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NON-INTERVENTIONAL (NI) STUDY REPORT PASS Information Title a Multinational Active Safety Surveillance Study of Crizotinib in Eu

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NON-INTERVENTIONAL (NI) STUDY REPORT PASS Information Title a Multinational Active Safety Surveillance Study of Crizotinib in Eu XALKORI® (crizotinib) A8081038 NON-INTERVENTIONAL STUDY REPORT FINAL, 12 June 2018 NON-INTERVENTIONAL (NI) STUDY REPORT PASS information Title A Multinational Active Safety Surveillance Study of Crizotinib in Europe and the United States Protocol number A8081038 Version identifier of the final study 1.0 report Date of last version of the final study 12 June 2018 report EU Post Authorisation Study (PAS) ENCEPP/SDPP/8097 register number Active substance L01XE16/crizotinib Medicinal product XALKORI® Product reference EU/1/12/793/001-004 Procedure number EMEA/H/C/002489 Marketing Authorisation Holder Pfizer Limited (MAH) Joint PASS No Research question and objectives To estimate the incidence rate and incidence proportion over an approximately 3-year period of observation for hepatotoxicity, pneumonitis/interstitial lung disease, QT prolongation-related events, bradycardia, and vision disorders among lung cancer patients receiving crizotinib dispensing/prescription Countries of study Denmark, Finland, Sweden, the Netherlands, and United States of America PFIZER CONFIDENTIAL Page 1 XALKORI® (crizotinib) A8081038 NON-INTERVENTIONAL STUDY REPORT FINAL, 12 June 2018 Authors Vera Ehrenstein, MPH, DSc Johnny Kahlert, PhD Henrik Toft Sørensen, MD, PhD, DMSc Department of Clinical Epidemiology Aarhus University Hospital Olof Palmes Allé 43-45 8200 Aarhus N, Denmark PFIZER CONFIDENTIAL Page 2 XALKORI® (crizotinib) A8081038 NON-INTERVENTIONAL STUDY REPORT FINAL, 12 June 2018 Marketing Authorisation Holder(s) Marketing Authorisation Holder(s) Pfizer Limited Ramsgate Road, Sandwich, Kent CT130NJ,United Kingdom MAH contact person Kui Huang, PhD, MPH Pfizer Inc. 235 East 42nd Street New York, NY 10017, USA This document contains confidential information belonging to Pfizer. Except as otherwise agreed to in writing, by accepting or reviewing this document, you agree to hold this information in confidence and not copy or disclose it to others (except where required by applicable law) or use it for unauthorized purposes. In the event of any actual or suspected breach of this obligation, Pfizer must be promptly notified. PFIZER CONFIDENTIAL Page 3 XALKORI® (crizotinib) A8081038 NON-INTERVENTIONAL STUDY REPORT FINAL, 12 June 2018 TABLE OF CONTENTS TABLE OF CONTENTS ...........................................................................................................4 LIST OF IN-TEXT TABLES ..................................................................................................10 LIST OF IN-TEXT FIGURES.................................................................................................10 1. ABSTRACT (STAND-ALONE DOCUMENT) .................................................................13 2. LIST OF ABBREVIATIONS ..............................................................................................14 3. INVESTIGATORS ..............................................................................................................16 4. OTHER RESPONSIBLE PARTIES....................................................................................18 5. MILESTONES .....................................................................................................................19 6. RATIONALE AND BACKGROUND ................................................................................20 7. RESEARCH QUESTION AND OBJECTIVES .................................................................22 7.1. Primary Objectives ..................................................................................................22 7.2. Secondary Objectives ..............................................................................................22 8. AMENDMENTS AND UPDATES .....................................................................................23 9. RESEARCH METHODS ....................................................................................................23 9.1. Study design ............................................................................................................24 9.2. Setting ......................................................................................................................24 9.3. Subjects ...................................................................................................................24 9.4. Inclusion criteria ......................................................................................................25 9.5. Exclusion criteria .....................................................................................................25 9.6. Variables ..................................................................................................................25 9.6.1. Exposure ........................................................................................................................25 9.6.2. Outcomes .......................................................................................................................26 9.6.3. Baseline characteristics ..................................................................................................27 9.6.4. Subgroups ......................................................................................................................27 9.7. Data sources and measurement ...............................................................................27 9.8. Adjudication and validation of the primary endpoints ............................................29 9.9. Bias ..........................................................................................................................30 9.10. Study size ..............................................................................................................30 9.11. Data transformation ...............................................................................................30 9.12. Statistical methods .................................................................................................31 9.12.1. Descriptive statistics ....................................................................................................31 PFIZER CONFIDENTIAL Page 4 XALKORI® (crizotinib) A8081038 NON-INTERVENTIONAL STUDY REPORT FINAL, 12 June 2018 9.12.2. Incidence rates and cumulative incidences ..................................................................31 9.12.3. Combining results across databases .............................................................................32 9.12.4. Validation statistics ......................................................................................................32 9.12.5. Missing values .............................................................................................................32 9.12.6. Sensitivity analyses ......................................................................................................32 9.12.7. Amendments to the statistical analysis plan ................................................................32 9.13. Quality control .......................................................................................................33 9.14. Protection of human subjects ................................................................................33 10. RESULTS ..........................................................................................................................34 10.1. Participants ............................................................................................................34 10.2. Descriptive data .....................................................................................................36 10.3. Outcome data .........................................................................................................42 10.4. Main results ...........................................................................................................43 10.4.1. Cumulative incidences of the endpoints during the follow-up period .........................43 10.4.2. Incidence rates of the endpoints with time at risk being the total-follow-up...............46 10.4.3. Stratified all-cause mortality ........................................................................................47 10.4.4. Incidence rates of endpoints during the on-treatment period .......................................48 10.4.5. Overall survival ............................................................................................................51 10.5. Patients in the crizotinib and ceritinib group ........................................................53 10.6. Use of crizotinib in patients without primary lung cancer ....................................54 10.7. Other analyses: validation of the primary endpoints .............................................54 10.8. Adverse events/adverse reactions ..........................................................................57 11. DISCUSSION ....................................................................................................................57 11.1. Key results .............................................................................................................57 11.2. Limitations ............................................................................................................59 11.3. Strengths ................................................................................................................60 11.4. Interpretation .........................................................................................................61 11.5. Generalizability
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