Elsevier

The Lancet

Volume 401, Issue 10374, 4–10 February 2023, Pages 347-356
The Lancet

Articles
A 12-gene pharmacogenetic panel to prevent adverse drug reactions: an open-label, multicentre, controlled, cluster-randomised crossover implementation study

https://doi.org/10.1016/S0140-6736(22)01841-4Get rights and content

Summary

Background

The benefit of pharmacogenetic testing before starting drug therapy has been well documented for several single gene–drug combinations. However, the clinical utility of a pre-emptive genotyping strategy using a pharmacogenetic panel has not been rigorously assessed.

Methods

We conducted an open-label, multicentre, controlled, cluster-randomised, crossover implementation study of a 12-gene pharmacogenetic panel in 18 hospitals, nine community health centres, and 28 community pharmacies in seven European countries (Austria, Greece, Italy, the Netherlands, Slovenia, Spain, and the UK). Patients aged 18 years or older receiving a first prescription for a drug clinically recommended in the guidelines of the Dutch Pharmacogenetics Working Group (ie, the index drug) as part of routine care were eligible for inclusion. Exclusion criteria included previous genetic testing for a gene relevant to the index drug, a planned duration of treatment of less than 7 consecutive days, and severe renal or liver insufficiency. All patients gave written informed consent before taking part in the study. Participants were genotyped for 50 germline variants in 12 genes, and those with an actionable variant (ie, a drug–gene interaction test result for which the Dutch Pharmacogenetics Working Group [DPWG] recommended a change to standard-of-care drug treatment) were treated according to DPWG recommendations. Patients in the control group received standard treatment. To prepare clinicians for pre-emptive pharmacogenetic testing, local teams were educated during a site-initiation visit and online educational material was made available. The primary outcome was the occurrence of clinically relevant adverse drug reactions within the 12-week follow-up period. Analyses were irrespective of patient adherence to the DPWG guidelines. The primary analysis was done using a gatekeeping analysis, in which outcomes in people with an actionable drug–gene interaction in the study group versus the control group were compared, and only if the difference was statistically significant was an analysis done that included all of the patients in the study. Outcomes were compared between the study and control groups, both for patients with an actionable drug–gene interaction test result (ie, a result for which the DPWG recommended a change to standard-of-care drug treatment) and for all patients who received at least one dose of index drug. The safety analysis included all participants who received at least one dose of a study drug. This study is registered with ClinicalTrials.gov, NCT03093818 and is closed to new participants.

Findings

Between March 7, 2017, and June 30, 2020, 41 696 patients were assessed for eligibility and 6944 (51·4 % female, 48·6% male; 97·7% self-reported European, Mediterranean, or Middle Eastern ethnicity) were enrolled and assigned to receive genotype-guided drug treatment (n=3342) or standard care (n=3602). 99 patients (52 [1·6%] of the study group and 47 [1·3%] of the control group) withdrew consent after group assignment. 652 participants (367 [11·0%] in the study group and 285 [7·9%] in the control group) were lost to follow-up. In patients with an actionable test result for the index drug (n=1558), a clinically relevant adverse drug reaction occurred in 152 (21·0%) of 725 patients in the study group and 231 (27·7%) of 833 patients in the control group (odds ratio [OR] 0·70 [95% CI 0·54–0·91]; p=0·0075), whereas for all patients, the incidence was 628 (21·5%) of 2923 patients in the study group and 934 (28·6%) of 3270 patients in the control group (OR 0·70 [95% CI 0·61–0·79]; p <0·0001).

Interpretation

Genotype-guided treatment using a 12-gene pharmacogenetic panel significantly reduced the incidence of clinically relevant adverse drug reactions and was feasible across diverse European health-care system organisations and settings. Large-scale implementation could help to make drug therapy increasingly safe.

Funding

European Union Horizon 2020.

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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