European Network of Centres for Pharmacoepidemiology and Pharmacovigilance EMA/95098/2010 Rev.9 The European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP) Guide on Methodological Standards in Pharmacoepidemiology (Revision 9) KEYWORDS methodological standards, pharmacoepidemiology, pharmacovigilance, ENCePP, research, guidance This document should be cited as follows: The European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP). Guide on Methodological Standards in Pharmacoepidemiology (Revision 9). EMA/95098/2010. Available at http://www.encepp.eu/standards_and_guidance Official address Domenico Scarlattilaan 6 ● 1083 HS Amsterdam ● The Netherlands Address for visits and deliveries Refer to www.ema.europa.eu/how-to-find-us Send us a question Go to www.ema.europa.eu/contact Telephone +31 (0)88 781 6000 An agency of the European Union © European Medicines Agency, 2021. Reproduction is authorised provided the source is acknowledged. Table of contents Foreword to ENCePP Guide revision 9 ......................................................... 5 1. Introduction ............................................................................................ 6 2. Formulating the research question and objectives .................................. 8 3. Development of the study protocol .......................................................... 9 4. Approaches to data collection ................................................................ 11 4.1. Primary data collection .................................................................................. 12 4.1.1. General considerations ..................................................................................... 12 4.1.2. Surveys .......................................................................................................... 12 4.1.3. Randomised controlled trials ............................................................................. 14 4.2. Secondary use of data .................................................................................... 14 4.3. Patient registries ........................................................................................... 16 4.3.1. Definitions ...................................................................................................... 16 4.3.2. Conceptual differences between a registry and a study ......................................... 16 4.3.3. Methodological aspects ..................................................................................... 16 4.3.4. Population registries ........................................................................................ 17 4.3.5. Registries which capture special populations ....................................................... 17 4.3.6. Disease registries in regulatory practice and health technology assessment ............ 18 4.4. Spontaneous reports ...................................................................................... 19 4.5. Social media................................................................................................... 21 4.5.1. Definition........................................................................................................ 21 4.5.2. Use in pharmacovigilance ................................................................................. 21 4.5.3. Challenges ...................................................................................................... 22 4.5.4. Data protection ............................................................................................... 22 4.6. Research networks for multi-database studies .............................................. 23 4.6.1. General considerations ..................................................................................... 23 4.6.2. Models of studies using multiple data sources ..................................................... 25 4.6.3. Challenges of different models .......................................................................... 27 5. Study design .......................................................................................... 28 5.1. Overview ........................................................................................................ 28 5.2. Types of study design .................................................................................... 30 5.2.1. Cohort studies ................................................................................................. 30 5.2.2. Case-control studies ........................................................................................ 31 5.2.3. Case-only designs ............................................................................................ 32 5.2.4. Cross-sectional studies ..................................................................................... 33 5.2.5. Ecological studies ............................................................................................ 33 5.3. Definition and validation of drug exposure, outcomes and covariates ........... 34 5.3.1. Assessment of exposure ................................................................................... 34 5.3.2. Assessment of outcomes .................................................................................. 34 5.3.3. Assessment of covariates ................................................................................. 35 5.3.4. Misclassification and validation .......................................................................... 35 5.4. Specific aspects of study design..................................................................... 37 5.4.1. Pragmatic trials and large simple trials ............................................................... 37 The European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP) Guide on Methodological Standards in Pharmacoepidemiology Page 2/168 5.4.2. The target trial approach .................................................................................. 39 5.4.3. Self-controlled case series and self-controlled risk interval designs ........................ 40 5.4.4. Positive and negative control exposures and outcomes ......................................... 42 5.4.5. Use of an active comparator ............................................................................. 43 5.4.6. Interrupted time series analyses........................................................................ 43 5.4.7. Case-population studies ................................................................................... 44 6. Methods to address bias and confounding ............................................. 45 6.1. Bias ................................................................................................................ 45 6.1.1. Selection bias .................................................................................................. 45 6.1.2. Information bias .............................................................................................. 46 6.1.3. Time-related bias ............................................................................................ 47 6.2. Confounding................................................................................................... 49 6.2.1. Confounding by indication ................................................................................. 49 6.2.2. Unmeasured confounding ................................................................................. 49 6.2.3. Methods to address confounding........................................................................ 50 6.3. Missing data ................................................................................................... 55 6.3.1. Impact of missing data ..................................................................................... 55 6.3.2. Patterns of missing data ................................................................................... 55 6.3.3. Handling missing data ...................................................................................... 55 6.3.4. Statistical software .......................................................................................... 56 6.4. Triangulation ................................................................................................. 56 7. Effect measure modification and interaction ......................................... 56 8. Systematic reviews and meta-analysis .................................................. 58 9. Signal detection methodology and application ...................................... 59 9.1. General aspects of signal detection ............................................................... 59 9.2. Methods of statistical signal detection ........................................................... 59 9.3. Performance comparison of signal detection methods ................................... 61 9.4. Stratification and sub-group analyses ............................................................ 62 9.5. Masking ......................................................................................................... 62 9.6. Complementary role of databases .................................................................. 62 10. The statistical analysis plan ................................................................. 63 10.1. General considerations ................................................................................ 63 10.2. Timing of the statistical analysis plan .........................................................