EU Releases Guidance on IVD Performance Studies, Finally

By Ken Pilgrim and Evangeline Loh

The European Commission (EC) released 54 Questions & Answers on In Vitro Diagnostic Medical Devices Regulation (EU) 2017/746 (IVDR) Performance Studies, MDCG 2025-5.  This follows the analogous guidance for the Medical Devices Regulation (EU) 2017/745 MDR) clinical investigations from 2021 (MDCG 2021-6, revised 2023).

This has been a long-awaited guidance document. In the interim, many competent authorities augmented their position with their own guidance on IVDR Performance Studies. All 54 Questions are delineated in the table of contents.

The Introduction section reminds entities that ethics review requirements are not imposed by the IVDR: “It is thus necessary to check national requirements in relation to submission to the ethics committee and where possible make sure that the ethics committees and competent authorities have access to the same versions of updated documents.”

In addition, while central institution review boards have been a topic of interest in the U.S., based on the 27 EU member states and signatories, the concept of a more centralized Ethics Review Board or Ethics Committee does not appear to yet exist.

Of the most value, the figures and appendices

The figures and appendices included are likely the most beneficial for affected parties. Figure 2 provides a synopsis of the relationship of the relevant performance study articles. Article 57 is relevant to all performance studies. This is in addition to the requirements based on the categorization (risk) of the study as described: Article 58(1) (application), Article 58(2) (notification), Article 70(1) (notification), and Article 70(2).  Figure 2 is probably the best representation of this information that we’ve noted and hopefully finally explains the differences clearly.

Appendix 1 is a flow diagram that facilitates determining the reporting requirements of the performance study: application, notification or not a performance study.

Appendix II assists with the interpretation of Article 71 by providing a (non-exhaustive) list of performance study modifications that may be deemed substantial.

To highlight a few of the questions and answers

While all the questions and answers are of interest, we will highlight a few that caught our attention:

Question 20 discusses specimen collection and specimen analysis sites, which occur in different member states.  Article 57 applies to both types of sites. Though the application (Article 58(1)) is only necessary for the sites where specimen collection is performed, we’ve experienced working with sponsors and manufacturers regarding specimen analysis in the EU where the sponsor has secured Ethics Committee approval from the institution, as well as with specimen analysis sites outside the EU.

Question 23 elaborates on “surgically invasive sample-taking” per Article 58(1)(a). The examples are: blood sampling (arterial, venous or capillary), puncture (body liquids, incl. cerebrospinal fluid or abscess), and collection of fresh tissue biopsy.

Question 30 further defines leftover samples. In general, these specimens/samples are remnants, collected during routine clinical practice, and “discarded as there is no remaining clinical need.” Note that samples can also be secured from tissue banks and commercial vendor collections.

As expected, there are also Questions 28 and 29 regarding companion diagnostics, specifically about when a companion diagnostic is considered a performance study and whether all companion diagnostic performance studies are considered interventional clinical performance studies.

Concluding remarks

Performance studies are a pivotal part of the regulatory strategy to bring a novel or high-risk IVD to market, especially for companion diagnostics. This is a comprehensive document that clarifies many questions related to the IVDR and performance studies. Figure 2 and Appendix 1 facilitate determining the requirements (or not) related to the performance study and if it would be an application, notification or neither.

n the future, we expect there to be a pilot of the coordinated assessment of performance studies, as there is currently one now with medical devices. This is in addition to further developments related to the COMBINE program (studies with medicinal products assessed with IVDs and medical devices).