Johnson, Danielle 
ORCID: 0000-0001-7820-1687
(2022)
The implementation of pharmacogenetics: evidence and preferences.
PhD thesis, University of Liverpool.
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Abstract
Pharmacogenetics has huge potential to transform the field of medicine and deliver personalised treatments to patients. However, its wider use is limited by many factors, particularly a lack of suitable evidence of efficacy or safety for regulatory approval and clinical use. The evidence required can be difficult to ascertain, presenting three main problems. The first issue is that regulatory guidance for the evidence required is complex and varies greatly between different authorities and contexts. Guidance from the UK Medicines and Healthcare products Regulatory Authority (MHRA) and the US Food and Drug Administration (FDA) was reviewed along with criteria formulated by other industry and academic groups. It was found that there is a clear need for a unified set of standards for evidence gathering in pharmacogenetics. This was strengthened by an analysis of the evidence used by five different randomised controlled trials to justify the inclusion of their pharmacogenetic biomarker. Large variation in the quality and type of this evidence was found. These findings were used to make recommendations for future evidence gathering for trials, regulators, and journals. Additionally, the evidence required for clinical implementation has traditionally been the prospective randomised controlled trial. Gathering information from two novel systematic reviews and meta-analyses of carbamazepine-induced Stevens-Johnson syndrome, it was shown how these sources of observational evidence can produce effect estimates and measures of clinical validity of greater precision than that of a prospective trial. Finally, the level of evidence for a pharmacogenetic test that would be acceptable to the general public is not known. A discrete choice experiment (DCE) was designed to quantify these views. The first step was a systematic review of existing DCEs in this area, to extract useful information from these to inform the work. An extensive programme of qualitative work with healthcare professionals, patients, and the general public then further informed the design of this novel DCE. Participants were randomised to complete one of eight DCEs in different disease areas, with either a ‘high’ evidence scenario or a ‘low’ evidence scenario described. Launched in May 2021, over 2,000 responses were collected and the results were analysed in preference-weighted utility models. Although there was no difference in utility between ‘high’ and ‘low’ evidence tests, several important insights were generated (particularly in regard to data sharing and privacy) that will potentially have large impacts on policy in this area.
| Item Type: | Thesis (PhD) |
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| Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Clinical Directorate |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 18 Nov 2022 16:49 |
| Last Modified: | 16 Jan 2024 17:21 |
| DOI: | 10.17638/03166180 |
| Supervisors: |
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| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3166180 |
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