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ENCePP Guide on Methodological Standards in Pharmacoepidemiology



The Guide on Methodological Standards in Pharmacoepidemiology offers a single online resource for methodological guidance in pharmacoepidemiology. For each topic covered, direct links to internationally agreed recommendations, key points from important guidelines, published articles and textbooks, are provided. Where relevant, gaps in existing guidance are addressed with what ENCePP considers good practice. 


The current version of the Guide is Revision 10, dated 30 June 2022.


The 10th Revision includes two new chapters on the use of artificial intelligence in pharmacoepidemiology (Chapter 15.5) and on real-world evidence and pharmacoepidemiology (15.6), and a new comprehensive Annex 2 on Methods for the evaluation of medicines in pregnancy and breastfeeding. Besides the updating of nearly all existing chapters, including considerations on methodological standards for COVID-19 studies, two chapters have been extensively revised: Comparative effectiveness research (15.1) and Vaccine research (15.2). Recommendations on the use of statistical significance for the interpretation of evidence have been added in the Overview of study designs (4.1). Most of the chapters include new references. Revisions were performed by the co-authors in collaboration with the editorial group.


The Foreword from the co-chairs of the ENCePP Steering Group highlights the continued involvement of ENCePP in COVID-19 research and the disorders related to long COVID, and in real-world evidence studies. Nearly all chapters contain relevant guidance on methodological standards to be applied in COVID-19 studies, with references to selected publications illustrating relevant methodological aspects.


This version will continue supporting sound pharmacoepidemiological research and real-world evidence studies, and provides a useful resource for researchers, regulators, and marketing authorisation holders and applicants.


The Guide is maintained by the ENCePP Research Standards and Guidance working group under EMA’s coordination and updated annually by structured review to maintain its dynamic nature. It may also be amended as necessary in response to comments received. For this purpose, any comment and additional relevant guidance document(s) may be forwarded to

Relevant documents:


Individual Chapters:


Foreword to ENCePP Guide Revision 10

1. Introduction

2. Formulating the research question and objectives and assessing study feasibility

3. Development of the study protocol

4. Study design

4.1. Overview

4.2. Types of study design

4.3. Definition and validation of drug exposure, outcomes and covariates

4.4. Specific aspects of study design

5. Methods to address bias and confounding

5.1. Bias

5.2. Confounding

5.3. Missing data

5.4. Triangulation

6. Effect measure modification and interaction

7. Approaches to data collection

7.1. Primary data collection

7.2. Secondary use of data

7.3. Patient registries

7.4. Spontaneous reports

7.5. Social media

8. Research networks for multi-database studies

8.1. General considerations

8.2. Models of studies using multiple data sources

8.3. Challenges of different models

9. Systematic reviews and meta-analysis

10. Signal detection methodology application

10.1. General aspects of signal detection

10.2. Methods of statistical signal detection

10.3. Triage of statistical safety signals

10.4. Performance comparison of signal detection methods

10.5. Stratification and sub-group analyses

10.6. Masking

10.7. Complementary role of databases

11. The statistical analysis plan

11.1. General considerations

11.2. Timing of the statistical analysis plan

11.3. Elements of the statistical analysis plan

12. Quality management

12.1. General principles of quality management

12.2. Data quality frameworks

12.3. Quality management in clinical trials

12.4. Quality management in observational studies

13. Dissemination and communication of study results
14. Data protection and ethical aspects

14.1. Personal data protection in the European Union

14.2. Scientific integrity and ethical conduct

15. Specific topics

15.1. Comparative effectiveness research

15.2. Vaccine safety and effectiveness

15.3. Design, implementation and analysis of pharmacogenomic studies

15.4. Methods for pharmacovigilance impact research

15.5. Artificial intelligence in pharmacoepidemiology

15.6. Real-world evidence and pharmacoepidemiology

Annex 1. Guidance on conducting systematic reviews and meta-analyses of completed comparative pharmacoepidemiological studies of safety outcomes
Annex 2. Guidance on methods for the evaluation of medicines in pregnancy and breastfeeding