`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`
`APPLICATION NUMBER:
`
`202570Orig1s000
`
`XALKORI® Capsules, 200 mg and 250 mg.
`
` XALKORI is a kinase inhibitor indicated for the
`treatment of patients with locally advanced or
`metastatic non-small cell lung cancer (NSCLC) that is
`anaplastic lymphoma kinase (ALK)-positive as
`detected by an FDA-approved test. (1) This indication
`is based on response rate. There are no data available
`demonstrating improvement in patient reported
`outcomes or survival with
`XALKORI.
`
`Trade Name:
`
`Generic Name:
`
`Sponsor:
`
`Approval Date:
`
`Indications:
`
`crizotinib
`
`Pfizer Inc.
`
`August 24, 2011
`
`

`

`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`202570Orig1s000
`
`CONTENTS
`
`Reviews / Information Included in this NDA Review.
`
`
`
`Approval Letter
`Other Action Letters
`Labeling
`REMS
`Summary Review
`Officer/Employee List
`Office Director Memo
`Cross Discipline Team Leader Review
`Medical Review(s)
`Chemistry Review(s)
`Environmental Assessment
`Pharmacology Review(s)
`Statistical Review(s)
`Microbiology Review(s)
`Clinical Pharmacology/Biopharmaceutics Review(s)
`Other Reviews
`Risk Assessment and Risk Mitigation Review(s)
`Proprietary Name Review(s)
`Administrative/Correspondence Document(s)
`
`
`X
`
`X
`
`X
`X
`X
`X
`X
`X
`
`X
`X
`X
`X
`X
`X
`X
`X
`
`

`

`
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`202570Orig1s000
`
`APPROVAL LETTER
`
`
`
`

`

`
`
`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
`
`
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`ACCELERATED APPROVAL
`
`NDA 202570
`
`
`Pfizer Inc.
`Attention: Ron C. Domingo, M.S., RAC
`Manager
`Worldwide Regulatory Strategy
`10646 Science Center Drive
`San Diego, CA 92121
`
`
`Dear Mr. Domingo:
`
`Please refer to your New Drug Application (NDA) dated March 30, 2011, received March 30,
`2011, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA) for
`XALKORI® (crizotinib) Capsules, 200 mg and 250 mg.
`
`We acknowledge receipt of your amendments dated January 4, 2011; February 22, 2011;
`February 24, 2011; March 31, 2011; April 13, 2011; April 15, 2011; April 26, 2011;
`May 3, 2011; May 19, 2011; May 24, 2011; May 26, 2011; June 6, 2011; June 8, 2011;
`June 9, 2011; June 13, 2011; June 14, 2011; June 15, 2011; June 17, 2011; June 23, 2011;
`June 24, 2011; June 30, 2011; July 1, 2011 (2); July 6, 2011; July 7, 2011; July 12, 2011;
`July 13, 2011 (2); July 15, 2011; July 21, 2011; July 22, 2011; July 26, 2011; July 27, 2011;
`August 1, 2011 (2); August 2, 2011(2); August 3, 2011; August 5, 2011; August 8, 2011;
`August 10, 2011; August 11, 201l; August 12, 2011; August 15, 2011; August 17, 2011;
`August 18, 2011; August 23, 2011 (2); August 24, 2011, and August 26, 2011.
`
`This new drug application provides for the use of XALKORI (crizotinib) Capsules, 200 mg and
`250 mg, for the treatment of patients with locally advanced or metastatic non-small cell lung
`cancer (NSCLC) that is anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-
`approved test. This indication is based on response rate. There are no data available
`demonstrating improvement in patient reported outcomes or survival with XALKORI.
`
`We have completed our review of this application, as amended. It is approved under the
`provisions of accelerated approval regulations (21 CFR 314.500), effective on the date of this
`letter, for use as recommended in the enclosed agreed-upon labeling text and required patient
`labeling. Marketing of this drug product and related activities must adhere to the substance and
`procedures of the referenced accelerated approval regulations.
`
`Based on the stability data provided in your application, the drug product is granted a fifteen (15)
`month expiry as packaged in the proposed commercial configuration (60 count/HDPE bottle)
`when stored at room temperature, 20° to 25°C (68° to 77°F); excursions permitted between
`15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].
`
`Reference ID: 3007054
`
`

`

`NDA 202570
`Page 2
`
`
`
`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
`patient package insert). 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/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM072392.pdf.
`
`The SPL will be accessible via publicly available labeling repositories.
`
`IMMEDIATE CONTAINER LABELS
`
`We acknowledge that your March 30, 2011, submission contains final printed container labels
`that will be used during the initial launch.
`
`We note your agreement on August 3, 2011, and August 23, 2011, to revise your container labels
`at the next printing September 2011, to unbold and relocate the “Rx only” wording to the bottom
`of the label and to change the wording on the left side panel to read “Store at room temperature
`20º to 25º C (68º to 77º F); excursions permitted between 15º to 30º C (59º to 86º F)
`[see USP Controlled Room Temperature]”. We acknowledge that your August 24, 2011,
`submission contains final printed container labels with these changes to be used at next printing.
`
`Marketing the product with final printed labeling (FPL) that is not identical to the approved
`labeling text may render the product misbranded and an unapproved new drug.
`
`ADVISORY COMMITTEE
`
`Your application for XALKORI (crizotinib) Capsules, 200 mg and 250 mg, was not referred to
`an FDA advisory committee because the application did not raise significant safety or efficacy
`issues in the intended population.
`
`ACCELERATED APPROVAL REQUIREMENTS
`
`Products approved under the accelerated approval regulations, 21 CFR 314.510, require further
`adequate and well-controlled studies/clinical trials to verify and describe clinical benefit. We
`remind you of your postmarketing requirement specified in your submission dated
`August 1, 2011. You are required to conduct such trials with due diligence. If postmarketing
`trials fail to verify that clinical benefit is conferred by XALKORI (crizotinib) Capsules, 200 mg
`and 250 mg, or are not conducted with due diligence, we may, following a hearing in accordance
`with 21 CFR 314.530(b), withdraw or modify approval.
`
`
`Reference ID: 3007054
`
`

`

`NDA 202570
`Page 3
`
`
`Granting of this approval is contingent upon completion of clinical trials to verify the clinical
`benefit of XALKORI (crizotinib) Capsules, 200 mg and 250 mg. These postmarketing trials are
`subject to the reporting requirements of 21 CFR 314.81. These requirements, along with
`required completion dates, are listed below.
`
`1789-1
`
`Clinical trial report and datasets from A8081007: Phase 3, Randomized, Open-label
`Study of the Efficacy and Safety of PF-02341066 vs. Standard of Care (Pemetrexed or
`Docetaxel) in Patients with Advanced Non-Small Cell Lung Cancer Harboring a
`Translocation or Inversion Event Involving the Anaplastic Lymphoma Kinase Gene
`Locus
`
`
`Final Protocol Submission: 09/2009 (submitted)
`Trial Completion:
`
`12/2013
`Final Report Submission:
`06/2014
`
`
`1789-2
`
`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
`
`
`
`
`
`
`
`
`Final Protocol Submission: 06/2010 (submitted)
`Trial Completion:
`
`12/2015
`Final Report Submission:
`06/2016
`
`
`Submit clinical protocols to your IND 73544, with a cross reference letter to this NDA. Submit
`all final reports to this NDA as supplemental applications. For administrative purposes, all
`submissions relating to this postmarketing requirement must be clearly designated "Subpart H
`Postmarketing Requirement(s).”
`
`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(s) in pediatric patients unless this requirement is waived,
`deferred, or inapplicable.
`
`Because this drug product for this indication has an orphan drug designation, you are exempt
`from this requirement.
`
`Reference ID: 3007054
`
`

`

`NDA 202570
`Page 4
`
`
`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.
`
`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 drug interactions caused by the induction of human CYP2B and CYP2C enzymes by
`XALKORI (crizotinib) Capsules, 200 mg and 250 mg.
`
`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.
`
`Therefore, based on appropriate scientific data, FDA has determined that you are required to
`conduct the following:
`
`
`1789-3
`
`
`Submit the final report on the ongoing in vitro evaluations of induction potential of
`crizotinib on CYP2B and CYP2C enzymes.
`
`The timetable you submitted on August 3, 2011, states that you will conduct this study
`according to the following schedule:
`
`
`Final Protocol Submission: 12/2011
`Study Completion:
`
`12/2011
`Final Report Submission:
`12/2011
`
`
`Finally, we have determined that only a clinical trial (rather than a nonclinical or observational
`study) will be sufficient to assess a known serious risk of visual disorders with XALKORI
`(crizotinib) Capsules, 200 mg and 250 mg, and to assess signals of a serious risk of QT
`prolongation, drug-drug interactions with CYP3A inhibitors and inducers and gastric pH
`elevating drugs, and increased concentrations of XALKORI (crizotinib) Capsules, 200 mg and
`250 mg in patients with hepatic impairment or severe renal impairment.
`
`Therefore, based on appropriate scientific data, FDA has determined that you are required to
`conduct the following:
`
`
`1789-4
`
`Clinical trial (existing trial or new clinical trial) in which at least 30 patients are
`studied. The following examinations should be performed in these patients at baseline, 2
`and 6 weeks after drug administration and 2-8 weeks after discontinuation of the
`therapy (single visit post therapy).
`
`
`Reference ID: 3007054
`
`

`

`NDA 202570
`Page 5
`
`
`
`1. Best corrected distance visual acuity
`2. Refractive error associated with best corrected distance visual acuity
`3. Pupil size under standardized lighting conditions
`4. Slit lamp biomicroscopy of the anterior segment
`5. Intraocular pressure
`6. Ocular coherence tomography of the macula
`7. Dilated fundus photography of the retina
`
`
`The timetable you submitted on August 11, 2011, states that you will conduct this trial
`according to the following schedule:
`
`
`Final Protocol Submission: 10/2011
`Trial Completion:
`
`12/2013
`Final Report Submission:
`06/2014
`
`
`
`
`1789-5
`
`Complete the ECG sub-study in trial A8081007 and submit the final report, along with a
`thorough review of cardiac safety data to address any potential impact of crizotinib on
`QTc interval prolongation in patients.
`
`The timetable you submitted on August 3, 201l, states that you will conduct this trial
`according to the following schedule:
`
`
`Final Protocol Submission: 09/2009 (submitted)
`Trial Completion:
`
`12/2013
`Final Report Submission:
`06/2014
`
`
`1789-6
`
`Conduct a multiple dose trial in patients to determine how to adjust the crizotinib dose
`when it is coadministered with a strong CYP3A inhibitor (e.g., ketoconazole).
`
`The timetable you submitted on August 11, 2011, states that you will conduct this trial
`according to the following schedule
`
`
`Final Protocol Submission: 03/2012
`Trial Completion:
`
`01/2015
`Final Report Submission:
`07/2015
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3007054
`
`

`

`NDA 202570
`Page 6
`
`
`
`1789-7
`
`Conduct a multiple dose trial in patients to determine how to adjust the crizotinib dose
`when it is coadministered with a strong CYP3A inducer (e.g., rifampin).
`
`The timetable you submitted on August 11, 2011, states that you will conduct this trial
`according to the following schedule
`
`
`
`Final Protocol Submission: 03/2012
`Trial Completion:
`
`01/2015
`Final Report Submission:
`07/2015
`
`
`1789-8
`
`Conduct a multiple dose trial to determine the appropriate crizotinib dose in patients with
`various degrees of hepatic impairment.
`
`The timetable you submitted on August 3, 2011, states that you will conduct this trial
`according to the following schedule
`
`
`Final Protocol Submission: 09/2011
`Trial Completion:
`
`07/2013
`Final Report Submission:
`01/2014
`
`
`1789-9
`
`Conduct a trial in humans to determine the appropriate crizotinib dose in patients with
`severe renal impairment.
`
`The timetable you submitted on August 12, 2011, states that you will conduct this trial
`according to the following schedule
`
`
`Final Protocol Submission: 09/2011
`Trial Completion:
`
`04/2012
`Final Report Submission:
`10/2012
`
`
`
`
`
`
`
`Reference ID: 3007054
`
`

`

`NDA 202570
`Page 7
`
`
`
`1789-10
`Conduct a trial in humans to determine how to dose crizotinib with regard to gastric pH
`elevating agents (i.e., a proton-pump inhibitor, an H2-receptor antagonist, and an
`antacid).
`
`The timetable you submitted on August 11, 2011, states that you will conduct this trial
`according to the following schedule
`
`
`Final Protocol Submission: 01/2012
`Trial Completion:
`
`03/2013
`Final Report Submission:
`09/2013
`
`
`Submit the protocols to your IND 073544, with a cross-reference letter to this NDA. Submit all
`final reports 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)”.
`
`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.
`
`POSTMARKETING COMMITMENTS SUBJECT TO REPORTING REQUIREMENTS
`UNDER SECTION 506B
`
`We remind you of your postmarketing commitments:
`
`
`1789-11
`
`To assess the adequacy of the current cut-off, conduct a clinical trial to explore response
`to crizotinib in ALK-negative patients based on current assay cut-off. This should be
`compared to historic controls and to the response in ALK-positive patients. Additional
`biomarkers should be assessed in ALK-negative patients.
`
`Reference ID: 3007054
`
`

`

`NDA 202570
`Page 8
`
`
`
`
`The timetable you submitted on August 24, 2011, states that you will conduct this trial
`according to the following schedule:
`
`
`Final Protocol Submission: 10/2011
`Trial Completion:
`
`05/2013
`Final Report Submission:
`11/2013
`
`
`
`
`
`
`1789-12
`
`To conduct exposure-response analysis for progression-free survival, response rate,
`overall survival and safety endpoints utilizing data from confirmatory trial A8081007 and
`to submit the analysis plan for review.
`
`The timetable you submitted on August 3, 2011, states that you will conduct this trial
`according to the following schedule:
`
`
`Final Protocol Submission: 09/2009 (submitted)
`Analysis Plan Submission: 05/2012
`Trial Completion:
`
`12/2013
`Final Report Submission:
`06/2014
`
`
`
`
`1789-13
`
`To conduct exposure-response analysis for progression free survival, response rate,
`overall survival and safety endpoints utilizing data from confirmatory trial A8081014 and
`to submit the analysis plan for review.
`
`The timetable you submitted on August 3, 2011, states that you will conduct this trial
`according to the following schedule:
`
`
`Final Protocol Submission: 06/2010 (submitted)
`Analysis Plan Submission: 05/2012
`Trial Completion:
`
`12/2015
`Final Report Submission:
`06/2016
`
`
`Submit clinical protocols to your IND 073544 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 studies/trials, number of patients entered into each study/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.”
`
`
`Reference ID: 3007054
`
`

`

`NDA 202570
`Page 9
`
`
`PROMOTIONAL MATERIALS
`
`Immediately submit all promotional materials (both promotional labeling and advertisements) to
`be used within the first 120 days after approval. Send one copy to this division and two copies of
`the promotional materials and the package insert directly 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
`
`
`In addition, as required by 21 CFR 314.550, submit all subsequent promotional materials at least
`30 days before the intended time of initial distribution of labeling or initial publication of the
`advertisement. Send two copies of the promotional materials and the package insert to the
`address above.
`
`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.
`
`REPORTING REQUIREMENTS
`
`We remind you that you must comply with the 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
`http://www.fda.gov/Safety/MedWatch/HowToReport/ucm166910.htm.
`
`POST-ACTION FEEDBACK MEETING
`
`New molecular entities and new biologics qualify for a post-action feedback meeting. Such
`meetings are used to discuss the quality of the application and to evaluate the communication
`process during drug development and marketing application review. The purpose is to learn
`from successful aspects of the review process and to identify areas that could benefit from
`improvement. If you would like to have such a meeting with us, call the Regulatory Project
`Manager for this application.
`
`Reference ID: 3007054
`
`

`

`NDA 202570
`Page 10
`
`
`If you have any questions, call Diane Hanner, Regulatory Project Manager, at (301) 796-4058.
`
`
`
`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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`
`ENCLOSURES:
`Content of Labeling
`Carton and Container Labeling
`
`Reference ID: 3007054
`
`

`

`---------------------------------------------------------------------------------------------------------
`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
`08/26/2011
`
`Reference ID: 3007054
`
`