CTS for High-Risk IVDs: Clinical Evidence When the Bar Moves

Written by HATEM RABEH, MD, MSc Ing

Your Clinical Evaluation Expert And Partner

in
S

Common Technical Specifications for high-risk in vitro diagnostic devices are not guidance documents. They are directly applicable regulatory requirements with the same legal force as the MDR itself. When a CTS is published for your device category, your clinical evidence strategy must adapt immediately.

Most manufacturers discover this too late. They structure their clinical evaluation around general MDR requirements, only to face rejection because they did not address the specific performance and clinical validity criteria outlined in the CTS. The gap is not always obvious. The language in a CTS can mirror MDR Article 56 and Annex XIII, but the execution demands are different.

What CTS Actually Changes for Clinical Evidence

A Common Technical Specification establishes minimum performance requirements and clinical validity thresholds for high-risk IVDs. It does not replace the clinical evaluation. It defines what the clinical evaluation must demonstrate.

Under MDR Article 47 and 48, a device that falls under a CTS must comply with that specification. If the device does not comply, the manufacturer must justify why the chosen solution offers an equivalent or higher level of safety and performance. This is not a checkbox. This is a documented clinical and technical rationale that the Notified Body will scrutinize.

The first implication is structural. Your clinical evaluation must explicitly map to the CTS requirements. That means identifying each performance claim in the CTS, locating the supporting clinical data, and demonstrating conformity. If you rely on literature, that literature must address the same intended use, same target population, and same clinical context described in the CTS.

Clinical Validity Under CTS: The Evidence Shift

High-risk IVDs are often used to inform critical clinical decisions. Companion diagnostics guide therapy selection. Screening tests determine patient pathways. The MDR already demands clinical validity under Annex XIII. A CTS specifies how that validity must be demonstrated.

This is where many clinical evaluations fail. Manufacturers present analytical performance data and assume clinical utility is implied. A CTS removes that assumption. It typically requires prospective clinical studies, defined endpoints, and statistical power calculations. If you planned to rely on retrospective literature or real-world evidence, the CTS may require more.

I see this repeatedly in submissions for devices with companion diagnostic claims. The manufacturer provides literature showing that the biomarker correlates with treatment response. The CTS, however, demands evidence that the device accurately identifies patients who will benefit from therapy, with sensitivity and specificity thresholds that the literature does not address. The gap is not in the quality of the evidence. It is in the mismatch between what was provided and what was required.

When Literature Cannot Close the Gap

Literature-based clinical evaluation is common in medical device submissions. For IVDs under CTS, that strategy becomes harder to defend. The CTS often defines performance metrics that are device-specific, population-specific, and context-specific. Published studies may use different cut-offs, different reference methods, or different patient cohorts.

If the literature does not match the CTS requirements, you have two options. You generate new clinical data, or you justify why the available evidence is sufficient. The second option is not a workaround. It is a documented argument that addresses each gap, explains why the difference is not clinically significant, and provides supporting data for that conclusion.

Notified Bodies do not accept generic justifications. If your device targets a European population but the literature is predominantly from Asia or North America, you must address whether population differences affect performance. If the CTS specifies a reference method and your studies used a different method, you must demonstrate equivalence or superiority. If the CTS defines a minimum sample size and your pivotal study falls short, you must show why the statistical power is still adequate.

This level of detail is rarely present in initial submissions. Manufacturers assume that strong literature compensates for missing CTS-specific data. It does not. The CTS is the standard. Your evidence must meet it, or your justification for deviation must be stronger than the evidence you are replacing.

PMCF Under CTS: Continuous Demonstration, Not Monitoring

Post-market clinical follow-up for high-risk IVDs under CTS is not passive surveillance. The MDR requires PMCF to confirm clinical performance and clinical validity throughout the device lifecycle. A CTS often defines what that confirmation must include.

For devices with companion diagnostic claims, PMCF must track whether the device continues to predict treatment response in real-world use. For screening tests, PMCF must monitor whether the device maintains its sensitivity and specificity across diverse populations. This is not about collecting complaints or adverse events. This is about generating continuous clinical evidence that the device still meets the CTS requirements.

Most PMCF plans I review do not reflect this. They describe post-market surveillance activities, literature monitoring, and periodic CER updates. They do not define specific clinical endpoints, sample sizes, or statistical methods for validating performance claims in the post-market phase. When the Notified Body asks how the PMCF plan will confirm CTS conformity, the answer is often vague.

The implication is clear. Your PMCF plan must be designed as a clinical study, not as a monitoring system. It must generate data that can be compared to the CTS thresholds. It must define what constitutes a performance drift and what corrective actions will be taken if the device no longer meets the specification.

Equivalence Claims and CTS: A Narrowing Path

Equivalence is already difficult under MDR. For high-risk IVDs under CTS, it becomes almost impractical. The CTS defines specific performance criteria that must be met. If you claim equivalence to a predicate device, you must show that your device meets the same CTS requirements. That requires head-to-head performance data, not just technical similarity.

Many manufacturers assume that if two devices measure the same biomarker using similar methods, they are equivalent. The CTS does not accept that logic. It requires evidence that both devices deliver the same clinical performance under the same conditions. If the predicate device was cleared under a previous regulatory framework that did not include CTS, you cannot rely on its clearance as proof of equivalence. You must generate the data yourself.

This is where submissions stall. Manufacturers present technical equivalence arguments without clinical performance data. The Notified Body asks for studies comparing the two devices in the intended use population. The manufacturer does not have that data. The equivalence claim collapses, and the submission moves to a full clinical investigation pathway.

The lesson is simple. If you plan to use equivalence for a high-risk IVD under CTS, verify that the predicate device meets the CTS and that you have comparative performance data. If you do not have that data, equivalence is not a viable strategy.

What This Means for Your Next Submission

If your device falls under a CTS, your clinical evaluation must be structured around that specification from the start. Do not build a general MDR-compliant CER and try to retrofit CTS requirements later. The framework does not work that way.

Begin by mapping each CTS requirement to your clinical evidence. Identify gaps early. If literature cannot close those gaps, plan for clinical investigations before submission. If you intend to deviate from any CTS requirement, document your justification with the same rigor as the clinical data itself.

Your PMCF plan must reflect the CTS requirements. Define the clinical endpoints, the data collection methods, and the performance thresholds you will monitor. Make it clear how you will confirm continued conformity, not just general safety.

This is not additional work layered on top of MDR compliance. This is the compliance baseline for high-risk IVDs. The CTS is the standard. Your clinical evidence strategy must meet it, or your submission will not progress.

When a CTS is published, the regulatory landscape for your device changes. The clinical evidence requirements are no longer implicit. They are defined, measurable, and enforceable. Your submission must reflect that reality.

Peace,
Hatem
Clinical Evaluation Expert for Medical Devices
Follow me for more insights and practical advice.