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Home > Standards & Guidances > Methodological Guide

ENCePP Guide on Methodological Standards in Pharmacoepidemiology

 

1. Introduction

The choice of epidemiological methods to answer a research question is based on principles rather than on rules, but certain standards are needed to assure validity and robustness of the study results. Textbooks describing methodological standards in pharmacoepidemiological research are numerous but cannot follow new developments in research. 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 chosen 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 structured review to maintain its dynamic nature. It may also be amended as necessary in response to comments received. For these purposes, any comment and additional relevant guidance document may be forwarded to encepp_comments@ema.europa.eu.

 

The Guide does not discuss general methods of pharmacoepidemiology 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 1 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. This chapter may be expanded in future revisions if there is a need for methodological guidance on other topics.

 

Annex 1 has been developed separately by an ENCePP working group to provide methodological guidance addressing the conduct of systematic reviews and meta-analyses of drug safety endpoints generated in completed (published or unpublished) comparative pharmacoepidemiological studies.

 

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 is especially useful for its recommendations on aspects rarely covered by guidelines, such as data quality issues and archiving. The EU legislation (Directive 2001/83/EU) includes the possibility for regulatory authorities to impose on marketing authorisation holders the conduct of post-authorisation safety study (PASS) as a condition of the marketing authorisation, a PASS being defined as ‘any study relating to an authorised medicinal product conducted with the aim of identifying, characterising or quantifying a safety hazard, confirming the safety profile of the medicinal product, or of measuring the effectiveness of risk management measures.’ The Guideline of good pharmacovigilance practices (GVP) Module VIII - Post-authorisation safety studies provides a general guidance on the development, conduct and reporting of PASS conducted by marketing authorisation holders voluntarily or pursuant to an obligation. 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 such criteria are sometimes interpreted differently at national level in different EU countries.

 

The following list proposes a list of textbooks on standard methods in pharmacoepidemiology recommended for consultation. The list is not exhaustive, as researchers may find other textbooks more appropriate to their specific needs and others are cited in specific chapters.

  • Epidemiology: Principles and Methods 2nd Edition (B. MacMahon, D. Trichopoulos. Lippincott Williams & Wilkins, 1996) offers an introductory understanding of epidemiological methods and processes, including on study designs and control for confounding.
  • Modern Epidemiology 3rd Edition (K. Rothman, S. Greenland, T. Lash. Lippincott Williams & Wilkins, 2008) serves as a comprehensive textbook on methods in epidemiology.

 

  • Pharmacoepidemiology 5th Edition (B. Strom, S.E. Kimmel, S. Hennessy. Wiley, 2012) provides a complete review of epidemiological methods applied to the study of drugs.

 

  • Pharmacoepidemiology and Therapeutic Risk Management 1st Edition (A.G. Hartzema, H.H. Tilson and K.A. Chan, Editors. Harvey Whitney Books Company, 2008). In addition to a general review of drug-specific methodologies, this textbook illustrates practical issues with a large number of real life examples.

 

  • Encyclopedia of Epidemiologic Methods (M.H. Gail, J. Benichou, Editors. Wiley, 2000). This compilation of articles complements existing textbooks by providing a large coverage of specialised topics in epidemiological and statistical methods.

 

  • Practical Statistics for Medical Research (D. Altman. Chapman & Hall, 1990) presents a problem-based statistical text for medical researchers.

 

  • Drug Utilization Research. Methods of Applications (Elseviers M, Wettermark B, Almarsdóttir AB, et al. Editors. Wiley Blackwell, 2016). This book provides a comprehensive manual of methodology and applications of drug utilisation research.

 

  • A Dictionary of Epidemiology 5th Edition (M Porta, Editor. J.M. Last S. Greenland, Associate Editors. Oxford University Press, 2008), sponsored by the International Epidemiological Association (IEA), provides a definition and concise explanation of epidemiologic terms and is a key to understanding epidemiological concepts.

 

  • Dictionary of Pharmacoepidemiology (Bernard Bégaud. Wiley, 2000) illustrates definitions with practical examples and is particularly useful for pharmacovigilance aspects of pharmacoepidemiology.

 

 

Individual Chapters:

 

1. Introduction

2. Formulating the research question

3. Development of the study protocol

4. Approaches to data collection

4.1. Primary data collection

4.1.1. Surveys

4.1.2. Randomised clinical trials

4.2. Secondary data collection

4.3. Patient registries

4.3.1. Definition

4.3.2. Conceptual differences between a registry and a study

4.3.3. Methodological guidance

4.3.4. Registries which capture special populations

4.3.5. Disease registries in regulatory practice and health technology assessment

4.4. Spontaneous report database

4.5. Social media and electronic devices

4.6. Research networks

4.6.1. General considerations

4.6.2. Models of studies using multiple data sources

4.6.3. Challenges of different models

5. Study design and methods

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

5.1.1. Assessment of exposure

5.1.2. Assessment of outcomes

5.1.3. Assessment of covariates

5.1.4. Validation

5.2. Bias and confounding

5.2.1. Selection bias

5.2.2. Information bias

5.2.3. Confounding

5.3. Methods to handle bias and confounding

5.3.1. New-user designs

5.3.2. Case-only designs

5.3.3. Disease risk scores

5.3.4. Propensity scores

5.3.5. Instrumental variables

5.3.6. Prior event rate ratios

5.3.7. Handling time-dependent confounding in the analysis

5.4. Effect measure modification and interaction

5.5. Ecological analyses and case-population studies

5.6. Pragmatic trials and large simple trials

5.6.1. Pragmatic trials

5.6.2. Large simple trials

5.6.3. Randomised database studies

5.7. Systematic reviews and meta-analysis

5.8. Signal detection methodology and application

6. The statistical analysis plan

6.1. General considerations

6.2. Statistical analysis plan structure

6.3. Handling of missing data

7. Quality management

8. Dissemination and reporting

8.1. Principles of communication

8.2. Communication of study results

9. Data protection and ethical aspects

9.1. Patient and data protection

9.2. Scientific integrity and ethical conduct

10. Specific topics

10.1. Comparative effectiveness research

10.1.1. Introduction

10.1.2. General aspects

10.1.3. Prominent issues in CER

10.2. Vaccine safety and effectiveness

10.2.1. Vaccine safety

10.2.2. Vaccine effectiveness

10.3. Design and analysis of pharmacogenetic studies

10.3.1. Introduction

10.3.2. Identification of generic variants

10.3.3. Study designs

10.3.4. Data collection

10.3.5. Data analysis

10.3.6. Reporting

10.3.7. Clinical practice guidelines

10.3.8. Resources

Annex 1. Guidance on conducting systematic revies and meta-analyses of completed comparative pharmacoepidemiological studies of safety outcomes