ArticlesA 12-gene pharmacogenetic panel to prevent adverse drug reactions: an open-label, multicentre, controlled, cluster-randomised crossover implementation study
Introduction
Variation in genes that encode drug-metabolising enzymes, drug transporters, and drug targets affects drug disposition and action, and therefore contributes to variability in drug response. Several studies, including randomised controlled trials, have shown that individualising drug therapy on the basis of pharmacogenetic testing leads to improved patient outcomes for specific drug–gene combinations.1, 2, 3, 4, 5
Consortia such as the Dutch Pharmacogenetics Working Group (DPWG) and the Clinical Pharmacogenetics Implementation Consortium have created guidelines,6, 7 based on evidence from the literature, which include more than 100 gene–drug pairs. Although the minor allele frequencies of specific variants in the genes are low and range from approximately 0·1–5·0%, testing for a panel that consists of multiple actionable variants in the 12 most important pharmacogenes identifies at least one actionable genotype in 90–95% of individuals across multiple populations.8 Therefore, a panel-based pharmacogenetic testing strategy appears to be the most efficient approach. Indeed, a small number of pilot studies9, 10, 11 that investigated the feasibility of a pharmacogenetic-panel test reported a decrease in hospitalisations, emergency department visits, and health-care costs, indicating a potential favourable outcome of this approach. However, although these results are encouraging, there is little convincing data for the clinical utility of genotype-guided drug therapy using a pharmacogenetic panel.12 Therefore, the Ubiquitous Pharmacogenomics Consortium conducted the Pre-emptive Pharmacogenomic Testing for Preventing Adverse Drug Reactions (PREPARE) study. The PREPARE study is the first, large scale, prospective clinical study investigating the effect of a genotype-guided drug prescribing strategy using a pre-emptive 12-gene pharmacogenetic panel approach across different health-care setting in seven European countries.
Section snippets
Study design
The PREPARE study was an investigator-initiated, open-label, multicentre, cluster-randomised crossover implementation study conducted in seven European countries (Austria, Greece, Italy, the Netherlands, Slovenia, Spain, and the UK) that investigated the clinical utility of a pre-emptive genotyping strategy with a pharmacogenetic panel. The study design has been outlined in detail previously.13 Countries as clusters were block randomised (block size 2) to start with either genotype-guided drug
Results
Between March 7, 2017, and June 30, 2020, 41 696 patients were assessed for eligibility and 6944 patients were enrolled, of whom 3342 (48·1%) were assigned to the genotype-guided treatment group and 3602 (51·9%) were assigned to the control group (figure 1). Spain, Greece, and Slovenia were randomly assigned to start with the genotype-guided treatment group, and Austria, Italy, the Netherlands, and the UK were assigned to start with standard care. On Oct 1, 2018, all sites crossed over to the
Discussion
This prospective real-world implementation study in seven different European countries encompassing 6944 patients showed that genotype-guided prescribing using a 12-gene pharmacogenetic panel significantly reduced the incidence of clinically relevant adverse drug reactions. To our knowledge, our results are the first to show the feasibility and clinical use of the large-scale implementation of a panel-based pharmacogenetic-testing strategy and underpin the benefits of implementing a
Data sharing
Data from the PREPARE study are not publicly available but are planned to be made available after preplanned analyses have been completed. A complete deidentified dataset will be made accessible, together with a data dictionary, for a minimum of 5 years. Requests for access to the data can be made by sending an email together with a research plan to the corresponding author and will be evaluated by and require authorisation from the Ubiquitous Pharmacogenomics Consortium executive board. The
Declaration of interests
MP received partnership funding from the UK Medical Research Council (MRC) Clinical Pharmacology Training Scheme (cofunded by MRC, Roche, Union Chimique Belge [UCB] Pharma, Eli Lilly, and Novartis); a PhD studentship jointly funded by the UK Engineering and Physical Sciences Research Council and AstraZeneca; unrestricted educational grant support for the UK Pharmacogenetics and Stratified Medicine Network from Bristol Myers Squibb; and human leucocyte antigen genotyping panel with MC
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