The International Medical Device Regulators Forum (IMDRF) has released a significant new draft guidance, IMDRF/CEIVD WG/N91: Clinical Evidence for IVD Medical Devices, Definitions and Principles of Performance Evaluation, open for public consultation from 4 March to 5 May 2026. For IVD manufacturers, regulatory affairs teams, and companion diagnostic developers, this is not a minor update. It is a comprehensive reset of the global reference framework for how clinical evidence is defined, generated, documented, and defended.
This article breaks down what N91 actually changes, what it means for different types of manufacturers, and based on Carlos Galamba’s experience supporting IVDR submissions and CDx programs at MDx CRO, what practical steps teams should be taking right now.
Why this matters now?
The IMDRF consultation opened on 4 March 2026 and closes on 5 May 2026. Manufacturers with products in development, legacy portfolios under review, CDx programs in progress, or AI-based IVDs in any stage should read this draft carefully, and consider submitting comments before the deadline.
IMDRF N91 is A Framework Reset, Not Just a Revision
IMDRF N91 is a draft guidance document developed by the IMDRF Clinical Evidence for IVD Devices Working Group. Its full title is Clinical Evidence for IVD Medical Devices, Definitions and Principles of Performance Evaluation, and it represents the most significant update to the global IVD clinical evidence framework since the original GHTF documents were published.
The document runs to 31 pages and introduces 17 defined terms, consolidating vocabulary that has historically been inconsistent across jurisdictions. More importantly, it establishes a lifecycle-based model for clinical evidence that goes beyond premarket evidence generation and explicitly links performance evaluation to intended purpose, state of the art, and post-market updates.
What it supersedes
IMDRF N91 replaces both:
- GHTF/SG5/N6:2012 Clinical Evidence for IVD Medical Devices: Scientific Validity Determination and Performance Studies for IVD Medical Devices
- GHTF/SG5/N7:2012 Clinical Evidence for IVD Medical Devices: Key Definitions and Concepts
These two documents have been the global reference point for IVD clinical evidence since 2012. Replacing them with a single updated framework is a significant consolidation.
IMDRF’s role in the regulatory landscape
IMDRF is not a legislative body. Its guidance documents are not legally binding. However, they carry significant weight because they are developed by the regulatory agencies of major markets, including the European Commission, the FDA, Health Canada, the TGA (Australia), PMDA (Japan), and others. MDCG documents (which govern EU IVDR interpretation) explicitly reference IMDRF concepts, and regulatory reviewers at Notified Bodies and competent authorities routinely use IMDRF frameworks as reference benchmarks.
In practice, this means that once an IMDRF guidance is finalized, manufacturers that are not aligned with it will increasingly face questions during technical reviews, audits, and submissions, even if the guidance is not formally cited as a legal requirement.
“In my experience, serious regulatory teams start aligning almost immediately, even before formal citation becomes routine. Active referencing in reviewer templates, training, and audit language often takes somewhere between 6 and 18 months, depending on jurisdiction and organization. My advice is not to wait for formal enforcement language, if the direction is clear, start aligning your evidence strategy now”.
Carlos Galamba, CEO MDx
The Three Pillars of Clinical Evidence Under IMDRF N91
N91 formalizes and aligns with the three-pillar structure already embedded in EU IVDR: scientific validity, analytical performance, and clinical performance. Together, these constitute the clinical evidence that manufacturers must generate, document, and maintain across the device lifecycle.
Understanding each pillar, and where manufacturers routinely fall short, is essential for teams planning their evidence strategy.
Scientific Validity: Establishing the Biomarker Association
Scientific validity addresses whether the analyte being measured is genuinely associated with the clinical condition or physiological state the device is intended to detect. For many established biomarkers, this is largely a literature-based exercise. For novel biomarkers, it is a substantial research task that must begin much earlier than most teams expect.
As Carlos Galamba notes: “In the context of CDx, this work should start as early as biomarker selection and intended-use definition. Under IVDR, the performance evaluation plan is supposed to map the development phases and the sequence for establishing scientific validity, analytical performance, and clinical performance, so this work really starts at the translational stage, not at the submission stage.”
N91 makes clear that scientific validity cannot be assumed. It must be documented, and for novel analytes without established clinical consensus, the absence of scientific validity will block the entire evidence pathway.
Analytical Performance: what IVD manufacturers Most Often Underestimate
Analytical performance covers the device’s ability to accurately and reliably detect or measure the analyte, including precision, reproducibility, cut-off justification, specimen stability, pre-analytical factors, interference, and comparability.
According to Carlos Galamba, this is the pillar that IVD manufacturers most frequently underprepare: “When dealing with clinical trial assays or CDx, teams are usually very focused on the biomarker story and the drug program, so they assume the assay can be optimized later. In reality, regulators often scrutinize analytical robustness first. IVDR itself already requires manufacturers to build the evidence case across all three pillars, not just clinical performance.”
This is a pattern MDx CRO encounters regularly, particularly in CDx programs where the clinical hypothesis is well-developed but the analytical package is treated as an afterthought. N91 reinforces that regulators, including Notified Bodies and the FDA, will assess analytical performance in depth, not simply accept it as a technical formality.
Clinical Performance: What Documentation Is Required vs. What Evidence Must Be Generated
Clinical performance refers to the device’s ability to yield results that correlate with a clinical condition in the intended patient population. N91 clarifies an important distinction that has significant operational implications: manufacturers must always document clinical performance, but they do not always need to generate new evidence through a prospective study.
Whether new evidence is required depends on the device’s risk class, novelty of the analyte, intended use population, and available published data. This mirrors the IVDR framework, where existing literature, registry data, and published experiences from routine diagnostic use can contribute to the clinical performance evidence base, if they are sufficient and methodologically sound.
For more detail on how clinical performance studies are designed and conducted under IVDR, see our guide: Running Clinical Studies Under IVDR: What You Need to Know.
Software as an IVD (SaIVD) and AI/ML: What IMDRF N91 Changes
One of the most substantive additions in N91 is its dedicated section on Software as an IVD (SaIVD), including IVDs that incorporate AI and machine learning. This reflects a genuine regulatory gap: the 2012 GHTF documents predated the widespread deployment of AI-based diagnostics, and manufacturers have been operating without a clear global framework for what clinical evidence looks like for these products.
N91 requires manufacturers of AI-based SaIVDs to address: data lifecycle traceability, performance drift monitoring, transparency of AI outputs, and documentation of the transition point at which AI recommendations are reviewed by qualified healthcare professionals. Critically, N91 affirms that final clinical decisions must always rest with qualified healthcare professionals, not with the AI system itself.
The Most Common Mistake in AI-Based IVD Evidence Packages
Carlos Galamba identifies a pattern he sees repeatedly in AI-based IVD programs: “The most common mistake is treating algorithm accuracy as if that alone were clinical evidence. For AI-based IVDs, you also need to show data provenance, representativeness, version control, performance across real-world input scenarios, monitoring for drift, and transparency about limitations. The IMDRF draft is quite clear that for AI-based SaIVD, manufacturers should document the whole data lifecycle, manage AI-specific failure modes, monitor post-market drift, and make outputs interpretable enough for human oversight.”
This is a significant operational gap for many software and AI companies entering the IVD space. Algorithm performance metrics, sensitivity, specificity, AUC, are necessary but not sufficient. N91 signals that regulators will expect a much broader evidence architecture for these products.
For related reading on IMDRF’s approach to AI in medical devices, see: IMDRF Machine Learning-enabled Medical Devices: Key Terms and Definitions.
IMDRF N91 and Companion Diagnostics: Co-Development, Cut-Off Locking, and Clinical Bridging
Companion diagnostics (CDx) receive dedicated and substantially more detailed treatment in N91 than in the 2012 GHTF documents. This reflects both the growing regulatory complexity of CDx programs globally and the specific challenges that arise when an IVD must be co-developed alongside, and validated in the context of, a therapeutic clinical trial.
N91 explicitly addresses the relationship between the CDx and its linked drug program, including clinical trial design considerations (therapy stratification vs. therapy selection), the role of the companion diagnostic in defining the eligible patient population, and the use of bridging studies to establish comparability between a clinical trial assay and the final commercial CDx.
The Hardest Practical Challenge in CDx development: Timeline Alignment
The core operational difficulty in CDx development is well-known to anyone who has run a real program. As Carlos Galamba describes it: “The hardest part is usually locking the assay and its cut-off early enough for the drug trial, while still leaving room to evolve toward the final commercial CDx. In practice, teams want flexibility during early clinical development, but regulators want traceability, reproducibility, and a defensible bridge to the final device. That tension is what makes CDx programs operationally difficult.”
N91 does not resolve this tension, but it does provide a clearer framework for documenting the development pathway, which is ultimately what Notified Bodies and regulatory authorities are looking for.
Clinical Bridging Studies: Where Evidence Packages Break Down
When a bridging study is required, linking a clinical trial assay to a subsequent commercial CDx, manufacturers frequently arrive at submission with incomplete packages. Based on Carlos Galamba’s experience with CDx submissions: “The common gaps are weak analytical comparability, poor justification for cut-off transfer, insufficient specimen representativeness, and incomplete explanation of discordant results. IMDRF N91 now directly recognizes bridging from a clinical trial assay to a subsequent CDx and says the study should establish clinical comparability using direct or indirect data.”
N91’s explicit recognition of bridging is significant because it gives regulatory teams a defined framework to reference, and it sets expectations that regulators in IMDRF member jurisdictions will increasingly apply.
For a step-by-step guide to CDx performance studies under IVDR, see: IVDR Annex XIV Performance Studies for Companion Diagnostics: A Step-by-Step Guide 2026.
IMDRF N91 vs. IVDR: What Changes for EU-Compliant Manufacturers?
A practical question for manufacturers already operating under IVDR: does N91 require significant additional work?
The short answer, according to Carlos Galamba, is no, with important nuances: “For a manufacturer that is genuinely IVDR-compliant, N91 should not feel like a reinvention. IVDR already requires clinical evidence based on scientific validity, analytical performance, and clinical performance, supported by a continuous performance-evaluation process tied to intended purpose and updated over the lifecycle. The additional work is mostly in tightening structure, terminology, and rationale, especially for software, AI, and CDx.”
The key phrase here is “genuinely IVDR-compliant.” Many manufacturers have documentation that is technically complete but not logically structured around intended use, clinical benefit, and lifecycle evidence updates, the elements N91 makes more central. For those teams, N91 is a useful diagnostic tool for identifying where their evidence architecture needs strengthening.
For EU manufacturers, it is also worth noting that IMDRF is referenced in MDCG documents, and MDCG has in some cases explicitly built on or endorsed IMDRF concepts. While IVDR remains the legally binding framework in the EU, alignment with IMDRF guidance is increasingly reflected in Notified Body expectations.
For clinical evidence requirements under IVDR specifically, see: MedTech Europe IVDR Clinical Evidence Requirements
Where additional work may be required
| Area | Likely additional work for IVDR-compliant manufacturers |
|---|---|
| SaIVD / AI-based IVDs | N91 adds specificity on data lifecycle documentation, drift monitoring protocols, and transparency requirements that may exceed current IVDR technical file scope |
| Companion diagnostics | Bridging study documentation and cut-off transfer justification may need to be more formally structured against N91 requirements |
| Legacy portfolios | Evidence packages that are technically complete but not logically structured around intended use and clinical benefit may need restructuring |
| Terminology alignment | N91 introduces 17 defined terms. Ensuring internal documentation uses consistent, N91-aligned terminology will reduce reviewer friction |
Who Is Most Exposed by IMDRF N91?
Not all manufacturers face the same level of exposure from N91’s new requirements. Based on Carlos Galamba’s assessment: “The most exposed are probably legacy portfolio holders and AI/software IVD developers. Legacy manufacturers often have evidence packages that are technically complete but not logically structured around intended use, clinical benefit, and lifecycle updates. AI and software companies face extra complexity because N91 explicitly addresses data lifecycle, drift, transparency, and the need for ongoing re-verification. CDx developers are also highly exposed because of the added bridging and co-development challenges.”
Startups building new products from scratch arguably face less disruption, if they build their evidence strategy around N91 from day one, they are building to the standard rather than retrofitting to it.
3 Actions to Take Before IMDRF Consultation Closes on 5 May 2026
N91 is unambiguous: clinical evidence is a lifecycle activity, not a premarket deliverable. If your organization’s evidence strategy is still organized around submission milestones rather than continuous performance evaluation and intended-use discipline, this is the moment to change that.
The IMDRF consultation for N91 is open until 5 May 2026. This is a genuine opportunity for IVD manufacturers to shape the final guidance. Carlos Galamba’s recommendation for teams reading N91 today:
“First, run a structured gap assessment against the draft using your current intended uses, performance evaluation reports, and evidence-generation plans. Second, identify where the draft creates operational friction for your products, especially if you work in CDx, AI/software, NGS, decentralized testing, or legacy portfolios, and submit concrete comments. Third, check whether your evidence strategy is truly lifecycle-based, or whether it is still a premarket-only mindset.”
How to prepare Before IMDRF Consultation Closes
- Run a structured gap assessment
Map your current intended uses, performance evaluation reports, and evidence-generation plans against the N91 draft. Focus specifically on: how your three-pillar evidence is documented and whether it is genuinely tied to intended purpose; whether your SaIVD or AI products have data lifecycle and drift monitoring documentation; and whether your CDx bridging evidence is structured in a way that satisfies the comparability requirements in N91’s Section 7.
- Identify operational friction and submit comments
The public consultation is a genuine opportunity to shape the final guidance. Manufacturers should identify where N91 creates operational friction for their specific product types, particularly in CDx, AI/software, NGS, decentralized testing, or legacy portfolios, and submit concrete, technically grounded comments to IMDRF before 5 May 2026
- Audit your evidence mindset
N91 is unambiguous: clinical evidence is a lifecycle activity, not a premarket deliverable. If your organization’s evidence strategy is still organized around submission milestones rather than continuous performance evaluation and intended-use discipline, this is the moment to change that.
The consultation period closes 5 May 2026. Feedback can be submitted via the IMDRF consultation page.
If your team needs support conducting a structured gap assessment or preparing a pre-submission technical review, MDx CRO’s IVDR Pre-Submission Assessment service is designed exactly for this type of exercise.
How MDx Can Help
MDx CRO combines 18+ years of IVD regulatory expertise with hands-on experience at Notified Bodies, European Commission advisory roles, and operational leadership across Class C/D IVDs, CDx, NGS, and AI-based diagnostic software. Our team has supported hundreds of IVDR submissions and continues to track global regulatory developments including IMDRF consultations in real time.
Whether you are running a gap assessment against the N91 draft, building your CDx evidence strategy, preparing for IVDR submission, or developing a clinical evidence plan for an AI-based IVD, our team can provide the regulatory depth and operational experience to move efficiently.
Ready to align with IMDRF N91?
Contact MDx CRO to discuss a structured gap assessment against the N91 draft, or to review your current clinical evidence strategy before the consultation closes on 5 May 2026.
Frequently Asked Questions
IMDRF N91 is the 2026 draft document Clinical Evidence for IVD Medical Devices, Definitions and Principles of Performance Evaluation. Open for public consultation from 4 March to 5 May 2026, it supersedes the 2012 GHTF N6 and N7 documents. It matters because it updates the global reference framework for how manufacturers should define, generate, document, and defend IVD clinical evidence, including for modern areas like software, AI, and companion diagnostics.
No. EU IVDR 2017/746 remains the legally binding framework in the EU. IMDRF N91 is best understood as a global convergence guidance document that is highly relevant to IVDR because the core architecture is already aligned: intended purpose, scientific validity, analytical performance, clinical performance, lifecycle updating, and state of the art. IMDRF is referenced in MDCG documents, and the binding framework in the EU remains MDR/IVDR, not IMDRF itself.
Scientific validity (establishing the association between the analyte and a clinical condition), analytical performance (the ability of the IVD to detect or measure the analyte correctly), and clinical performance (the ability of the IVD to yield results that correlate with a clinical condition in the target population). All three must be addressed in an integrated performance evaluation strategy tied to the device’s intended purpose.
Yes. N91 includes a dedicated section on Software as an IVD (SaIVD) that explicitly addresses AI and machine learning-based devices. Requirements include data lifecycle documentation, performance drift monitoring, AI transparency, version control, and the principle that final clinical decisions must rest with qualified healthcare professionals.
A clinical bridging study is used to link a new commercial CDx to an existing clinical trial assay that was used during a drug’s pivotal study. N91 formally recognizes this approach and requires that bridging studies establish clinical comparability using direct or indirect comparability data. This addresses a significant gap in the existing regulatory framework for CDx development.
N91 is currently in public consultation, which closes on 5 May 2026. The guidance will be finalized after comments are reviewed. It is not currently in force, but manufacturers who align with it proactively will be better positioned as Notified Bodies and regulatory agencies begin referencing it in reviews, training, and audit frameworks, which typically occurs 6 to 18 months after finalization.
A scientific validity report (SVR) documents the established association between an analyte and a specific clinical condition, physiological state, or intended use. It forms the foundation of the clinical evidence package. Under IVDR Annex XIII, an SVR is already a mandatory component of technical documentation for IVDs. N91 reinforces this requirement globally and provides updated definitions and expectations for how scientific validity should be determined and documented.
