Redefining clinical evidence for IVDs

The IMDRF CE-IVD draft (WG/N91) introduces a refined framework for generating and evaluating clinical evidence for in vitro diagnostic medical devices. It builds upon existing GHTF-era regulatory principles while placing significantly greater emphasis on a lifecycle-based approach to performance evaluation — one that extends from pre-market development through to continuous post-market surveillance.

The guidance recognises that IVD medical devices occupy a unique position in clinical practice: their risks and benefits operate indirectly through impact on patient management and public health, rather than through direct device-patient interaction. A substantial proportion of all clinical decisions rely on information generated by IVD medical devices. This dependency makes the robustness of clinical evidence not merely a regulatory obligation, but a patient safety imperative.

From a Pure Clinical perspective, this reframing is long overdue. The IVD sector has historically operated under a lighter clinical evidence burden than therapeutic devices. N91 explicitly closes that gap, aligning IVD expectations with the standards manufacturers are already navigating under Regulation (EU) 2017/746 (IVDR) and its associated MDCG guidance.

From analytical performance to clinical relevance

A foundational element of the draft is the three-pillar structure of clinical evidence: scientific validity of the analyte, analytical performance, and clinical performance. These are not merely sequential stepsm they form an integrated evidence chain, each informing the others throughout the device lifecycle.

The draft draws a critical distinction that manufacturers must internalise:

  • Analytical performance, the ability of the IVD medical device to detect or measure a particular analyte with accuracy, precision, specificity, and traceability,
  • Clinical performance, the correlation of device outputs with a particular clinical condition, physiological or pathological process, in accordance with the intended purpose,
  • Scientific validity, the established association of an analyte to a clinical condition or physiological state, forming the evidentiary foundation for the device’s intended purpose,

This structure mirrors IVDR Article 56 and Annex XIII obligations, where manufacturers must demonstrate that device outputs are clinically meaningful and aligned with the intended purpose as stated in technical documentation. The document explicitly states that clinical evidence must not be treated as a one-time regulatory checkpoint, but as an evolving, continuously updated dataset — a principle directly translatable to IVDR post-market performance follow-up (PMPF) obligations.

From a Pure Clinical IVD team standpoint, the distinction between ‘documenting’, ‘demonstrating’, and ‘generating’ evidence, as explicitly introduced in N91, is a practical tool that simplifies the proportionality decision for manufacturers. Many organisations conflate these three activities, creating unnecessary study burden. N91 provides the regulatory basis to challenge that assumption with evidence and justification, rather than defaulting to new study generation.

Risk-based approach to performance evaluation

The draft formalises a risk-proportionate approach to evidence generation that reflects the device’s risk classification, intended purpose, novelty, and the degree of variability in the intended use population. This is not a departure from existing regulatory logic, it is its codification at international level.

Key risk-stratification principles in the draft include:

  • higher-risk devices and novel analytes require prospective clinical performance studies and more extensive scientific validity data,
  • lower-risk devices with well-established technology may rely on existing literature, published performance data, and analytical evidence,
  • companion diagnostics (CDx) face the most stringent evidence requirements, including clinical bridging studies and co-development obligations with the corresponding medicinal product,
  • Software as an IVD (SaIVD), particularly those incorporating machine learning or artificial intelligence, face additional requirements for algorithm validation, data lifecycle traceability, and continuous post-market performance monitoring.

This approach aligns with global regulatory convergence efforts and reflects increasing expectations for scientific robustness. For manufacturers, the practical implication is that the evidence strategy must be developed early — at the point of intended purpose definition — not retrofitted after analytical studies are complete.

The SaIVD and CDx sections of N91 deserve particular attention from regulatory affairs teams. For AI-based diagnostics, the draft introduces requirements around data representativeness, version control, audit trails, and post-market monitoring for performance drift — requirements that go significantly beyond traditional IVD validation frameworks and demand cross-functional engagement between regulatory, clinical, and software development teams from the earliest stages of product development.

Integration with the lifecycle approach to performance evaluation

One of the most consequential shifts in N91 is the formal embedding of post-market data within the performance evaluation framework. The draft characterises performance evaluation as a continuous process, updated throughout the entire device lifecycle — not concluded at the point of initial conformity assessment.

The lifecycle evidence architecture described in the draft encompasses:

  • pre-market clinical performance studies and analytical validation as the baseline for initial conformity assessment,
  • post-market performance follow-up (PMPF) studies and systematic literature surveillance to refine and update the evidence base,
  • real-world data and evidence — including adverse event reports, vigilance data, external quality assessment (EQA) results, and investigator-initiated studies — as ongoing inputs to the clinical evidence report.

This lifecycle approach directly mirrors obligations under Regulation (EU) 2017/746 (IVDR), specifically the requirements for post-market performance follow-up plans and periodic safety update reports (PSURs) under Article 82 and Annex XIII, Part B. Manufacturers who have already built PMPF infrastructure compliant with IVDR will find the N91 framework familiar — and may use their existing processes as the operational foundation for demonstrating N91 compliance in markets beyond the EU.

From a Pure Clinical perspective, one of the most actionable aspects of N91 is its explicit recognition of real-world data as a legitimate evidence source — not merely a supplementary signal, but a structured input to performance evaluation. This has direct implications for how PMS plans are designed: data collection must be purposeful, systematic, and linked to specific performance parameters, not limited to complaint monitoring and adverse event reporting.

Strategic impact on global market access

For manufacturers targeting multiple regulatory jurisdictions, the implications of N91 are both significant and strategically positive. The document forms part of the IMDRF’s broader harmonisation effort — providing a reference framework that, where adopted, reduces the need to generate jurisdiction-specific evidence packages.

Key strategic implications include:

  • earlier clinical strategy planning, with evidence architecture defined at the product concept stage rather than the pre-submission stage,
  • increased investment in prospective clinical performance studies for novel or higher-risk devices, where existing literature will not be sufficient,
  • systematic integration of real-world evidence into regulatory submissions, requiring structured PMS data collection from the point of market entry,
  • greater alignment between EU IVDR, FDA, and PMDA submission packages where N91-compliant evidence frameworks are used as the common basis.

Notified Bodies operating under IVDR will inevitably reference N91 as an interpretive framework, even before its formal adoption in any jurisdiction. Manufacturers that align their clinical evidence reports and PMPF plans with N91 principles now will be better positioned for technical file audits, both under IVDR and in markets where IMDRF guidance directly informs regulatory expectations.

From our perspective, N91 should be read not as additional burden but as a clarification tool. It provides the regulatory language and evidence logic needed to justify proportionate evidence strategies — including the use of existing evidence, literature synthesis, and real-world data — rather than defaulting to costly new study generation. The manufacturer who understands N91 deeply will use it to streamline, not expand, their evidence generation obligations.

Toward evidence-centric IVD regulation

The IMDRF CE-IVD draft signals a clear and deliberate shift toward evidence-centric regulatory frameworks for in vitro diagnostics. By emphasising clinical relevance, lifecycle data integration, risk-based proportionality, and the specific demands of emerging technologies including AI and companion diagnostics, N91 sets a new international benchmark for IVD performance evaluation.

For manufacturers, adapting to these expectations will be essential — not only for regulatory compliance, but for maintaining competitive credibility in an increasingly data-driven environment where clinical evidence is scrutinised by regulators, notified bodies, healthcare purchasers, and clinical users alike.

The organisations that invest now in building N91-aligned clinical evidence frameworks will have a structural advantage: more defensible technical documentation, more efficient global submissions, and a stronger foundation for navigating the regulatory landscape as it continues to evolve.

Key references

[1] IMDRF/CEIVD WG/N91 DRAFT: 2026 — Clinical Evidence for IVD Medical Devices – Definitions and Principles of Performance Evaluation (10 February 2026)