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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 11, dated July 2023.


In the 11th Revision, the table of contents has been restructured to better reflect the evidence generation flow and provide greater emphasis on important methodology. New recommendations include the use of the causal inference target trial emulation approach to improve internal validity and increase transparency on study designs; the use of the estimand framework to inform study design and analysis choices; and the use of the HARPER protocol template to foster transparency, reproducibility and harmonisation of non-interventional study protocols and facilitate their assessment.


Nearly all chapters have been updated and include new references, and some chapters have been revised to reflect the fast changing environment in the field of pharmacoepidemiology and real-world evidence (RWE): Chapter 9 on Research networks for multi-database studies addresses the expansion and use of DARWIN EU®, and Chapters 16.1 on Comparative Effectiveness Research, 16.5 on Artificial intelligence in pharmacoepidemiology, and 16.6 on RWE and pharmacoepidemiology, have been extensively revised. 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 to draw lessons from the COVID-19 pandemic and address new challenges, such as post-acute COVID-19 syndrome (or long COVID) and the lasting impact of the pandemic on secondary use of real-world data (RWD).


This version will continue supporting sound pharmacoepidemiological research and RWE generation and provides a useful resource for researchers, regulators, and marketing authorisation holders and applicants.


The Guide is developed in collaboration between EMA and the ENCePP Research Standards and Guidance Working Group and is regularly updated by structured review to maintain its dynamic nature. It may also be amended as necessary in response to comments received. For this purpose, comments and additional relevant guidance documents are welcome and may be forwarded to

Relevant documents:


Individual Chapters:


Foreword to ENCePP Guide Revision 11

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. Specific aspects of study design

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

5.1. Assessment of exposure

5.2. Assessment of outcomes

5.3. Assessment of covariates

5.4. Misclassification and validation

6. Methods to address bias and confounding

6.1. Bias

6.2. Confounding

6.3. Missing data

6.4. Triangulation

7. Effect modification and interaction

8. Approaches to data collection

8.1. Primary data collection

8.2. Secondary use of data

8.3. Patient registries

8.4. Spontaneous reports

8.5. Social media

9. Research networks for multi-database studies

9.1. General considerations

9.2. Models of studies using multiple data sources

9.3. Challenges of different models

10. Systematic reviews and meta-analysis

11. Signal detection methodology application

11.1. General aspects of signal detection

11.2. Methods of statistical signal detection

11.3. Triage of statistical safety signals

11.4. Performance comparison of signal detection methods

11.5. Stratification and sub-group analyses

11.6. Masking

11.7. Complementary role of databases

12. Statistical analyses

12.1. General considerations

12.2. Timing of the statistical analysis plan

12.3. Information in the statistical analysis plan

13. Quality management

13.1. General principles of quality management

13.2. Data quality frameworks

13.3. Quality management in clinical trials

13.4. Quality management in observational studies

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

15.1. Personal data protection in the European Union

15.2. Scientific integrity and ethical conduct

16. Specific topics

16.1. Comparative effectiveness research

16.2. Vaccine safety and effectiveness

16.3. Design, implementation and analysis of pharmacogenomic studies

16.4. Methods for pharmacovigilance impact research

16.5. Artificial intelligence in pharmacoepidemiology

16.6. 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