TY - JOUR
T1 - Generating evidence for precision medicine
T2 - considerations made by the Ubiquitous Pharmacogenomics Consortium when designing and operationalizing the PREPARE study
AU - van der Wouden, Cathelijne H
AU - Böhringer, Stefan
AU - Cecchin, Erika
AU - Cheung, Ka-Chun
AU - Dávila-Fajardo, Cristina Lucía
AU - Deneer, Vera H M
AU - Dolžan, Vita
AU - Ingelman-Sundberg, Magnus
AU - Jönsson, Siv
AU - Karlsson, Mats O
AU - Kriek, Marjolein
AU - Mitropoulou, Christina
AU - Patrinos, George P
AU - Pirmohamed, Munir
AU - Rial-Sebbag, Emmanuelle
AU - Samwald, Matthias
AU - Schwab, Matthias
AU - Steinberger, Daniela
AU - Stingl, Julia
AU - Sunder-Plassmann, Gere
AU - Toffoli, Giuseppe
AU - Turner, Richard M
AU - van Rhenen, Mandy H
AU - van Zwet, Erik
AU - Swen, Jesse J
AU - Guchelaar, Henk-Jan
PY - 2020/8
Y1 - 2020/8
N2 - 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.
AB - 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.
U2 - 10.1097/FPC.0000000000000405
DO - 10.1097/FPC.0000000000000405
M3 - Article
C2 - 32317559
SN - 1744-6872
VL - 30
SP - 131
EP - 144
JO - Pharmacogenetics and Genomics
JF - Pharmacogenetics and Genomics
IS - 6
ER -