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

Cathelijne H. Van Der Wouden, Stefan Böhringer, Erika Cecchin, Ka Chun Cheung, Cristina Lucía Dávila-Fajardo, Vera H.M. Deneer, Vita Dolžan, Magnus Ingelman-Sundberg, Siv Jönsson, Mats O. Karlsson, Marjolein Kriek, Christina Mitropoulou, George P. Patrinos, Munir Pirmohamed, Emmanuelle Rial-Sebbag, Matthias Samwald, Matthias Schwab, Daniela Steinberger, Julia Stingl, Gere Sunder-PlassmannGiuseppe Toffoli, Richard M. Turner, Mandy H. Van Rhenen, Erik Van Zwet, Jesse J. Swen, Henk Jan Guchelaar

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)131-144
Number of pages14
JournalPharmacogenetics and Genomics
Publication statusAccepted/In press - 2020


  • adverse drug reactions
  • clinical implementation
  • genotyping
  • next-generation sequencing
  • pharmacogenetics
  • pharmacogenomics
  • pre-emptive
  • randomized controlled trial

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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