182 Chapter 8 with a migration background 100-103. Non-attendees of cervical cancer screening are at increased risk of developing cervical cancer; hence it is important to reach these women 101. Urine-based tests could be a successful addition to current cervicovaginal self-sampling and clinician-collection to reach low-/non-participating groups of women because of the ease of urine collection lowering barriers to screening. In a study conducted by van den Helder et al., comparison was made between the detection of hrHPV DNA detection in urine samples, clinician-collected cervical samples and self-collected samples 104. The study revealed a high overall agreement of 89% for hrHPV DNA between urine samples and both clinician-collected cervical samples (kappa κ 0.52; 95% CI 0.23-0.74) and selfcollected samples (κ 0.54; 95% CI 0.30-0.74). Preliminary assessments of methylation analysis in urine for the detection of CIN3 and cervical cancer have shown promising results 104-109. These developments in utilising methylation markers on easy to collect samples represent important advancements in achieving equitable access to cervical cancer screening. 8.2.4 CONSIDERATIONS FOR EFFECTIVE IMPLEMENTATION OF DNA METHYLATION MARKERS IN SCREENING To enable efficient translation to real-life screening settings, the methylation markers currently under evaluation in research setting need to be developed into regulatoryapproved In Vitro Diagnostic (IVD) tests. In Europe, regulation (EU) 2017/746 on in vitro diagnostic medical devices (IVDR) is the regulatory framework for in vitro diagnostic medical devices. It replaces the in Vitro Diagnostics Medical Device Directive 98/790/ EC (IVDD) and aims to safeguard that all devices available for use on the EU market are safe and perform as intended providing clinical benefit to patients. To ensure that new innovations reach end users, clinical research should consider the needs and regulatory requirements of IVDs at an early stage, as advised by the European Commission 110. Although many methylation markers for cervical cancer have been discovered to date, only a subset of them are currently available as IVD assay Conformité Européenne (CE)- marked according to IVDD. These include FAM19A4 and miR124-2 (QIAsure Methylation Test®, Qiagen, Hilden, Germany / PreCursor-M+, Fujirebio, Gent, Belgium) 42, 84; POU4F3 (CONFIDENCE Marker™, NEUMANN Diagnostics Ltd., Budapest, Hungary); PAX-1 (Cervi-M®, iStat Biomedical Co. Ltd., New Taipei City, Taiwan) 111; ASTN1, DLX1, ITG4, RXFP3, SOX17 and ZNF671 (GynTect®, Oncgnostics, Jena, Germany) 36, 112. However, none of these methylation assays have yet been certified according to IVDR. Furthermore, the introduction of new technologies in the healthcare systems requires
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