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Ubiquitous Pharmacogenomics (U-PGx): Making actionable pharmacogenomic data and effective treatment optimization accessible to every European citizen

Periodic Reporting for period 3 - U-PGx (Ubiquitous Pharmacogenomics (U-PGx): Making actionable pharmacogenomic data and effective treatment optimization accessible to every European citizen)

Reporting period: 2019-01-01 to 2020-06-30

Pharmacogenomics (PGx) is the study of genetic variability affecting an individual’s response to a drug. Clinical application of pharmacogenomics knowledge will result in less ‘trial and error’ prescribing and more efficacious, safer and cost-effective drug therapy. However, despite the major advances in PGx and several commercially available PGx tests, its implication in routine patient care remains very limited. The U-PGx consortium addresses major challenges and obstacles for implementation of PGx testing in patient care. Specifically, U-PGx will investigate if the emerging approach of pre-emptive genotyping of an entire panel of important PGx markers results in a better outcome for patients and is cost-effective. With the pre-emptive PGx testing approach data on multiple important pharmacogenes are collected prospectively and embedded into the patients’ electronic record. Typically, it alerts prescribers and pharmacists through electronic clinical decision support systems when a drug is ordered or dispensed for a patient with an at-risk genotype.
For this approach, we combine existing PGx guidelines and novel health IT solutions. The new model of personalised medicine through pre-emptive PGx testing will be implemented at a large scale in several existing European health care environments across the Netherlands, Spain, UK, Italy, Austria, Greece and Slovenia which accounts for the diversity in health system organisations and setting. Our main goal is to improve the safety and efficacy of pharmacotherapy for every European patient by enabling clinical pharmacogenomics. Based on the findings of the U-PGx project we will formulate European strategies for improving clinical implementation of pharmacogenomics.
In the first year of the U-PGx project, all relevant enabling tools for pre-emptive pharmacogenomics (PGx) testing have been designed, developed and implemented at the seven clinical sites of the U-PGx study. Thereafter, the U-PGx consortium has maintained, evaluated and improved the infrastructural basis for carrying out PGx testing and guideline-based clinical decision support. These tools include translated, continuously updated, validated and endorsed PGx guidelines, high-throughput genotyping platforms, validated PGx assays, optimized workflows, and improved clinical decisions support systems. In addition, educational material about PGx has been generated and used to train medical professionals involved in the U-PGx study as well as other professionals and students in all seven countries.
In the next phase of the U-PGx project the U-PGx clinical study, i.e. PREPARE (Preemptive Pharmacogenomic Testing for Preventing Adverse Drug Reactions) has started in the Netherlands, United Kingdom, Austria, Italy, Spain, Greece, and Slovenia. Ethical approval to conduct the study was obtained for all recruiting centres in the 7 countries and a huge amount of effort was put into the successful recruitment of patients in each site. Although the COVID-19 pandemic disabled patient inclusion in the end-stage of recruitment, the consortium managed to include on average 200 patients per month. In total, 6,951 patients have been included in the PREPARE study which is 86% of the original target. Clinical and follow-up data of all patients as well as patient-reported outcomes have been collected. In addition, the key features that are required for the cost-effectiveness analysis of the PGx-guided interventions in all 7 clinical sites have been established and a standard cost-effectiveness model for the economic analysis has been generated.
For the U-PGx substudy ’A Next Step into the Future’, the first pharmacometric and systems pharmacology models to predict the consequences of drug-drug and drug-gene interactions have been developed and reported. An analytical mass spectrometry LC-MS/MS panel has been established to comprehensively measure blood plasma concentrations of PGx drugs and corresponding metabolites in patients with an extreme phenotype. Within this same substudy, a pipeline to retrieve pharmacogenetic information from whole exome sequencing (WES) data has been established. Extensive analyses of the ExAC WES data has revealed the relative frequency of rare variants in 208 different pharmacogenes and encompassed a translation of the effect of rare variants on the inter-individual variability of 205 different drugs. This provides information regarding the contributions of rare variants to the interindividual differences in pharmacokinetics of these drugs in 7 different populations. Novel algorithms have been developed and applied for computational prediction methods that allow evaluation of the functional consequences of amino acid sequence alterations in drug metabolizing enzymes and transporters.
The ethical and legal basis for the future guidelines of the U-PGx project have been established and published on the U-PGx website. Furthermore, the challenges raised by the update of the European legislation on data protection and in vitro diagnostic medical devices (IVDs) were addressed and the necessary measures were implemented. Furthermore, various U-PGx dissemination activities have been organized according to the needs of the various stakeholders such as healthcare professionals, regulators, policy makers, insurance bodies, patients and the general public. Also, a dedicated and continuously updated public-domain web-based U-PGx information portal was constructed and being revamped to include all relevant information about the U-PGx project and the PREPARE clinical study.
The U-PGx consortium foresees the following 2 expected impacts:
-The U-PGx project will provide both quantitative and qualitative evidence for this new model of personalised medicine
-These data will be instrumental for policy makers and decision makers improving health and care systems in Europe

The U-PGx project has shown major impact on the development of both existing and newly developed tools in pharmacogenomics implementation. Through several educational and information activities, the U-PGx project has had its impact on patients and stakeholders in order to understand the results and implications of PGx, which is necessary to enable patients to be more proactive with their health care. In addition, through education and experience, physicians’ and pharmacists’ as well as patients’ knowledge on individualized therapy has significantly been improved.

Many different organizations and institutions (in EU, Asia and USA) has expressed their interest to join the U-PGx consortium. U-PGx infrastructure and expertise will be offered to them to be able to start pre-emptive PGx testing and implementation of the DPWG guidelines, which is in fact the ultimate aim of the U-PGx project.

The next phase of the U-PGx study group is to form a continuous European U-PGx consortium which has two aims. First, to facilitate PGx implementation in all EU countries by providing expertise, knowledge and tools as developed in the U-PGx project. The second aim is to stimulate and guide PGx scientific research at a top level in the EU. The U-PGx consortium is also a strong player in the initiative to build a Global PGx network, bringing together well acknowledged experts from a wide range of disciplines from all over the world at the forefront of PGx.