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Home > Standards & Guidances > Methodological Guide

ENCePP Guide on Methodological Standards in Pharmacoepidemiology General aspects

Specific aspects of vaccines to be considered in pharmacovigilance and pharmacoepidemiology have been highlighted in several documents. The report of the CIOMS/WHO Working Group on Definition and Application of Terms for Vaccine Pharmacovigilance (2012) emphasises that characteristics of the vaccine and the vaccinated population, settings and circumstances of vaccine administration and data analysis issues are worthy of special attention in vaccine safety monitoring. It also provides definitions and explanatory notes for the terms ‘vaccine pharmacovigilance’, ‘vaccination failure’ and ‘adverse event following immunisation (AEFI)’. Recommendations on vaccine-specific aspects of the EU pharmacovigilance system, including on risk management, signal detection and post-authorisation safety studies (PASS) are presented in the Module P.I: Vaccines for prophylaxis against infectious diseases of the Good pharmacovigilance practices (GVP).


Methods for vaccine pharmacovigilance have been developed by the Brighton Collaboration, which provides resources to facilitate and harmonise collection, analysis and presentation of vaccine safety data, including case definitions, an electronic tool to help the classification of reported signs and symptoms, template protocols and guidelines. Module 4 (Surveillance) of the e-learning training course Vaccine Safety Basics of the World Health Organization (WHO) describes phamacovigilance principles, causality assessment procedures, surveillance systems and factors influencing the risk-benefit balance of vaccines. In particular, in contrast to the use of other medicines, vaccines are often used in healthy people and it is not only important to identify possible risks but also to emphasize safety if it does exist.


Individual Chapters:


1. General aspects of study protocol

2. Research question

3. Approaches to data collection

3.1. Primary data collection

3.2. Secondary use of data

3.3. Research networks

3.4. Spontaneous report database

3.5. Using data from social media and electronic devices as a data source

3.5.1. General considerations

4. Study design and methods

4.1. General considerations

4.2. Challenges and lessons learned

4.2.1. Definition and validation of drug exposure, outcomes and covariates Assessment of exposure Assessment of outcomes Assessment of covariates Validation

4.2.2. Bias and confounding Choice of exposure risk windows Time-related bias Immortal time bias Other forms of time-related bias Confounding by indication Protopathic bias Surveillance bias Unmeasured confounding

4.2.3. Methods to handle bias and confounding New-user designs Case-only designs Disease risk scores Propensity scores Instrumental variables Prior event rate ratios Handling time-dependent confounding in the analysis

4.2.4. Effect modification

4.3. Ecological analyses and case-population studies

4.4. Hybrid studies

4.4.1. Pragmatic trials

4.4.2. Large simple trials

4.4.3. Randomised database studies

4.5. Systematic review and meta-analysis

4.6. Signal detection methodology and application

5. The statistical analysis plan

5.1. General considerations

5.2. Statistical plan

5.3. Handling of missing data

6. Quality management

7. Communication

7.1. Principles of communication

7.2. Guidelines on communication of studies

8. Legal context

8.1. Ethical conduct, patient and data protection

8.2. Pharmacovigilance legislation

8.3. Reporting of adverse events/reactions

9. Specific topics

9.1. Comparative effectiveness research

9.1.1. Introduction

9.1.2. General aspects

9.1.3. Prominent issues in CER Randomised clinical trials vs. observational studies Use of electronic healthcare databases Bias and confounding in observational CER

9.2. Vaccine safety and effectiveness

9.2.1. Vaccine safety General aspects Signal detection Signal refinement Hypothesis testing studies Meta-analyses Studies on vaccine safety in special populations

9.2.2. Vaccine effectiveness Definitions Traditional cohort and case-control studies Screening method Indirect cohort (Broome) method Density case-control design Test negative design Case coverage design Impact assessment Methods to study waning immunity

9.3. Design and analysis of pharmacogenetic studies

9.3.1. Introduction

9.3.2. Identification of genetic variants

9.3.3. Study designs

9.3.4. Data collection

9.3.5. Data analysis

9.3.6. Reporting

9.3.7. Clinical practice guidelines

9.3.8. Resources

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