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.

Generating evidence for precision medicine: considerations made by the Ubiquitous Pharmacogenomics Consortium when designing and operationalizing the PREPARE study.

OBJECTIVES: Pharmacogenetic panel-based testing represents a new model for precision medicine. A sufficiently powered prospective study assessing the (cost-)effectiveness of a panel-based pharmacogenomics approach to guide pharmacotherapy is lacking. Therefore, the Ubiquitous Pharmacogenomics Consortium initiated the PREemptive Pharmacogenomic testing for prevention of Adverse drug Reactions (PREPARE) study. Here, we provide an overview of considerations made to mitigate multiple methodological challenges that emerged during the design. METHODS: An evaluation of considerations made when designing the PREPARE study across six domains: study aims and design, primary endpoint definition and collection of adverse drug events, inclusion and exclusion criteria, target population, pharmacogenomics intervention strategy, and statistical analyses. RESULTS: Challenges and respective solutions included: (1) defining and operationalizing a composite primary endpoint enabling measurement of the anticipated effect, by including only severe, causal, and drug genotype-associated adverse drug reactions; (2) avoiding overrepresentation of frequently prescribed drugs within the patient sample while maintaining external validity, by capping drugs of enrolment; (3) designing the pharmacogenomics intervention strategy to be applicable across ethnicities and healthcare settings; and (4) designing a statistical analysis plan to avoid dilution of effect by initially excluding patients without a gene-drug interaction in a gatekeeping analysis. CONCLUSION: Our design considerations will enable quantification of the collective clinical utility of a panel of pharmacogenomics-markers within one trial as a proof-of-concept for pharmacogenomics-guided pharmacotherapy across multiple actionable gene-drug interactions. These considerations may prove useful to other investigators aiming to generate evidence for precision medicine.

Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction of DPYD and fluoropyrimidines.

Despite advances in the field of pharmacogenetics (PGx), clinical acceptance has remained limited. The Dutch Pharmacogenetics Working Group (DPWG) aims to facilitate PGx implementation by developing evidence-based pharmacogenetics guidelines to optimize pharmacotherapy. This guideline describes the starting dose optimization of three anti-cancer drugs (fluoropyrimidines: 5-fluorouracil, capecitabine and tegafur) to decrease the risk of severe, potentially fatal, toxicity (such as diarrhoea, hand-foot syndrome, mucositis or myelosuppression). Dihydropyrimidine dehydrogenase (DPD, encoded by the DPYD gene) enzyme deficiency increases risk of fluoropyrimidine-induced toxicity. The DPYD-gene activity score, determined by four DPYD variants, predicts DPD activity and can be used to optimize an individual's starting dose. The gene activity score ranges from 0 (no DPD activity) to 2 (normal DPD activity). In case it is not possible to calculate the gene activity score based on DPYD genotype, we recommend to determine the DPD activity and adjust the initial dose based on available data. For patients initiating 5-fluorouracil or capecitabine: subjects with a gene activity score of 0 are recommended to avoid systemic and cutaneous 5-fluorouracil or capecitabine; subjects with a gene activity score of 1 or 1.5 are recommended to initiate therapy with 50% the standard dose of 5-fluorouracil or capecitabine. For subjects initiating tegafur: subjects with a gene activity score of 0, 1 or 1.5 are recommended to avoid tegafur. Subjects with a gene activity score of 2 (reference) should receive a standard dose. Based on the DPWG clinical implication score, DPYD genotyping is considered "essential", therefore directing DPYD testing prior to initiating fluoropyrimidines.

Development of the PGx-Passport: A Panel of Actionable Germline Genetic Variants for Pre-Emptive Pharmacogenetic Testing.

Pre-emptive pharmacogenetics (PGx) testing of a panel of germline genetic variants represents a new model for personalized medicine. Clinical impact of PGx testing is maximized when all variant alleles for which actionable clinical guidelines are available are included in the test panel. However, no such standardized panel has been presented to date, impeding adoption, exchange, and continuity of PGx testing. We, therefore, developed such a panel, hereafter called the PGx-Passport, based on the actionable Dutch Pharmacogenetics Working Group (DPWG) guidelines. Germline-variant alleles were systematically selected using predefined criteria regarding allele population frequencies, effect on protein functionality, and association with drug response. A PGx-Passport of 58 germline variant alleles, located within 14 genes (CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A5, DPYD, F5, HLA-A, HLA-B, NUDT15, SLCO1B1, TPMT, UGT1A1, and VKORC1) was composed. This PGx-Passport can be used in combination with the DPWG guidelines to optimize drug prescribing for 49 commonly prescribed drugs.