Print page Resize text Change font-size Change font-size Change font-size High contrast


methodologicalGuide9_3_1.shtml
Home > Standards & Guidances > Methodological Guide

ENCePP Guide on Methodological Standards in Pharmacoepidemiology

 

9.3.1. Introduction

Individual variation in the response to drugs is an important clinical issue and may range from a lack of therapeutic effect to serious adverse drug reactions.

 

Pharmacogenetics is defined as the study of genetic variation as a determinant of drug response. It can complement information on clinical factors and disease sub-phenotypes to optimise the prediction of treatment response.

This heterogeneity of response has important policy implications if individual patients not responding to conventional agents are denied access to other agents based on clinical trial evidence and systematic reviews that show no overall benefit. While clinical variables such as disease severity, age, concomitant drug use and illnesses are potentially important determinants of the response to drugs, heterogeneity in drug disposition (absorption, metabolism, distribution, and excretion) and targets (such as receptors and signal transduction modulators) may be an important cause of inter-individual variability in the therapeutic effects of drugs (see Pharmacogenomics: translating functional genomics into rational therapeutics. Science 1999;286(5439):487-91). Identification of variation in genes which modify the response to drugs provides the opportunity to optimise safety and effectiveness of the currently available drugs and develop new drugs for paediatric and adult populations (see Drug discovery: a historical perspective. Science 2000;287(5460):1960-4).

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

4.2.1.1. Assessment of exposure

4.2.1.2. Assessment of outcomes

4.2.1.3. Assessment of covariates

4.2.1.4. Validation

4.2.2. Bias and confounding

4.2.2.1. Choice of exposure risk windows

4.2.2.2. Time-related bias

4.2.2.2.1. Immortal time bias

4.2.2.2.2. Other forms of time-related bias

4.2.2.3. Confounding by indication

4.2.2.4. Protopathic bias

4.2.2.5. Surveillance bias

4.2.2.6. Unmeasured confounding

4.2.3. Methods to handle bias and confounding

4.2.3.1. New-user designs

4.2.3.2. Case-only designs

4.2.3.3. Disease risk scores

4.2.3.4. Propensity scores

4.2.3.5. Instrumental variables

4.2.3.6. Prior event rate ratios

4.2.3.7. 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

9.1.3.1. Randomised clinical trials vs. observational studies

9.1.3.2. Use of electronic healthcare databases

9.1.3.3. Bias and confounding in observational CER

9.2. Vaccine safety and effectiveness

9.2.1. Vaccine safety

9.2.1.1. General aspects

9.2.1.2. Signal detection

9.2.1.3. Signal refinement

9.2.1.4. Hypothesis testing studies

9.2.1.5. Meta-analyses

9.2.1.6. Studies on vaccine safety in special populations

9.2.2. Vaccine effectiveness

9.2.2.1. Definitions

9.2.2.2. Traditional cohort and case-control studies

9.2.2.3. Screening method

9.2.2.4. Indirect cohort (Broome) method

9.2.2.5. Density case-control design

9.2.2.6. Test negative design

9.2.2.7. Case coverage design

9.2.2.8. Impact assessment

9.2.2.9. 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