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Home > Standards & Guidances > Methodological Guide

ENCePP Guide on Methodological Standards in Pharmacoepidemiology


5.3.6. Prior event rate ratios


Another method proposed to control for unmeasured confounding is the Prior Event Rate Ratio (PERR) adjustment method, in which the effect of exposure is estimated using the ratio of rate ratios (RRs) from periods before and after initiation of a drug exposure as discussed in Replicated studies of two randomized trials of angiotensin converting enzyme inhibitors: further empiric validation of the ‘prior event rate ratio’ to adjust for unmeasured confounding by indication (Pharmacoepidemiol Drug Saf. 2008;17:671-685).  For example, when a new drug is launched, direct estimation of the drugs effect observed in the period after launch is potentially confounded. Differences in event rates in the period before the launch between future users and future non-users may provide a measure of the amount of confounding present. By dividing the effect estimate from the period after launch by the effect obtained in the period before launch, the confounding in the second period can be adjusted for. This method requires that confounding effects are constant over time, that there is no confounder-by-treatment interaction, and outcomes are non-lethal events.


Performance of prior event rate ratio adjustment method in pharmacoepidemiology: a simulation study (Pharmacoepidemiol Drug Saf. 2015;24:468-477) discusses that the PERR adjustment method can help to reduce bias as a result of unmeasured confounding in certain situations but that theoretical justification of assumptions should be provided.



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