Beyond the Guidance: Realities of Clinical and Performance Evidence for IVDs under the IVDR
MDCG 2022-21 gave the industry something unique and valuable, clarifying expectations for clinical evidence under the IVDR. It laid out detailed principles around scientific validity, analytical performance, and clinical performance offering a structured foundation for manufacturers. However, guidance alone, regardless of how well-framed, cannot deliver the precise, context-driven evidence that IVDR demands.
In the early decades of modern diagnostics before reliable assays existed and systematic screening was established, contaminated blood products transmitted HIV and Hepatitis to tens of thousands of patients with haemophilia and transfusion recipients across Europe leading to thousands of deaths. This travesty exposed the urgent need for reliable diagnostic screening and became one of the most sobering reminders of how essential timely, accurate testing is to public health. While today’s regulatory landscape is far more structured, the underlying lesson remains unchanged: diagnostic evidence matters because real world consequences are profound, and IVDR formalises this by requiring that performance claims are anchored in evidence that reflects clinical relevance and real world use.
For Regulatory Affairs teams, Diagnostic Manufacturers, and Clinical Laboratory Directors, translating guidance to evidence reveals a complex reality. It is often found in practice that the path to compliance is rarely linear but shaped by data limitations, operational constraints, and day-to-day realities of clinical environments. This piece examines key tensions and offers a pragmatic view for IVD manufacturers to align evidence generation with clinical relevance and regulatory expectations.
The Gap Between Guidance and Reality
“Performance evaluation of a device is a continuous process by which data are assessed and analysed to demonstrate the scientific validity, analytical performance and clinical performance of that device for its intended purpose as stated by the manufacturer.” — IVDR, Annex XIII, Part A3.
Meeting these requirements demands clinical insight, strategic foresight, and operational agility in addition to technical capability. While the guidance outlines expectations, navigating the actual constraints that shape real-world evidence generation is an entirely distinct undertaking. For larger manufacturers with extensive portfolios of legacy devices, the shift to IVDR presents a significant operational burden. Many of these technologies were developed under previous frameworks, with limited access to prospective data or detailed performance documentation. Remediating hundreds of devices requires careful triage, resource planning and evidence prioritization. This creates a structural challenge within organizations, testing operational agility and long-term planning.
As manufacturers work to align legacy documentation with IVDR standards, even foundational elements can reveal unexpected gaps. Scientific validity is often viewed as the most straightforward pillar of clinical evidence, particularly for well established analytes supported by consensus and robust literature. However, MDCG 2022 2 highlights that gaps can still emerge when intended use changes, populations differ, or legacy data does not meet current expectations for demonstrating state-of-the-art, equivalence, or methodological rigor. In these cases, manufacturers may need to reassess comparator data, generate bridging evidence, or refine claims to ensure alignment with the evidence base.
When working with emerging biomarkers, multi analyte panels, or novel diagnostic targets, the clarity around scientific validity can fade quickly. In these cases, the evidence base may be limited, heterogeneous, or evolving, making it difficult to demonstrate state-of-the-art or establish equivalence as required by MDCG 2022 2. Manufacturers must ensure that their sources reflect current clinical understanding and that comparator data is sufficiently detailed, peer reviewed, and methodologically robust. This is especially important in fast moving fields such as oncology, infectious disease, and genomics, where clinical relevance can shift rapidly and where gaps in evidence may require bridging studies or clearly defined limitations in performance claims.
Compounding this complexity is the tension between retrospective and prospective data. While prospective studies offer greater control and rigor, they are not always feasible. For rare diseases or legacy technologies, retrospective datasets may be the only viable source, but MDCG 2022 2 emphasises that such data often lack the granularity needed to demonstrate equivalence or state-of-the-art. This creates both logistical and ethical considerations, requiring manufacturers to balance feasibility with transparent communication of limitations and, where necessary, the generation of bridging evidence.
Comparator data, central to establishing the state-of-the-art, introduces yet another layer of complexity. Under IVDR, equivalence is tightly constrained. Publicly available sources such as literature or marketing materials offer partial insights but often lack the depth needed to support robust performance claims, leaving a weak basis for comparison. This raises an important question: if the foundational data used for comparison is inadequate, can the resulting performance claims truly be considered reliable? Manufacturers must assess whether available data is current, clinically relevant, and methodologically sound. Where comparator data lacks depth or alignment with the intended use, the regulations emphasise the need to generate bridging evidence or clearly articulate limitations to ensure a defensible performance claim.
Beyond methodology, sample availability and population diversity heavily influence feasibility. For novel biomarkers or low prevalence diseases, assembling statistically robust cohorts is a persistent challenge. MDCG 2022 2 highlights that such constraints can limit the ability to demonstrate equivalence or establish state-of-the-art, particularly when comparator data is sparse or heterogeneous. Clinical diversity is essential, yet access remains uneven, requiring manufacturers to assess whether available evidence is sufficient for the intended use or whether bridging studies and clearly defined limitations are needed to support defensible performance claims.
Real-World Examples: Context Matters
The scenarios outlined shape diagnostic development every day, across diverse technologies and clinical settings. In rare disease diagnostics, manufacturers often rely on literature reviews, registry data, and real world evidence to support scientific validity. However, MDCG 2022 2 highlights that such sources may not provide sufficient comparator data to demonstrate equivalence or establish the state-of-the-art. Prospective studies may be infeasible due to small patient populations or ethical constraints, requiring adaptive designs, bridging evidence, or clearly defined limitations in performance claims.
For companion diagnostics, the link between diagnostic performance and therapeutic outcomes introduces additional complexity. Comparator data must reflect stratified patient populations, evolving treatment protocols, and the clinical context in which the test informs therapy selection. This requires close alignment between diagnostic developers, pharmaceutical partners, and clinical investigators to ensure that evidence used to support performance claims is both current and clinically relevant.
Point of care diagnostics introduce further considerations. Comparator studies conducted in controlled laboratory environments may not adequately reflect real world use, where variability in user training, environmental conditions, and workflow integration can influence performance. MDCG 2022 2 emphasises that comparator data must be aligned with the intended use setting; where this is not possible, manufacturers must transparently communicate limitations or generate bridging evidence to support claims.
In the context of blood safety, the evolution of screening assays for HIV, Hepatitis B, and Hepatitis C illustrates how the state-of-the-art shifts over time. The transition from first generation assays to today’s highly sensitive NAT based screening transformed transfusion safety across Europe. Under IVDR and MDCG 2022 2, updating Instructions for Use and performance claims for such assays requires manufacturers to reflect not only analytical capability but also real world deployment conditions, donor population variability, and post market surveillance insights. These considerations are essential for ensuring that performance claims remain aligned with state-of-the-art and supported by sufficient evidence.
BSI’s Approach: Practical Strategies for Evidence Generation
At BSI, advancement is about clarifying the path forward by aligning evidence strategies with evolving regulatory and clinical demands. As an EU Notified Body committed to patient safety and timely market access, we support clients in navigating this complexity with clarity, confidence, and regulatory rigor.
To translate regulatory expectations into actionable evidence, manufacturers should focus on practical, high-impact strategies that can be deployed across the product lifecycle:
Real-World Evidence Integration
Real-world evidence, drawn from registries and electronic health records, and can supplement clinical performance data. It is especially valuable for post-market follow-up and long-term safety monitoring. When methodologically sound this strengthens relevance and trust.
Adaptive and Staged Study Designs
Staged evidence collection allows manufacturers to generate initial data for early conformity assessment, followed by expanded post-market studies. Adaptive designs enable flexibility in endpoints and sample sizes, building resilience into the process.
Collaborative Models
Engagements with healthcare systems, academic institutions, and pharmaceutical companies facilitate access to data, patient cohorts, and clinical expertise. These models support more robust and contextually relevant evidence, particularly for complex or high-risk technologies. These cross-sectorial partnerships strengthen regulatory alignment and support shared accountability.
Responsible Use of Literature
Systematic reviews and meta-analyses can support scientific validity claims, provided the underlying studies are current, peer-reviewed, and methodologically vigorous. However, landmark studies, widely cited in clinical guidelines or reflecting real-world diagnostic practice, often carry greater weight. Transparency in selection criteria and limitations remains essential to maintain regulatory confidence.
Instructions for Use Updates
Within the framework of MDCG 2022 2, the Instructions for Use becomes a critical output of the performance evaluation process, reflecting the state-of-the-art, the strength of comparator data, and the limitations of the evidence base. Updates to the IFU must ensure that performance claims remain consistent with the data used to establish equivalence, that limitations arising from gaps in comparator evidence are transparently communicated, and that users understand the conditions under which the claimed performance is valid. Where comparator data is incomplete, heterogeneous, or not fully aligned with the intended use, MDCG 2022 2 emphasises the need for manufacturers to clearly articulate these constraints within the IFU or to generate bridging evidence. In this context, the IFU is a key mechanism for ensuring that performance claims are credible, clinically relevant, and supported by all available evidence.
Conclusion: From Compliance to Credibility
As the IVDR continues to evolve, industry leaders must move beyond interpretation and reactive compliance to strategic implementation. As manufacturers adapt, the challenge is no longer simply meeting expectations outlined in MDCG 2022-2, but actively building evidence frameworks that withstand scrutiny, support clinical integration, and scale globally. At BSI, we support manufacturers in navigating this shift by providing structured, expert-led assessment that reflects regulatory expectations, clinical realities, and the shifting demands of global deployment.
Across the industry, we are seeing a transition: from static documentation to dynamic, post-market evidence ecosystems; from narrow performance claims to integrated usability and deployment data. The rise of AI-enabled diagnostics, decentralized testing, and equitable diagnostic access strategies demands new thinking - evidence must be relevant, inclusive, and iteratively refined.
The IVDR is a recalibration of evidence expectations across the diagnostic landscape. As the field evolves, BSI continues to support manufacturers globally in navigating this space and building evidence strategies that are robust, future-ready and aligned with real-world clinical practice.
At BSI, our commitment is to support manufacturers as they navigate this evolving landscape with clarity and confidence, ensuring that high quality, evidence-driven diagnostics reach the market, protect patients, uphold public trust and strengthen healthcare systems worldwide.
About the Author
Lorna Ingoldsby serves as an Internal Clinician IVD at BSI since December 2023. Prior to this role, Lorna held senior management roles in both the private clinical laboratory and public hospital sectors. Lorna holds a B.Sc. and Ph.D. in Biochemistry & Molecular Biology from University College Dublin, an MSc in Biomedical Science from the University of Ulster and a Specialist Diploma in Lean Systems from the University of Limerick.
References
1. Medical Device Coordination Group Document. Guidance on general principles of clinical evidence for In Vitro Diagnostic medical devices (IVDs).
2. Infected Blood Inquiry. Infected Blood Inquiry: The Report (HC 569 III). London: His Majesty’s Stationery Office; 2024.
3. European Parliament and Council. Regulation (EU) 2017/746 on in vitro diagnostic medical devices (IVDR). Official Journal of the European Union. 2017. Annex XIII, Part A
