Determining the Clinical Utility of Panel-Based Pharmacogenetic Testing and Defining Optimal Models for Implementation

Abstract

Background: Medicines are the most common therapeutic intervention in healthcare, yet their safety and effectiveness show significant intra- and inter-individual variation. This variability is related to a number of factors, but it is increasingly recognised that an individual’s genetics plays a role, a concept known as pharmacogenetics. Pharmacogenetic prescribing guidelines have been developed for many commonly prescribed medicines and, in the National Health Service (NHS) in England, reactive testing has been implemented for a small number of genes to guide prescribing. This has traditionally been performed via single gene testing; however, it is now possible to test for a range of genes at the same time via panel-based testing. Information from these panels could, in theory, be re-used to guide prescribing practice across an individual’s life. However, it has not been established how this could be achieved in the NHS. This PhD considers pharmacogenetics as a complex intervention, aiming to assess the clinical utility of panel-based pharmacogenetic testing and investigate models of service delivery for implementation in the NHS. Methods: This thesis comprises four empirical chapters. First, a cross-sectional study recruited patients admitted to hospital. Participants underwent pharmacogenetic panel-based testing and their genetic results were analysed in the context of medicines they had been exposed to as an inpatient. To assess practice in other health systems, a systematic scoping review was undertaken to identify global pharmacogenetic implementation programmes. This literature was then synthesised using the Consolidated Framework for Implementation Research (CFIR) to characterise the barriers and facilitators to implementation. The findings from this assessment were then used to develop two distinct discrete choice experiments (DCEs) which aimed to quantify public and clinical stakeholder preferences for a pharmacogenetic service for primary care in the NHS. Results: In the cross-sectional study, genetic and prescribing data were available for 482 individuals, 97.9% of whom carried a pharmacogenetic result which could confer an atypical response to medicine. During their admission, 79.5% of participants were exposed to a medicine for which there was pharmacogenetic prescribing guidance and just under 1 in 7 individuals (13.7%) had a clinically actionable gene-drug interaction. Increasing age was positively correlated with the likelihood of having a clinically actionable interaction. The systematic scoping review identified 40 pharmacogenetic programmes which were heterogeneous in their design and scale. The CFIR domains most cited as facilitators to implementation were a positive institutional culture, leadership engagement, engaging stakeholders, and the use of clinical champions. Clinician self-efficacy, lack of stakeholder knowledge, and the cost of the intervention were commonly cited barriers. Both discrete choice experiments demonstrated that predicted uptake of a pharmacogenetic service would vary considerably based on its design. 1993 individuals were included in the public DCE. Respondents were more likely to choose models of service delivery which included non-invasive testing and where their results were shared between healthcare organisations to guide future prescribing. 235 healthcare professionals completed the clinical DCE, and all respondents preferred pharmacogenetic testing over no testing, though preference heterogeneity was identified between general practitioners (GPs) and pharmacists. Both professional groups preferred panel-based over single-gene testing and wanted data returned to the electronic health record. Conclusion: Panel-based pharmacogenetic testing represents a complex healthcare intervention which has the potential to impact prescribing practice at scale across the NHS and for which there is broad acceptability amongst stakeholders. Successful implementation will require a mo

Date of Award	6 Jan 2025
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Katherine Payne (Supervisor), William Newman (Supervisor) & Paul Wilson (Supervisor)