The choice of epidemiological methods to answer a research question should be based on principles and methodological standards supporting the validity of the study results. There are many textbooks describing methodological standards in pharmacoepidemiology 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.
This Guide aims to offer a dynamic and publicly available web resource for methodological English language guidance in pharmacoepidemiology. It provides links to selected published articles and guidelines that illustrate important principles of pharmacoepidemiological research. For each topic covered, recommendations are provided with direct electronic access to textbooks, reference documents and examples selected by experts from ENCePP. Where relevant, gaps in existing guidance are addressed with what ENCePP considers as being 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 ENCePP_Secretariat@ema.europa.eu.
The Guide does not discuss general methods of pharmacoepidemiology as they are already covered in existing textbooks. For example, it does not describe traditional study designs like the cross-sectional, cohort and case-control designs but it discusses important aspects of more recent designs such as the self-controlled case series (SCCS) design. Chapters 2 to 9 describe 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 10 provides more extensive guidance on three specific topics, comparative effectiveness research, vaccine safety and effectiveness and pharmacogenetic studies.
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.
Annex 2 has been developed by an ENCePP Special Interest Group and provides recommendations on methods for measuring the impact of pharmacovigilance activities on patients and public health.
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 everyone involved in the planning, preparation, execution, analysis, and evaluation of epidemiological research and is relevant for the evaluation of medicines.
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). It also describes the criteria applicable in the European Union (EU) to define a post-authorisation study as non-interventional, but investigators should be aware that implementation of these criteria may vary at national level in different EU countries. 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 secondary 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 introduces the OPTIMAL framework to describe the 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 also provides definitions and links to a set of useful guidelines on the submission and use of RWD and RWE to support decision-making.
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, Fourth Edition (K. Rothman, S. Greenland, T. Lash. Lippincott Williams & Wilkins, 2020) 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.
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 science of 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.