.3, 5.4), a new Warnings and Precautions subsection entitled Severe Visual
`Loss (5.5), modifications to Dosage and Administration (2.2), modifications to Warnings and
`Precautions, Embryofetal Toxicity (5.6) and Use in Specific Populations (8.1, 8.2, 8.3, and 8.4),
`for compliance with the Pregnancy and Lactation Labeling Rule, removal of information in
`information in Clinical Pharmacology (12.2) based on updates to this information that is now
`included in Warnings and Precautions (5.3), and modifications to Patient Counseling (17) and
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` Patient Labeling corresponding to modifications of other sections of product labeling.
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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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`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
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`Reference ID: 3819612
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`

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`NDA 202570/S-014
`Page 2
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`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
`patient package insert), with the addition of any labeling changes in pending “Changes Being
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`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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`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 COMMITMENTS
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`We have also reviewed the results from study A8081014, submitted on November 14, 2015, to
`fulfill Postmarketing Commitment (PMC) 2100-2. This PMC was listed in the November 20,
`2013 sNDA approval letter, as:
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`2100-2
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`Clinical trial report and datasets from A8081014: Phase 3, Randomized, Open-
`label Study of the Efficacy and Safety of Crizotinib vs. Pemetrexed/Cisplatin or
`Pemetrexed/ Carboplatin in Previously Untreated Patients with Non-Squamous
`Carcinoma of the Lung Harboring a Translocation or Inversion Event Involving
`the Anaplastic Lymphoma Kinase Gene Locus.
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`
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`We have reviewed your submission and conclude that the above commitment was fulfilled.
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`Reference ID: 3819612
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`

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`NDA 202570/S-014
`Page 3
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`We remind you that there are still postmarking requirements and commitments listed in the
`August 26, 2011, and November 20, 2013, approval letters that are still open.
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`POSTMARKETING REQUIREMENTS UNDER 505(o)
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`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.
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`Since XALKORI (crizotinib) was approved on August 26, 2011, we have become aware of cases
`of severe visual loss from clinical trial data and postmarketing adverse event reports. We
`consider this information to be “new safety information” as defined in section 505-1(b)(3) of the
`FDCA.
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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 the known serious
`risk of severe visual loss.
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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 this serious risk.
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`Therefore, based on appropriate scientific data, FDA has determined that you are required to
`conduct the following:
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`2956-1
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`Conduct an Enhanced Pharmacovigilance Study to evaluate the risk factors for
`and outcomes of severe visual loss following exposure to XALKORI (crizotinib).
`This study will include a mechanism to collect, classify, and analyze data on
`Grade 4 severe visual loss in patients exposed to crizotinib The study, at a
`minimum, will include the following key elements:
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` Data collection of retrospective data points (best corrected visual acuity,
`retinal photographs, visual fields, optical coherence tomography (OCT),
`and other evaluations as appropriate for new onset of severe visual loss) to
`produce informative, reliable outcome measures.
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` Data analysis utilizing descriptive statistics for summarizing data that will
`fully capture the outcome of concern.
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`The timetable you submitted on September 14, 2015, states that you will conduct this study
`according to the following schedule:
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`Reference ID: 3819612
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`NDA 202570/S-014
`Page 4
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`Final Protocol Submission: 03/16
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`Study Start:
`03/16
`Interim Report Submission: 10/16
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`Interim Report Submission: 10/17
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`Interim Report Submission: 10/18
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`Interim Report Submission: 10/19
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`Interim Report Submission: 10/20
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`Study Completion:
`03/21
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`Final Report Submission:
`12/21
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`Each annual interim and final report should constitute a stand- alone report of cumulative severe
`visual loss outcomes data.
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`Submit the protocol(s) to your IND 73544, with a cross-reference letter to this NDA. Submit all
`final report(s) to your 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
`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.
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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 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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`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
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`Food and Drug Administration
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`Center for Drug Evaluation and Research
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`Office of Prescription Drug Promotion (OPDP)
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`Reference ID: 3819612
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`NDA 202570/S-014
`Page 5
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`5901-B Ammendale Road
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`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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`All promotional materials that include representations about your drug product must be promptly
`revised to be consistent with the labeling changes approved in this supplement, including any
`new safety information [21 CFR 314.70(a)(4)]. The revisions in your promotional materials
`should include prominent disclosure of the important new safety information that appears in the
`revised package labeling. Within 7 days of receipt of this letter, submit your statement of intent
`to comply with 21 CFR 314.70(a)(4) to the address above, by fax to 301-847-8444, or
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`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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`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, call Ingrid Fan, Regulatory Project Manager, at (301) 796-5053.
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`Sincerely,
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`{See appended electronic signature page}
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`Patricia Keegan, M.D.
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`Director
`Division of Oncology Products 2
`Office of Hematology and Oncology Products
`Center for Drug Evaluation and Research
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`Reference ID: 3819612
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`NDA 202570/S-014
`Page 6
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`ENCLOSURE(S):
`Content of Labeling
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`Reference ID: 3819612
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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
`09/14/2015
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`Reference ID: 3819612
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