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Home > Standards & Guidances > Methodological Guide

ENCePP Guide on Methodological Standards in Pharmacoepidemiology Studies on vaccine safety in special populations

The article Vaccine safety in special populations (Hum Vaccin 2011;7(2):269-71) highlights common methodological issues that may arise in evaluating vaccine safety in special populations, especially infants and children who often differ in important ways from healthy individuals and change rapidly during the first few years of life, and elderly patients.


Observational studies on vaccine adverse effects during pregnancy (especially on pregnancy loss), which often use pregnancy registries or healthcare databases, are faced with three challenges: embryonic and early foetal loss are often not recognised or recorded, data on the gestational age at which these events occur are often missing, and the likelihood of vaccination increases with gestational age whereas the likelihood of foetal death decreases. Assessing the effect of vaccine on spontaneous abortion using time-dependent covariates Cox models (Pharmacoepidemiol Drug Saf 2012;21(8):844-850) demonstrates that rates of spontaneous abortion can be severely underestimated without survival analysis techniques using time-dependent covariates to avoid immortal time bias and shows how to fit such models. Risk of miscarriage with bivalent vaccine against human papillomavirus (HPV) types 16 and 18: pooled analysis of two randomised controlled trials (BMJ 2010; 340:c712) explains methods to calculate rates of miscarriage, address the lack of knowledge of time of conception during which vaccination might confer risk and perform subgroup and sensitivity analyses. The Systematic overview of data sources for drug safety in pregnancy research provides an inventory of pregnancy exposure registries and alternative data sources useful to assess the safety of prenatal vaccine exposure.

Few vaccine studies are performed in immunocompromised subjects. Influenza vaccination for immunocompromised patients: systematic review and meta-analysis by etiology (J Infect Dis 2012;206(8):1250-9) illustrates the importance of performing stratified analyses by aetiology of immunocompromise and possible limitations due to residual confounding, differences within and between etiological groups and small sample size in some etiological groups. Further research is needed on this topic.


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