The regulatory landscape for clinical metagenomics-based diagnostics in Europe: a critical review.

Metagenomic next-generation sequencing (mNGS) enables broad, untargeted pathogen detection and is increasingly used in the diagnosis of central nervous system infections, infections in immunocompromised or post-transplant patients, ICU patients, and sepsis. This growing clinical role makes the regulatory landscape surrounding mNGS an urgent subject for evaluation, particularly given the phased implementation of the European In Vitro Diagnostic Regulation (IVDR). The transition from the In Vitro Diagnostic Directive (IVDD) to the IVDR marks a shift toward a harmonized, risk-based framework for in vitro diagnostics in the European Economic Area (EEA), but several aspects remain unclear for complex laboratory-developed tests (LDTs) such as clinical mNGS - including the practical implementation of the health institution exemption under Article 5(5), the classification of broad mNGS assays within the current risk tiers, and the scope of required analytical and clinical validation. Notably, validation strategies for mNGS may need to focus on the overall analytical method and intended use rather than on individual target pathogens. Further priorities include harmonized quality requirements, broader availability of external quality assessment (EQA), and clearer frameworks for transferring validated protocols between institutions. This review critically evaluates the current European regulatory framework for clinical mNGS-based LDTs and identifies areas requiring further clarification. Continued collaboration between healthcare institutions, regulators, scientific societies, and industry will be essential to keep requirements proportionate while supporting safe, reliable, and clinically useful implementation of mNGS in routine diagnostics.