Periodic Reporting for period 4 - U-PGx (Ubiquitous Pharmacogenomics (U-PGx): Making actionable pharmacogenomic data and effective treatment optimization accessible to every European citizen)
Reporting period: 2020-07-01 to 2021-12-31
Pharmacogenomics (PGx) is the study of genetic variability affecting an individual’s response to a drug. Clinical application of PGx knowledge will result in less ‘trial and error’ prescribing and more efficacious, safer and cost-effective drug therapy. The U-PGx consortium investigated 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 is implemented at a large scale in existing European health care environments across the Netherlands, Spain, UK, Italy, Austria, Greece and Slovenia with the main goal to improve the safety and efficacy of pharmacotherapy for every European patient by enabling clinical PGx. Based on the findings of the U-PGx project we will formulate European strategies for improving clinical implementation of PGx.
For this approach, we combine existing PGx guidelines and novel health IT solutions. The new model of personalised medicine through pre-emptive PGx testing is implemented at a large scale in existing European health care environments across the Netherlands, Spain, UK, Italy, Austria, Greece and Slovenia with the main goal to improve the safety and efficacy of pharmacotherapy for every European patient by enabling clinical PGx. Based on the findings of the U-PGx project we will formulate European strategies for improving clinical implementation of PGx.
In the first year of the U-PGx project, all relevant enabling tools for pre-emptive 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. PGx quality management schemes were developed in cooperation with the European Molecular Genetics Quality Network (EMQN). PGx guidelines were continuously updated, translated and validated. Specific education was developed and provided to all stakeholder groups healthcare professionals, medical and pharmacy students, and persons that do not have any scientific or medical training.
In the next phase of the U-PGx project, the U-PGx clinical study has been set up and executed in multiple clinical sites in seven European countries (the Netherlands, United Kingdom, Austria, Italy, Spain, Greece, and Slovenia). In this PREPARE (Preemptive Pharmacogenomic Testing for Preventing Adverse Drug Reactions) study, a total of 6,944 patients have been included and clinical and follow-up data of all patients as well as patient-reported outcomes have been collected. After independent project monitoring, the final dataset was prepared and severity and causality analysis have been executed. In addition, the key features that are required for the cost-effectiveness analysis of the PGx-guided interventions in all seven clinical sites have been established and a standard cost-effectiveness model for the economic analysis has been generated. The final clinical and economic outcomes of the PREPARE study are expected in 2022.
For the U-PGx substudy ’A Next Step into the Future’, 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 measure blood plasma concentrations of selected drugs and corresponding metabolites in subjects with extreme phenotype. The comparison of blood concentrations with PBPK model predictions is ongoing. Drug-drug interaction (DDI) data have been provided from the PREPARE study and is currently being systematically analysed.
Within this same substudy, a pipeline to retrieve PGx information from whole exome sequencing data has been established. 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. GWAS analyses using gDNA of extreme phenotype patients showed preliminary linkage of novel mutations in 2-13 different genes to the drug ADRs. However, due to the low number of patients available for analyses, no statistical conclusions could be drawn.
The main ethical, legal and social issues (ELSI) that relate to the clinical PGx implementation have been studied and guidelines have been established and published. ELSI training has been provided to both U-PGx and non-U-PGx members. 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. The final U-PGx Personalised Medicine Symposium, which will also present the final outcomes of the PREPARE study, will be organized in 2022.
In the next phase of the U-PGx project, the U-PGx clinical study has been set up and executed in multiple clinical sites in seven European countries (the Netherlands, United Kingdom, Austria, Italy, Spain, Greece, and Slovenia). In this PREPARE (Preemptive Pharmacogenomic Testing for Preventing Adverse Drug Reactions) study, a total of 6,944 patients have been included and clinical and follow-up data of all patients as well as patient-reported outcomes have been collected. After independent project monitoring, the final dataset was prepared and severity and causality analysis have been executed. In addition, the key features that are required for the cost-effectiveness analysis of the PGx-guided interventions in all seven clinical sites have been established and a standard cost-effectiveness model for the economic analysis has been generated. The final clinical and economic outcomes of the PREPARE study are expected in 2022.
For the U-PGx substudy ’A Next Step into the Future’, 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 measure blood plasma concentrations of selected drugs and corresponding metabolites in subjects with extreme phenotype. The comparison of blood concentrations with PBPK model predictions is ongoing. Drug-drug interaction (DDI) data have been provided from the PREPARE study and is currently being systematically analysed.
Within this same substudy, a pipeline to retrieve PGx information from whole exome sequencing data has been established. 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. GWAS analyses using gDNA of extreme phenotype patients showed preliminary linkage of novel mutations in 2-13 different genes to the drug ADRs. However, due to the low number of patients available for analyses, no statistical conclusions could be drawn.
The main ethical, legal and social issues (ELSI) that relate to the clinical PGx implementation have been studied and guidelines have been established and published. ELSI training has been provided to both U-PGx and non-U-PGx members. 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. The final U-PGx Personalised Medicine Symposium, which will also present the final outcomes of the PREPARE study, will be organized in 2022.
The U-PGx project has shown major impact on the development of both existing and newly developed tools in PGx implementation in different health care settings in Europe. Through several educational and information activities, the U-PGx project has had its impact on patients and other 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 in Europe.
The U-PGx consortium, bringing together well acknowledged European experts from a wide range of disciplines in the field of PGx, has become a strong player in Personalised Medicine networks worldwide. Many different organizations and institutions in Europe, USA and Asia have expressed their interest in the U-PGx project and want to collaborate with the U-PGx consortium. The U-PGx study group continues to facilitate PGx implementation in other countries by providing expertise, knowledge and tools as developed in the U-PGx project. Secondly, the U-PGx consortium remains to stimulate and guide scientific PGx research at a top level in Europe. To this end several U-PGx consortium members are collaborating in follow-up projects such as INSPIRATION and SAFEPOLYMED.
Overall, the U-PGx project has been very successful in achieving its aims and objectives. Ultimately, the U-PGx project foresees to improve the safety and efficacy of pharmacotherapy by providing both quantitative and qualitative evidence for implementation of pre-emptive PGx testing. These data will be instrumental for policy makers and decision makers improving health and care systems in Europe.
The U-PGx consortium, bringing together well acknowledged European experts from a wide range of disciplines in the field of PGx, has become a strong player in Personalised Medicine networks worldwide. Many different organizations and institutions in Europe, USA and Asia have expressed their interest in the U-PGx project and want to collaborate with the U-PGx consortium. The U-PGx study group continues to facilitate PGx implementation in other countries by providing expertise, knowledge and tools as developed in the U-PGx project. Secondly, the U-PGx consortium remains to stimulate and guide scientific PGx research at a top level in Europe. To this end several U-PGx consortium members are collaborating in follow-up projects such as INSPIRATION and SAFEPOLYMED.
Overall, the U-PGx project has been very successful in achieving its aims and objectives. Ultimately, the U-PGx project foresees to improve the safety and efficacy of pharmacotherapy by providing both quantitative and qualitative evidence for implementation of pre-emptive PGx testing. These data will be instrumental for policy makers and decision makers improving health and care systems in Europe.