Background: [protocol] 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.

Method: We conducted an open-label, multicentre, controlled, cluster-randomized, crossover implementation study of a 12-gene pharmacogenetic panel in 18 hospitals, 9 community health centres, and 28 community pharmacies in 7 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.

Results: Between March 7, 2017, and June 30, 2020, 41,696 patients were assessed for eligibility and 6,944 (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 = 3,342) or standard care (n = 3,602). 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 = 1,558), 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 = 0.0,075), whereas for all patients, the incidence was 628 (21.5%) of 2,923 patients in the study group and 934 (28.6%) of 3,270 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 statistically-significantly reduced the incidence of clinically relevant adverse drug reactions and was feasible across diverse European health-care system organizations and settings. Large-scale implementation could help to make drug therapy increasingly safe.

Research in context: Evidence before this study: The benefit of pharmacogenetic testing before starting drug treatment has been well documented for several single gene-drug pairs. However, the clinical utility of large-scale implementation of a pre-emptive genotyping strategy with a pharmacogenetic panel remains unclear. Several studies investigating the implementation of pharmacogenetics are available, many of which are US-based. These studies focused on implementing either single drug-gene pairs one at a time and were done in highly specialised care settings. On August 8, 2022, we searched PubMed for trials published in English from database inception and before July 1, 2022 that investigated the implementation of pre-emptive pharmacogenetic panel testing using the search terms “pharmacogenetics”, “clinical utility”, “implementation”, “prospective”, and “panel”. There were no prospective studies that assessed the clinical utility of a pre-emptive genotyping strategy with a pharmacogenetic panel across multiple European countries and health-care settings.

Added value of this study: To our knowledge, our study is the first to investigate the benefits of a pharmacogenetic panel strategy combined with the Dutch Pharmacogenetics Working Group guidelines across a diversity of European health-system organizations and settings. Our results show that pharmacogenetics-guided prescribing results in a 30% reduction of clinically relevant adverse drug reactions. Furthermore, our results underpin the benefits of implementing a standardized, validated, and harmonized pharmacogenetic test system that supports pharmacogenetics-guided decision making at the point of care and show the value of an educational programme to ascertain a similar knowledge base on personalized medicine and pharmacogenetic testing at the beginning of a study.

Implications of all the available evidence: Together with the evidence from randomized clinical trials for various of single drug-gene combinations, our results support a personalized-medicine approach with pharmacogenetics-guided drug prescribing to reduce the incidence of clinically relevant adverse drug reactions.

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