Aclidinium Bromide Drug Utilisation Post-Authorisation Safety Study Common Protocol, Version 1.1 14 April 2014 Prepared for Esther Garcia Gil Head of Late Stage Development Respiratory Almirall, S.A. Ctra. Laureà Miró, 408-410 Sant Feliu de Llobregat, 08980 Barcelona, Spain Telephone: +34.93.291.7519 E-mail: [email protected] Prepared by Cristina Varas-Lorenzo, MD, PhD Jordi Castellsague, MD, MPH Susana Perez-Gutthann, MD, PhD, FRCP, FISPE RTI Health Solutions Barcelona, Spain, and Research Triangle Park, NC E-mail: [email protected] RTI-HS Project No.: 0302097 TABLE OF CONTENTS Approval Page ................................................................................................... 2 List of Tables ..................................................................................................... 4 List of Figures ................................................................................................... 4 Abbreviations .................................................................................................... 5 1 Title ........................................................................................................... 7 2 Marketing Authorisation Holder ................................................................. 7 3 Responsible Parties ................................................................................... 7 4 Abstract ..................................................................................................... 8 5 Amendments and Updates ....................................................................... 12 6 Milestones and Timeline .......................................................................... 12 7 Rationale and Background ....................................................................... 13 8 Research Question and Objectives ........................................................... 14 9 Research Methods ................................................................................... 15 9.1 Study Design ..................................................................................... 16 9.1.1 Follow-up ............................................................................ 17 9.1.2 Study Period ........................................................................ 17 9.2 Setting ............................................................................................. 17 9.2.1 Study Cohorts ...................................................................... 17 9.2.2 Index Prescription ................................................................ 18 9.2.3 Health Databases ................................................................. 19 9.3 Variables ........................................................................................... 24 9.3.1 Demographic Variables .......................................................... 24 9.3.2 Lifestyle and Socioeconomic Variables ..................................... 24 9.3.3 Treatment Indication and Identification of Off-Label Use ............ 25 9.3.4 Identification of Patients With COPD ........................................ 25 9.3.5 Identification of Potential Off-Label Use ................................... 28 9.3.6 Comorbidities of Interest Including Those With Missing Information in the RMP ........................................................................... 28 9.3.7 Overall Comorbidity Index ..................................................... 30 9.3.8 Exposures ........................................................................... 31 9.4 Data Sources ..................................................................................... 36 9.5 Study Size ........................................................................................ 36 9.5.1 Monitoring of Aclidinium Bromide Users ................................... 36 9.6 Data Collection and Management .......................................................... 37 9.7 Data Analysis .................................................................................... 37 9.8 Quality Control .................................................................................. 39 9.9 Limitations of the Research Methods ..................................................... 39 10 Protection of Human Subjects and Good Research Practice ..................... 40 10.1 CPRD, UK ......................................................................................... 41 10.2 GePaRD, Germany .............................................................................. 41 10.3 Denmark ......................................................................................... 41 11 Management and Reporting of Adverse Events ........................................ 42 12 Plans for Disseminating and Communicating Study Results ..................... 42 CONFIDENTIAL 3 of 56 13 References ............................................................................................... 42 Annex 1. ATC Codes: Respiratory Medications and Other Medications of Interest ................................................................................................................ 47 Annex 2. ENCePP Checklist for Study Protocols ............................................... 50 LIST OF TABLES Table 1. Inhaled Long-Acting Anticholinergic and Selective Beta2-Adrenoreceptor Agonists Drugs Used for COPD ............................................................ 18 Table 2. Main Features of Proposed European Databases .................................... 22 Table 3. Diagnoses to Identify Users of Aclidinium Bromide, by Indication ............. 26 Table 4. Assessment of COPD Severity ............................................................. 27 Table 5. Comorbidities—Including Those Listed in the Risk Management Plan as Having Missing Information ................................................................ 29 Table 6. The Charlson Comorbidity Index Components and Weights ..................... 30 Table 7. Initial Pharmacologic Management of COPD According to European Clinical Guidelines ....................................................................................... 32 Table 8. Binomial Confidence Intervals for Different Study Sizes and Possible Percentages of Off-Label Use .............................................................. 36 Table 1-1. Inhaled Selective Beta2-Adrenoreceptor Agonists and Anticholinergics Used for COPD .............................................................................................. 48 Table 1-2. Inhaled Glucocorticoids Used for COPD ................................................... 49 LIST OF FIGURES Figure 1. Study Overview ................................................................................ 16 Figure 2. Model of Symptoms/Risk of Evaluation for COPD ................................... 32 CONFIDENTIAL 4 of 56 ABBREVIATIONS AIDS acquired immune deficiency syndrome AMI acute myocardial infarction ATC Anatomical Therapeutic Chemical (classification) BMI body mass index CAT CAT= COPD assessment test CHMP Committee for Medicinal Products for Human Use CI confidence interval CONSORT Consolidated Standards of Reporting Trials COPD chronic obstructive pulmonary disease CPRD Clinical Practice Research Database (UK) DDD defined daily dose DUS drug utilisation study EBM Einheitlicher Bewertungsmaßstab codes (Germany) EMA European Medicines Agency GOLD Global Initiative for Chronic Obstructive Lung Disease GP general practitioner GPP Good Pharmacoepidemiology Practices GPRD General Practice Research Database (UK) HES Hospital Episode Statistics (UK) HIV human immunodeficiency virus ICD-10 International Statistical Classification of Diseases and Related Health Problems, 10th Revision ICD-10-CM International Statistical Classification of Diseases and Related Health Problems, 10th Revision, Clinical Modification ICD-10-GM International Statistical Classification of Diseases and Related Health Problems, 10th Revision, German Modification ICH International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use ICMJE International Committee of Medical Journal Editors ID identification number ISPE International Society for Pharmacoepidemiology LA long-acting LABA long-acting beta-agonist OPED Odense University Pharmacoepidemiology Database PASS post-authorisation safety study PPV positive predictive value PSUR Periodic Safety Update Report RMP risk management plan RTI-HS RTI Health Solutions SA short-acting SES socioeconomic status SHI statutory health insurance agency (Germany) CONFIDENTIAL 5 of 56 STROBE Strengthening the Reporting of Observational Studies in Epidemiology (checklist) UK United Kingdom WHO World Health Organization CONFIDENTIAL 6 of 56 Aclidinium Bromide Drug Utilisation Post-Authorisation Safety Study, Common Protocol Version 1.1, 14 April 2014 1 TITLE Aclidinium Bromide Drug Utilisation Post-Authorisation Safety Study: Common Protocol, Version 1.1 2 MARKETING AUTHORISATION HOLDER Almirall, S.A. 3 RESPONSIBLE PARTIES RTI Health Solutions—Barcelona Trav. Gracia 56, Atico 1 08006 Barcelona, Spain Cristina Varas-Lorenzo, MD, PhD; Director, Epidemiology Jordi Castellsague, MD, MPH; Director, Epidemiology Susana Perez-Gutthann MD, PhD, FRCP, FISPE; Vice-President, Global Head Epidemiology Almirall, S.A. Ctra. Laureà Miró, 408-410 Sant Feliu de Llobregat, 08980 Barcelona, Spain Esther Garcia Gil, MD; Head of Late Stage Development Respiratory Gemma Jiménez, EU QPPV, Head of Corporate Drug Safety Note: