Generating evidence for precision medicine: considerations made by the Ubiquitous Pharmacogenomics Consortium when designing and operationalizing the PREPARE study

Abstract

Objectives Pharmacogenetic panel-based testing represents a new model for precision medicine. A sufficiently powered prospective study assessing the (cost-)effectiveness of a panel-based pharmacogenomics approach to guide pharmacotherapy is lacking. Therefore, the Ubiquitous Pharmacogenomics Consortium initiated the PREemptive Pharmacogenomic testing for prevention of Adverse drug Reactions (PREPARE) study. Here, we provide an overview of considerations made to mitigate multiple methodological challenges that emerged during the design. Methods An evaluation of considerations made when designing the PREPARE study across six domains: study aims and design, primary endpoint definition and collection of adverse drug events, inclusion and exclusion criteria, target population, pharmacogenomics intervention strategy, and statistical analyses. Results Challenges and respective solutions included: (1) defining and operationalizing a composite primary endpoint enabling measurement of the anticipated effect, by including only severe, causal, and drug genotype-associated adverse drug reactions; (2) avoiding overrepresentation of frequently prescribed drugs within the patient sample while maintaining external validity, by capping drugs of enrolment; (3) designing the pharmacogenomics intervention strategy to be applicable across ethnicities and healthcare settings; and (4) designing a statistical analysis plan to avoid dilution of effect by initially excluding patients without a gene–drug interaction in a gatekeeping analysis. Conclusion Our design considerations will enable quantification of the collective clinical utility of a panel of pharmacogenomics-markers within one trial as a proof-of-concept for pharmacogenomics-guided pharmacotherapy across multiple actionable gene–drug interactions. These considerations may prove useful to other investigators aiming to generate evidence for precision medicine.

Adverse Drug Reactions in the Emergency Department: Is There a Role for Pharmacogenomic Profiles at Risk?—Results from the ADRED Study

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“…However, the clinical implication score of the DPWG includes criteria that would determine the outcome of a cost-effectiveness study such as the clinical impact meaning the severity of the drug’s side effect or the clinical impact of diminished efficacy, the number needed to genotype. It is worthwhile mentioning that currently the PREPARE study is investigating the (cost)-effectiveness and clinical utility of applying the DPWG guideline after a panel of genes being tested ( van der Wouden et al, 2017 ; Van Der Wouden et al, 2020 ).…”

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“…Retrospectively, using an individualized risk assessment may have been more effective when used upon initiation of an antithrombotic therapy, when serious ADRs might even occur more often [ 21 ]. GPs have a high degree of experience with the indication and handling of antithrombotic agents and the benefit of an individualized risk assessment might be highest in patients initiating a new drug treatment such as that performed in the PREPARE trial within the U-PGx project and other PGx implementation projects [ 22 , 23 ].…”