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. 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 , and is closed to new participants. 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). 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. European Union Horizon 2020.

中文翻译：

---

预防药物不良反应的 12 基因药物遗传学面板：开放标签、多中心、对照、整群随机交叉实施研究

对于几种单基因药物组合，在开始药物治疗之前进行药物遗传学测试的好处已得到充分证明。然而，使用药物遗传学小组的先发制人基因分型策略的临床效用尚未得到严格评估。我们在 7 个欧洲国家（奥地利、希腊、意大利、意大利、奥地利、希腊、意大利）的 18 家医院、9 家社区卫生中心和 28 家社区药房对 12 基因药物遗传学小组进行了开放标签、多中心、对照、整群随机、交叉实施研究。荷兰、斯洛文尼亚、西班牙和英国）。作为常规护理一部分的年满 18 岁或以上的患者，首次接受荷兰药物遗传学工作组指南中临床推荐的药物（即索引药物）处方的患者有资格纳入。排除标准包括先前对与指示药物相关的基因进行过基因检测、计划治疗持续时间少于连续 7 天以及严重肾或肝功能不全。所有患者在参加研究前均签署了书面知情同意书。对参与者的 12 个基因中的 50 个种系变异进行了基因分型，并对那些具有可操作变异的参与者（即荷兰药物遗传学工作组 [DPWG] 建议改变标准护理药物治疗的药物-基因相互作用测试结果）进行了基因分型。根据 DPWG 的建议进行处理。对照组患者接受标准治疗。为了让临床医生做好预防性药物遗传学检测的准备，当地团队在现场启动访问期间接受了教育，并提供了在线教育材料。主要结局是 12 周随访期内临床相关药物不良反应的发生情况。分析与患者是否遵守 DPWG 指南无关。主要分析是使用把关分析进行的，其中对研究组与对照组中具有可操作药物基因相互作用的人的结果进行比较，并且只有当差异具有统计学显着性时，才进行包括所有研究中的患者。对研究组和对照组之间的结果进行了比较，包括具有可操作的药物-基因相互作用测试结果（即 DPWG 建议改变标准护理药物治疗的结果）的患者以及接受治疗的所有患者。至少一剂指标药物。安全性分析包括所有接受至少一剂研究药物的参与者。这项研究已在 注册，并且不对新参与者开放。2017年3月7日至2020年6月30日期间，对41 696名患者进行了资格评估，其中6944名患者（51·4%女性，48·6%男性；97·7%自我报告的欧洲、地中海或中东种族）入组并分配接受基因型指导药物治疗 (n=3342) 或标准护理 (n=3602)。99 名患者（研究组 52 名 [1·6%] 和对照组 47 名 [1·3%]）在分组后撤回同意。652 名参与者（研究组 367 名 [11·0%]，对照组 285 名 [7·9%]）失访。在具有可操作指标药物检测结果的患者 (n=1558) 中，研究组 725 名患者中有 152 名 (21·0%) 发生了临床相关药物不良反应，833 名患者中有 231 名 (27·7%) 发生了临床相关药物不良反应。对照组（比值比 [OR] 0·70 [95% CI 0·54–0·91]；p=0·0075），而对于所有患者，发生率为 2923 例中的 628 例 (21·5%)研究组患者和对照组 3270 名患者中的 934 名患者 (28·6%)（OR 0·70 [95% CI 0·61–0·79]；p <0·0001）。使用 12 基因药物遗传学面板进行基因型指导的治疗可显着降低临床相关药物不良反应的发生率，并且在不同的欧洲医疗保健系统组织和环境中都是可行的。大规模实施有助于提高药物治疗的安全性。欧盟地平线 2020。