GENOMICS
infectious disease, NGS demonstrates its promise while also highlighting important regulatory considerations in real-world applications:
Oncology
Reproducibility across laboratories and sequencing platforms remains a pressing concern, driven by the inherent complexity of NGS workflows that involve multiple interdependent steps.
dynamic nature of genomic knowledge bases, where variant classifications and clinical significance evolve over time. Together, these factors stretch the boundaries of traditional regulatory models and require a more nuanced approach to conformity assessment. As the world’s first National Standards
Body, BSI is deeply knowledgeable with NGS sequencing, genomic knowledge bases and the complex interplay between evolving scientific innovation, clinical safety requirements and IVD regulatory frameworks. Our deep understanding of NGS technologies and genomic data enables us to conduct conformity assessments that fully account for analytical, bioinformatics, and regulatory complexities, helping manufacturers navigate IVDR expectations with clarity.
Regulatory reality Establishing clinical evidence in accordance with Annex XIII of the IVDR can be particularly complex for NGS devices, especially because evidence generation for rare variants is inherently challenging when patient numbers are limited. This complexity is heightened when the intended purpose spans multiple tumour types, where biological heterogeneity and tissue- specific differences in variant prevalence make both analytical validation and
clinical performance justification more demanding. Furthermore, reproducibility
across laboratories and sequencing platforms remains a pressing concern, driven by the inherent complexity of NGS workflows that involve multiple interdependent steps. Variability in pre-analytical processing, library preparation, enrichment methods, sequencing chemistry, and downstream bioinformatics algorithms can all influence variant detection performance, making reproducibility a key challenge to demonstrate under the IVDR. Post-market monitoring must
also be factored into the equation, as variant classifications can change over time, forcing laboratories and manufacturers to adapt their reporting while maintaining compliance. In certain cases, such reclassification can also have regulatory implications for the device itself – for example, when a variant becomes determinative for eligibility to a targeted therapy in specific tissue types, potentially bringing the device within the scope of a companion diagnostic and thereby triggering a different Annex VIII classification and conformity assessment route under the IVDR.
Real-world applications of NGS Across oncology, rare disease, and
Unlike traditional IVDs, NGS assays generate highly multiplexed genomic outputs and rely on continuously evolving workflows
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Next-generation sequencing has become a cornerstone of modern oncology, generating genomic information that can support or determine diagnosis, prognosis, therapy selection and management, disease monitoring, risk assessment, and cancer screening. Diagnostic applications may include identification of driver fusions or defining tumour type through genomic signatures; prognostic information may be derived from mutations associated with disease aggressiveness; therapy selection is guided by actionable biomarkers linked to targeted therapies or immuno-oncology agents; disease monitoring can be enabled through serial sequencing for molecular residual disease; hereditary cancer risk can be assessed through the detection of germline variants such as BRCA1/2; and early cancer screening applications may leverage circulating-tumour DNA–based NGS assays.
Under the IVDR, Annex XIII provides the
framework: manufacturers are required to demonstrate scientific validity (Section 1.2.1), analytical performance (Section 1.2.2), and clinical performance (Section 1.2.3) in alignment with the device’s intended purpose. For assays addressing a broad range of analytes and clinical conditions, a well-reasoned evidence strategy – explicitly scoping claims and justifying data sources – is necessary.
Genetic diseases
For genetic diseases, NGS offers unparalleled potential to uncover elusive causes – ranging from whole-exome and whole-genome sequencing for rare monogenic disorders to high-volume reproductive genetics applications such as non-invasive prenatal testing (NIPT). The core challenge is evidence: rare and low-prevalence conditions limit the size of clinical datasets, while screening contexts like NIPT require performance estimates that reflect both prevalence subgroup characteristics spanning subgroups such as gestational age, fetal fraction and pregnancy type, spanning singleton, twin, and other multifetal pregnancies.
Infectious disease sequencing
Next-generation sequencing has proven indispensable in infectious disease management, from tracing COVID-19 outbreaks to monitoring antimicrobial resistance. The technology enables rapid identification of pathogens and their variants, supporting public health
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