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Home > Standards & Guidances > Methodological Guide

ENCePP Guide on Methodological Standards in Pharmacoepidemiology


5.6.1. Pragmatic trials


RCTs are considered the gold standard for demonstrating the efficacy of medicinal products and for obtaining an initial estimate of the risk of adverse outcomes. However, as is well understood, these data are often not necessarily indicative of the benefits, risks or comparative effectiveness of an intervention when used in clinical practice populations. The IMI GetReal Glossary defines a pragmatic clinical trial (PCT) as ‘a study comparing several health interventions among a randomised, diverse population representing clinical practice, and measuring a broad range of health outcomes.’ PCTs are focused on evaluating benefits and risks of treatments in patient populations and settings more representative of routine clinical practice. To ensure generalisability, pragmatic trials should represent the patients to whom the treatment will be applied, for instance, inclusion criteria would be broad (e.g. allowing co-morbidity, co-medication, wider age range), the follow-up would be minimized and allow for treatment switching etc. Monitoring safety in a phase III real-world effectiveness trial: use of novel methodology in the Salford Lung Study (Pharmacoepidemiol Drug Saf. 2017;26(3):344-352) describes the model of a phase III pragmatic RCT where patients were enrolled through primary care practices using minimal exclusion criteria and without extensive diagnostic testing and where potential safety events were captured through patients’ electronic health records and in turn triggered review by the specialist safety team.


Pragmatic explanatory continuum summary (PRECIS): a tool to help trial designers (CMAJ 2009; 180: E45-57) is a tool to support pragmatic trial designs and helps define and evaluate the degree of pragmatism. The PRECIS tool has been further refined and now comprises nine domains each scored on a 5 point Likert scale ranging from very explanatory to very pragmatic with an exclusive focus on the issue of applicability (The PRECIS-2 tool: designing trials that are fit for purpose. BMJ 2015; 350: h2147).  A checklist and additional guidance is also provided in Improving the reporting of pragmatic trials: an extension of the CONSORT statement (BMJ 2008; 337 (a2390): 1-8).



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