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Home > Standards & Guidances > Methodological Guide

ENCePP Guide on Methodological Standards in Pharmacoepidemiology


5.7. Systematic reviews and meta-analysis


There may be results from more than one study with the same or similar research objective, and identification and integration of this evidence can extend our understanding of the issue. The focus of this activity may be to learn from the diversity of designs, results and associated gaps in knowledge as well as to obtain overall risk estimates. An example is the meta-analysis of results of individual studies with potentially different design e.g. Variability in risk of gastrointestinal complications with individual NSAIDs: results of a collaborative meta-analysis (BMJ 1996;312:1563-6), which compared the relative risks of serious gastrointestinal complications reported with individual NSAIDs by conducting a systematic review of twelve hospital and community based case-control and cohort studies, and found a relation between use of the drugs and admission to hospital for haemorrhage or perforation.


A systematic literature review aims to collect all empirical evidence that fits pre-specified eligibility criteria to answer a specific research question. These reviews use systematic and explicit methods to identify and critically appraise relevant research, and to analyse the data included in the review. A meta-analysis involves the use of statistical techniques to integrate and summarize the results of identified studies.


Systematic review and meta-analysis of observational studies and other epidemiological sources are becoming as common as those of RCTs.  Challenges in systematic reviews that assess treatment harms (Ann Intern Med 2005;142:1090-9) explains the different reasons why both are important in providing relevant information and knowledge for pharmacovigilance.


A detailed guidance on the methodological conduct of systematic reviews and meta-analysis is reported in Annex 1 of this guide. This guidance includes links to other relevant resources.


It should be noted that meta-analysis, even of randomised controlled trials, shares characteristics with observational research: the studies are often produced according to an unplanned process and subjective processes are involved in selection of studies to include. Careful planning in design of a meta-analysis and pre-specification of selection criteria, outcomes and analytical methods before review of any study results may thus add appreciably to the confidence that is placed in the results. A further useful reference is the CIOMS Working Group X Guideline on Evidence Synthesis and Meta-Analysis for Drug Safety (Geneva 2016).



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