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ENCePP Guide on Methodological Standards in Pharmacoepidemiology


Chapter 1: Introduction

Epidemiology is the discipline of how to study the occurrence of phenomena of interest among people in the health field. It measures their frequency of occurrence and the relationship with their determinants (O. Miettinen. Theoretical Epidemiology: Principles of Occurrence Research in Medicine, Wiley, 1985,vii-viii). Pharmacoepidemiology is the application of epidemiological methods to study the use and effects of drugs in specified populations. The choice of epidemiological methods for a research question should be based on methodological standards supporting the validity of the study results. There are many textbooks describing these standards, but they cannot incorporate all new developments. ENCePP therefore considered there was a need for a regularly updated resource providing recommendations on the practical implementation of pharmacoepidemiological principles and innovative methods, based on published guidance and illustrative examples.


The ENCePP Guide aims to offer a dynamic and publicly available web resource for methodological English language guidance in pharmacoepidemiology. For each topic covered, recommendations are provided with electronic links to selected published articles, guidelines and public documents selected by experts in pharmacoepidemiology from ENCePP. Where relevant, gaps in existing guidance are addressed with what ENCePP considers good practice. The Guide is updated annually by a structured review in order 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 may be forwarded to


The Guide only briefly describes general methods of pharmacoepidemiology and study designs stemming from traditional epidemiological research, such as the cohort, case-control and cross-sectional designs, as they are already fully described in existing textbooks. It rather discusses important aspects of more recent designs such as self-controlled designs and specific analytical approaches to traditional designs. It also discusses methods that may be used in studies with different goals, be they safety, effectiveness, drug utilisation, health technology assessment or any other objective. For some specific topics, specific recommendations and references are provided where they differ from general principles. Chapter 14 provides extensive guidance on specific topics: comparative effectiveness research, vaccine safety and effectiveness, design and analysis of pharmacogenomic studies and method for pharmacovigilance impact research.


Annex 1 has been developed separately by an ENCePP working group and provides methodological guidance addressing the conduct of systematic reviews and meta-analyses of drug safety endpoints.


General guidance on the conduct of pharmacoepidemiology studies can be found in the ISPE Good Pharmacoepidemiology Practices (GPP) and the IEA Good Epidemiology Practice (GEP). The GPP guidance is especially useful for its recommendations on aspects rarely covered by guidelines, such as data quality issues and archiving. The Guidelines and recommendations for ensuring Good Epidemiological Practice (GEP): a guideline developed by the German Society for Epidemiology (Eur J Epidemiol. 2019;34(3):301-17) provides detailed recommendations addressed to those involved in the planning, preparation, execution, analysis, and evaluation of epidemiological research.


The Guideline of good pharmacovigilance practices (GVP) Module VIII - Post-authorisation safety studies provides a general guidance on the development, conduct and reporting of post-authorisation safety studies (PASS) conducted by marketing authorisation holders voluntarily or pursuant to the EU legislation (Directive 2001/83/EC). The Scientific guidance on post-authorisation efficacy studies provides general scientific guidance in the context of EU regulatory decision-making with regard to the need for such studies and methodological considerations.


The terms “Real-world data” (RWD) and “Real-world evidence” (RWE) are increasingly used in the regulatory setting to denote the use of observational data and pharmacoepidemiological methods for regulatory decision-making. The article Real-World Data for Regulatory Decision Making: Challenges and Possible Solutions for Europe (Clin Pharmacol Ther. 2019;106(1):36-9) defines RWD as “routinely collected data relating to a patient’s health status or the delivery of health care from a variety of sources other than traditional clinical trials”, and RWE as “the information derived from the analysis of RWD”. The article describes operational, technical and methodological challenges for the acceptability of RWE for regulatory purposes and presents possible solutions to address these challenges, including the use of best methodological standards in statistics and epidemiology. The FDA’s Real-World Evidence website provides definitions and links to a set of useful guidelines on the submission and use of RWD and RWE to support decision-making. Today, there is however no internationally agreed definition of RWD and RWE, and of what data or piece of information should be considered as RWD or RWE. Quality frameworks for RWE and RWD are presented in Chapter 11 of this Guide.


Textbooks on standard methods in pharmacoepidemiology that are considered useful are listed below. The list is not exhaustive, and researchers may find other textbooks more appropriate to their specific needs. Others are cited in specific chapters.


  • Modern Epidemiology, 3rd ed. (K. Rothman, S. Greenland, T. Lash. Lippincott Williams & Wilkins, 2008) is a comprehensive textbook on methods in epidemiology.
  • Epidemiology: Study Design and Data Analysis, Third Edition (M. Woodward, Chapman & Hall, 2014) focuses on the quantitative aspects of epidemiological research.
  • A Dictionary of Epidemiology, Sixth Edition (M Porta, Editor. Oxford University Press, 2014), sponsored by the International Epidemiological Association (IEA), provides a definition and concise explanation of epidemiologic terms and is a key to understanding epidemiological concepts.
  • Clinical epidemiology: practice and methods, Second Edition (PS Parfrey, BJ Barret, Human Press, 2015) focuses on the diagnosis, prognosis and management of human disease using appropriate research design, measurement and evaluation.
  • Causal Inference: What If (Hernán MA, Robins JM, Chapman & Hall/CRC, 2020) aims to help scientists generate and analyse data to make causal inferences that are explicit about both the causal question and the assumptions underlying the data analysis.
  • Pharmacoepidemiology, Sixth Edition (B. Strom, S.E. Kimmel, S. Hennessy, Wiley, 2019) provides a comprehensive guidance on pharmacoepidemiology addressing data sources, applications and methodologies.
  • Pharmacoepidemiology and Therapeutic Risk Management, First Edition (A.G. Hartzema, H.H. Tilson and K.A. Chan, Editors, Harvey Whitney Books Company, 2008) illustrates practical issues with a large number of real-life examples in addition to a general review of drug-specific methodologies.
  • Practical Statistics for Medical Research, Second Edition (D. Altman. Chapman & Hall, 2020) presents a problem-based statistical text for medical researchers.
  • Drug Utilization Research. Methods and Applications (M Elseviers, B Wettermark, AB Almarsdóttir, et al. Editors. Wiley Blackwell, 2016) provides a comprehensive manual of methodology and applications of drug utilisation research.
  • Mann's Pharmacovigilance, Third Edition (EB Andrews, N Moore, Editors, Wiley-Blackwell, 2014) is a reference for the detection, assessment, understanding and prevention of the adverse effects of medicines, including vaccines and biologics.
  • Post-Authorization Safety Studies of Medicinal Products. The PASS Book, 1st Edition (Ayad Ali, Abraham Hartzema, Ed., Academic Press, 2018) covers the use of observational studies in post-marketing drug safety assessment, presents various types of post-authorisation safety studies and discusses challenges and solutions in the design and conduct of these studies.



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