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

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.

Drug abuse monitoring: which pharmacoepidemiological resources at the European level?

Monitoring the potential for abuse and dependence of psychoactive substances falls within the scope of international conventions on narcotic drugs. At the European level, this monitoring is based on activities controlled by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) for substance abuse in general and by the European Medicines Agency (EMA) for marketed drugs, in the context of pharmacovigilance. If France has set up in the early 1990s an original system to assess potential for abuse of psychoactive substances, with specific tools combining both the evaluation of the use of these substances (illicit substances or diverted drugs), and the consequences of that use in terms of morbidity and mortality, there is no equivalent in other European countries. Indeed, unlike the USA, who, for several decades, organized this type of surveillance, with a multisource approach (sentinel systems, databases, medical and administrative data, databases for seeking care in relation abuse), we have not found in other European countries integrated system for identifying a signal of drug abuse, or to assess the impact of measures for minimizing the risk of abuse. However, some recent examples show a growing concern about drug addiction, based on a pharmacoepidemiological approach using pharmacovigilance databases or medical administrative data. These examples illustrate the interest of these approaches in the field of drug of abuse.

Interest of large electronic health care databases in addictovigilance: Lessons from 15 years of pharmacoepidemiological contribution.

In France, the monitoring of drug abuse and dependence is based on the implementation of national surveys and the collection of spontaneous reports of health professionals. Medico-administrative information completes these data sources through the creation of pharmacoepidemiological tools to exploit them in the field of addictovigilance. This article purposes an overview of this contribution through the presentation of several studies and/or methods developed by the French addictovigilance network to assess the psychoactive drugs diversion and its consequences at the population level. These examples underline the value of these databases and confirm that they could become a systematic routine tool for addictovigilance, particularly in complementary multi-source approaches.