IVDR Compliance for Large-Panel Next-Generation Sequencing (NGS) Devices: A Strategic Guide

• A more difficult path to IVDR approval
• Deep interconnection between risk management, clinical evidence, and post-market surveillance (PMS/PMPF)
• Ongoing need for updates as new variants, classifications, or therapeutic guidelines emerge

The intended purpose determines the scope of your entire IVDR submission. For large-panel NGS devices, this should include:

• Genes and variant types included (e.g., SNVs, CNVs, fusions)
• Sample types validated (e.g., FFPE tissue, liquid biopsy)
• Clinical uses (diagnosis, therapy selection, etc.)
• Limitations and exclusions

Avoid broad or ambiguous claims. Instead, focus on defining a scope that is clinically relevant, scientifically justified, and realistically supported by evidence.

Scientific validity shows that a genetic variant is associated with a clinical condition. For large-panel Next-Generation Sequencing (NGS) assays, validating each biomarker individually is rarely feasible. Instead:

• Leverage published literature, databases, and clinical guidelines to support the scientific validity of the analytes.
• Consider the relevance of broad panel testing
• Document a clear rationale for inclusion of the genes in the panel.

Remember: scientific validity evolves. Your Post-Market Performance Follow-Up (PMPF) plan must anticipate changes in evidence, such as new therapeutic indications or revised variant classifications.

State-of-the-Art embodies what is currently and generally accepted as good practice in technology and medicine. Clinical evidence needs to be established and evaluated against State-of-the-art. State-of-the-art encompasses two pillars:

• Clinical practice: what is the current clinical practice for a clinical disorder
• Performance specifications: what is expected in terms of analytical and clinical performance specifications. This information can come from regulations, standards or guidelines, or it can come from information on similar devices.

Manufacturers must demonstrate how their Next-Generation Sequencing (NGS) panel meets—or exceeds—these standards. Continuous PMPF monitoring helps track evolving SotA expectations and support sustained compliance.

Analytical performance must be demonstrated across the relevant parameters stated in IVDR Annex I, 9.1 (a). In addition to these, the manufacturer is responsible for identifying other analytical performance characteristics that are applicable.

For Next-Generation Sequencing (NGS) devices, typically following characteristics need to be considered:

• Analytical sensitivity (defined as TP/TP+FN) and specificity (defined as TN/TN+FP)
• Detection capability: incl. Minimal variant allele frequency (VAF) and minimum and maximum DNA input
• Reportable range: region of the genome covered & range of VAF and Copy Number Alterations (CNAs) copies covered
• Performance of molecular barcoding
• ...

Given the size of these panels, a method-based or representative approach can often be justified. Be sure to:

• Justify the analytical approach using the device’s risk assessment
• Document any known weaknesses (e.g., GC-rich regions, STR repeats, challenges related to the sequencing and library prep techology)
• Demonstrate analytical performance per variant type (SNV, indels, CNA, large genomic rearrangements, ...) and per specimen type (FFPE derived DNA, liquid biopsy, RNA, ...)

A representative or method-based validation strategy may be acceptable, especially for large gene panels. Justify your approach using a risk-based rationale and present the results in a clear, well-structured format within the technical documentation.

Clinical performance links the test result to a particular clinical condition or physiological state in accordance with the target population and intended user. Under IVDR, this can be demonstrated through:

• Clinical performance studies
• Scientific peer-reviewed literature
• Published experience gained by routine diagnostic testing

For large-panel genomic profiling:

• Clinical classification (such as ESMO Scale for Clinical Actionability of molecular Targets - ESCAT) is the basis for the strategy to demonstrate clinical performance
• Differentiate multiple Intended Purpose claims: a Companion Diagnostics claim requires a different clinical performance strategy than a Tumor Profiling claim
• Clinical performance studies must comply with IVDR Annex XIII, 2 (and XIV if applicable)
• Provide a rationale for relying on literature for established variants
• Identify gaps and address them through Post-Market Performance Follow-up (PMPF)

Like for analytical performance, present the data and justifications for clinical performance clearly and in a structured way.

IVDR requires proactive surveillance and real-world data collection. For large-panel Next-Generation Sequencing (NGS) devices:

• Plan for regular updates to bioinformatics pipelines and interpretation databases
• Monitor changes in scientific validity and state of the art (SotA)
• Address gaps identified during validation with targeted PMPF studies
• Identify off-label use or unintended clinical interpretations

PMPF is particularly important for complex Next-Generation Sequencing (NGS) panels, where updates to variant classification or treatment guidelines can happen frequently. Ensure having a process to respond to those changes adequately. 

• Clear and precise intended purpose
• Evidence-based scientific validity, maximizing existing clinical information
• Analytical performance strategy driven by thorough risk assessment
• Clinical performance that aligns with the intended purpose claims
• Continuous surveillance and evidence updates via a strong and proactive PMPF program
• A well-presented technical file that reflects real-world use and risk

• Design robust analytical and clinical performance strategies
• Build compliant, audit-ready technical documentation
• Navigate IVDR Article 5(5) for lab-developed tests
• Anticipate and mitigate post-market risks
• Translate bioinformatics complexity into regulatory clarity