`NDA 202570/S-030
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`SUPPLEMENT APPROVAL
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` PF Prism C.V.
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` c/o Pfizer Inc.
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` Attention: Nicole Earnhardt Aldrich, PhD, RAC
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` Director, Pfizer Global Regulatory Affairs
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` 10646 Science Center Drive
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` Sand Diego, CA 92121
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`Dear Dr. Aldrich:
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`Please refer to your supplemental new drug application (sNDA) dated July 20, 2020,
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`received July 20, 2020, and your amendments, submitted under section 505(b) of the
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`Federal Food, Drug, and Cosmetic Act (FDCA) for Xalkori (crizotinib) capsules.
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`This Prior Approval supplemental new drug application provides for a new indication for
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`the treatment of pediatric patients 1 year of age and older and young adults with
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`relapsed or refractory, systemic anaplastic large cell lymphoma (ALCL) that is ALK-
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`positive. Limitations of use: The safety and efficacy of Xalkori have not been established
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`in older adults with relapsed or refractory, systemic ALK-positive ALCL.
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`APPROVAL & LABELING
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`We have completed our review of this application, as amended. It is approved, effective
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`on the date of this letter, for use as recommended in the enclosed agreed-upon labeling.
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`WAIVER OF ½ PAGE LENGTH REQUIREMENT FOR HIGHLIGHTS
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`Please note that we have previously granted a waiver of the requirements of 21 CFR
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`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
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`content of labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using
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`the Food and Drug Administration (FDA) automated drug registration and listing system
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`(eLIST), as described at FDA.gov.1 Content of labeling must be identical to the enclosed
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`labeling (text for the Prescribing Information and Medication Guide), with the addition of
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` 1 http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm
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`Reference ID: 4730020
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` NDA 202570/S-030
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` Page 2
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`any labeling changes in pending “Changes Being Effected” (CBE) supplements, as well
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`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
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`industry SPL Standard for Content of Labeling Technical Qs and As.2
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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 include labeling
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`changes for this NDA, including CBE supplements for which FDA has not yet issued an
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`action letter, with the content of labeling [21 CFR 314.50(l)(1)(i)] in Microsoft Word
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`format, that includes the changes approved in this supplemental application, as well as
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`annual reportable changes. To facilitate review of your submission(s), provide a
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`highlighted or marked-up copy that shows all changes, as well as a clean Microsoft
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`Word version. The marked-up copy should provide appropriate annotations, including
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`supplement number(s) and annual report date(s).
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`CARTON AND CONTAINER LABELING
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`Submit final printed carton and container labeling that are identical to the enclosed
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`container labeling, as soon as they are available, but no more than 30 days after they
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`are printed. Please submit these labeling electronically according to the guidance for
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`industry Providing Regulatory Submissions in Electronic Format — Certain Human
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`Pharmaceutical Product Applications and Related Submissions Using the eCTD
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`Specifications. For administrative purposes, designate this submission “Final Printed
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`Carton and Container Labeling for approved NDA 202570/S-030.” Approval of this
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`submission by FDA is not required before the labeling is used.
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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
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`new active ingredients (which includes new salts and new fixed combinations), new
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`indications, new dosage forms, new dosing regimens, or new routes of administration
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`are required to contain an assessment of the safety and effectiveness of the product for
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`the claimed indication in pediatric patients unless this requirement is waived, deferred,
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`or inapplicable.
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`Because this drug product for this indication has an orphan drug designation, you are
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`exempt from this requirement.
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` 2 We update guidances periodically. For the most recent version of a guidance, check the FDA Guidance
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` Documents Database https://www.fda.gov/RegulatoryInformation/Guidances/default.htm.
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`U.S. Food and Drug Administration
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`Silver Spring, MD 20993
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`www.fda.gov
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`Reference ID: 4730020
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` NDA 202570/S-030
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` Page 3
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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
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` biological product applications to conduct postmarketing studies and clinical trials for
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` 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
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`a serious risk of visual disorders identified from clinical trials of pediatric and young
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`adult patients with ALCL who were administered a new higher dose of crizotinib. We
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`consider this information to be “new safety information” as defined in section 505-1(b)(3)
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`of the FDCA.
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`We have determined that an analysis of spontaneous postmarketing adverse events
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`reported under subsection 505(k)(1) of the FDCA will not be sufficient to assess the
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`signal of serious risk of ocular toxicities in pediatric and young adult patients receiving
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`crizotinib.
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`Furthermore, the active postmarket risk identification and analysis system as available
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`under section 505(k)(3) of the FDCA will not be sufficient to assess this serious risk.
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`Finally, we have determined that only a clinical trial (rather than a nonclinical or
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`observational study) will be sufficient to assess this serious risk.
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`Therefore, based on appropriate scientific data, FDA has determined that you are
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`required to conduct the following:
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`4003-1
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`Conduct a prospective study to evaluate the risk factors,
`manifestations, and outcomes of ocular toxicity associated with
`crizotinib in pediatric and young adult patients with anaplastic large
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`cell lymphoma (ALCL). The study will include a mechanism to
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`collect, classify, and analyze data on ocular toxicity in patients
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`exposed to crizotinib. Evaluate a minimum of 30 total patients
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`(6 patients at 165 mg/m2 twice daily and 24 patients at 280 mg/m2
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`twice daily) who receive crizotinib monotherapy for ALCL,
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`inflammatory myofibroblastic tumor (IMT), or other tumor types that
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`are ALK-positive, ROS1-positive, or MET-positive. At least 50% of
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`patients evaluated should be pediatric patients less than 17 years
`old. Include baseline, scheduled follow-up, and symptom-driven
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`ocular assessments to include visual acuity assessments,
`ophthalmologic evaluations including slit lamp examination, and
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`elicitation for visual symptoms.
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`U.S. Food and Drug Administration
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`Silver Spring, MD 20993
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`www.fda.gov
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`Reference ID: 4730020
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` Draft Protocol Submission:
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` Final Protocol Submission:
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` Study Completion:
` Final Report Submission:
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` 05/2021
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` 08/2021
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` 02/2026
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` 02/2027
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` NDA 202570/S-030
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` Page 4
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`The timetable you submitted on January 12, 2021, states that you will conduct this study
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`according to the following schedule:
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`Submit datasets with the final report.
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`FDA considers the term final to mean that the applicant has submitted a protocol, the
`FDA review team has sent comments to the applicant, and the protocol has been
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`revised as needed to meet the goal of the study or clinical trial.3
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`Submit the protocol(s) to your IND 117215, with a cross-reference letter to this NDA.
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`Submit nonclinical and chemistry, manufacturing, and controls protocols and all
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`postmarketing final report(s) to your NDA. Prominently identify the submission with the
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`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
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`Postmarketing Final Report Under 505(o)”, “Required Postmarketing
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`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
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`periodically report to FDA on the status of any study or clinical trial otherwise
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`undertaken to investigate a safety issue. Section 506B of the FDCA, as well as
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`21 CFR 314.81(b)(2)(vii) requires you to report annually on the status of any
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`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
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`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
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`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
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`undertaken to investigate a safety issue. Failure to submit an annual report for studies
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`or clinical trials required under 505(o) on the date required will be considered a violation
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`of FDCA section 505(o)(3)(E)(ii) and could result in enforcement action.
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` 3 See the guidance for Industry Postmarketing Studies and Clinical Trials—Implementation of Section
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` 505(o)(3) of the Federal Food, Drug, and Cosmetic Act (October 2019).
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` https://www.fda.gov/RegulatoryInformation/Guidances/default.htm.
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`U.S. Food and Drug Administration
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`Silver Spring, MD 20993
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`www.fda.gov
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`Reference ID: 4730020
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` NDA 202570/S-030
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` Page 5
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`POSTMARKETING COMMITMENT SUBJECT TO REPORTING REQUIREMENTS
`UNDER SECTION 506B
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`We remind you of your postmarketing commitment:
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` 4003-2
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` Submit the final results from a clinical trial(s) of crizotinib
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`monotherapy conducted in pediatric and young adult patients with
`relapsed or refractory, ALK-positive systemic anaplastic large cell
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`lymphoma (ALCL), with a starting dosage of crizotinib that is lower
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`than 280 mg/m2 twice daily (165 mg/m2 twice daily). At least 50%
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`of the patients should be less than 17 years old. The primary
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`efficacy endpoint should be overall response rate (ORR) using
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`uniform response criteria. Other endpoints should include duration
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`of response, pharmacokinetics from approximately 50% of patients,
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`and safety. Data from more than one prospective clinical trial of
`crizotinib in the intended population may be used to support the
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`analyses. Evaluate a minimum of 25 patients with ALCL at the
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`165 mg/m2 twice daily dosage of crizotinib to estimate the ORR.
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`The results of this trial may inform product labeling.
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`The timetable you submitted on January 12, 2021, states that you will conduct this study
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`according to the following schedule:
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`08/2021
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`02/2026
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`08/2027
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`Final Protocol Submission:
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`Trial Completion:
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`Final Report Submission:
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`Submit datasets with the final report.
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`PROMOTIONAL MATERIALS
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`You may request advisory comments on proposed introductory advertising and
`promotional labeling. For information about submitting promotional materials, see the
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`final guidance for industry Providing Regulatory Submissions in Electronic and Non-
`Electronic Format-Promotional Labeling and Advertising Materials for Human
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`Prescription Drugs.4
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`You must submit final promotional materials and Prescribing Information, accompanied
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` 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 FDA.gov.5 Information and
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`Instructions for completing the form can be found at FDA.gov.6
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` 4 For the most recent version of a guidance, check the FDA guidance web page at
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` https://www.fda.gov/media/128163/download.
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` 5 http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM083570.pdf
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` 6 http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM375154.pdf
`U.S. Food and Drug Administration
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`Silver Spring, MD 20993
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`www.fda.gov
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`Reference ID: 4730020
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` NDA 202570/S-030
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` Page 6
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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
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`supplement, including any new safety information [21 CFR 314.70(a)(4)]. The revisions
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`in your promotional materials should include prominent disclosure of the important new
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`safety information that appears in the revised labeling. Within 7 days of receipt of this
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`letter, submit your statement of intent to comply with 21 CFR 314.70(a)(4).
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` REPORTING REQUIREMENTS
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`We remind you that you must comply with reporting requirements for an approved NDA
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`(21 CFR 314.80 and 314.81).
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`If you have any questions, contact Patricia Garvey, Lead Regulatory Project Manager,
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`at (301) 796-8493.
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`Sincerely,
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`{See appended electronic signature page}
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`Nicole J. Gormley, MD
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`Director
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`Division of Hematologic Malignancies II
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`Office of Oncologic Diseases
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`Center for Drug Evaluation and Research
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`ENCLOSURES:
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`• Content of Labeling
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`o Prescribing Information
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`o Medication Guide
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`• Container Labeling
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`U.S. Food and Drug Administration
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`Silver Spring, MD 20993
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`www.fda.gov
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`Reference ID: 4730020
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`Signature Page 1 of 1
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`This is a representation of an electronic record that was signed
`electronically. Following this are manifestations of any and all
`electronic signatures for this electronic record.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
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`NICOLE J GORMLEY
`01/14/2021 12:43:58 PM
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`Reference ID: 4730020
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`(
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