“Proposal for a regulation to simplify rules on medical and in vitro diagnostic devices” – Impact on Precision Medicine Clinical Trials

Article By: James Lappin – Associate Director Global Regulatory Compliance, Translational Biomarkers

On 16^th December, 2025, the European Commission published its proposal for a targeted revision of the In Vitro Diagnostic Regulation (IVDR; 2017/746). This proposal comes off the back of an open Call for Evidence in Q3 2025, where stakeholders were invited to share their views and experiences with IVDR with the aim of simplifying procedures and reducing administrative burden, while preserving the high level of public health protection and patient safety intended by the original text.

The proposed changes are substantial and address many areas of the regulation relating to manufacturers, notified bodies and other stakeholders. In this blog post, we will focus on some of the changes relevant to Performance Studies, including combined studies involving companion diagnostics (CDx) and investigational medicinal products (IMP). It should be noted that the changes are ‘proposed’ only at this stage and will be subject to further scrutiny and potential amendment by EU Member States and Parliament over the coming months.

Firstly, there is a small change to the definition of a companion diagnostic acknowledging that a CDx may be used with multiple medicinal products. A definition for combined studies is also suggested:

“a clinical trial as defined in Article 2(2), point (2), of Regulation (EU) No 536/2014, combined with a performance study, and/or a clinical investigation as defined in Article 2, point (45), of Regulation (EU) 2017/745”

The term ‘combined study’ has been in common use for precision medicine studies involving a diagnostic test, so this is a welcome clarification and acknowledgment. It also aligns with the COMBINE pilot that is currently underway to assess the feasibility of a coordinated process for authorisation of combined studies of a medical device and medicinal product.

A number of changes are proposed to the ‘in-house exemption’ outlined in Article 5(5) of the Regulation. Notably, the scope of in-house testing is expanded to include testing for clinical trials:

This paragraph shall also apply to devices manufactured and used within a laboratory that is established in the Union and provides consistent, state of the art testing services for clinical research, provided those devices are intended exclusively for use in the framework of a clinical trial subject to Regulation (EU) No 536/2014

Laboratories that provide tests for use in clinical trials would be considered as health institutions under the proposed changes, provided that these tests are not manufactured on an industrial scale and are not commercialised. In addition, more flexibility has been introduced around the requirements for in-house tests to reduce the administrative burden for health institutions, particularly where the laboratory is accredited to EN ISO 15189. This potentially opens the door for EU based laboratories to provide ‘in-house tests’ for patient enrolment in clinical trials without the need for a full IVDR Annex XIV Performance Study application and would be a welcome change for many precision medicine Sponsors, particularly for early phase studies. This change also aligns with guidance from the UK MHRA, who have confirmed that ARC Laboratories can offer testing for precision medicine clinical trials involving UK and EU patient samples under the in-house exemption at our Northern Ireland based site under existing IVDR rules.

In terms of Performance Studies of IVD and CDx devices, there are key changes to the requirements outlined in Chapter VI of the regulation (Clinical Evidence, Performance Evaluation and Performance Studies), including simplification where studies don’t present additional risks to subjects, such as where they involve routine blood draws or left-over samples. Article 56 of the Regulation (Performance evaluation and clinical evidence) is simplified and made more concise.

Article 58 (Additional requirements for certain performance studies) sees some significant changes. Requirement 1(a) regarding surgically invasive sample taking done only for the purpose of the performance study is removed, and ‘high-risk procedures for collection of specimens’ is added to point 1(c), resulting in a paragraph as follows:

Any performance study:

(a) that is an interventional clinical performance study as defined in point (46) of Article 2; or

(b) where the conduct of the study involves additional invasive procedures, including high-risk procedures for collection of specimens, or other risks for the subjects of the studies shall, in addition to meeting the requirements set out in Article 57 and Annex XIII, be designed, authorised, conducted, recorded and reported in accordance with this Article and Articles 59 to 77 and Annex XIV.

Although additional guidance will be needed to clarify what these high-risk procedures may include, this proposed change may remove the need to submit an Annex XIV application for performance studies that include procedures such as venepuncture for sample collection, provided there is no interventional component or other significant risk for patients.

Article 58(2) regarding performance studies of CDx is removed entirely. In practice, many CDx studies are interventional and it was often a point of confusion for Sponsors (and NCAs) on whether to select Article 58(b) or Companion diagnostic study (or both!) on the IVDR Performance Study application form. Removing the requirement for notification of CDx studies involving left-over samples aligns with the Commissions intention to reduce administrative burden without compromising safety. Under these changes, CDx studies will likely be evaluated as either an interventional or high-risk study (Art. 58), or a combined study (see below).

Another key change to Article 58 aligns with the recent MDCG 2025-5 Guidance, ‘Questions & Answers regarding performance studies’, where performance studies will only be subject to authorisation requirements (e.g. Annex XIV application) in the Member State(s) in which the specimens are to be collected. An EU-based central testing site does not need an Annex XIV application on its own, although the General Requirements of Article 57 and local requirements for clinical research involving human subjects will apply. These changes are also reflected in Article 66 regarding the application for performances.

The remaining changes to chapter VI Articles 70-74 are summarised below:

• Article 70(1): an Investigator Brochure is no longer required when notifying NCAs of a PMPF study of a CE-marked device used within the scope of its intended use but involves additional invasive or burdensome procedures for subjects,
• Article 71: the requirement to notify substantial modification ‘within one week’ is removed, and some additional clarification is added as to when substantial modifications can be implemented (‘on authorisation, or after 38 days if no authorisation and no negative opinion’),
• Article 73: removal of requirement to notify within 24 hours for studies that have been halted or terminated early on safety grounds,
• Article 74: member states may request additional information from Sponsors regarding the application for a performance study on a single occasion and the Sponsor should submit this information within 12 days of receipt of the request. In addition, NCAs may only extend the evaluation period for applications by 20 days (down from 50) for consultation with experts for Class C and D devices.

A new article (75a) is introduced for ‘Combined Studies’, with the commission acknowledging the complexity of applying multiple regulations and procedures for clinical trials/studies involving both an IMP and a device for performance study. This represents one of the biggest changes for Sponsors of precision medicine studies, and will be heavily reliant on the outcome of the COMBINE pilot for coordinated assessment of combined studies that is currently underway. The new Article states:

‘Performance studies that are part of combined studies, and which are subject to authorisation in accordance with Article 58, may be carried out in accordance with Article 14c of Regulation (EU) No 536/2014.

If the sponsor chooses to apply Article 14c of Regulation (EU) No 536/2014, the requirements laid down therein and in any implementing and delegated acts adopted in accordance with that Article shall apply in place of the corresponding requirements laid down in this Regulation.’

Article 14c of EU CTR will be added following adoption of the Biotech Act, which was also proposed on 16^th December, 2025 (this has not yet been implemented and is subject to change); however, there are few details on how this combined process will be carried out. Article 14c allows the EU Commission to implement a streamlined procedure for initial applications and substantial modifications, set requirements for the conduct of combined studies (including safety reporting) and clarify the responsibilities of Sponsors and Investigators. At present, there is no indication of what these procedures and requirements may look like but the outcome of the COMBINE pilot will undoubtedly serve as the foundation for the process and the Commission will need to take into consideration the requirements of IVDR and any relevant MDCG Guidance. In addition, Member States will need to incorporate any new CTR/IVDR requirements into their national processes.

Annex 13 sees some changes to the Performance Evaluation process, including the removal of separate, specific reports for Scientific Validity, Analytical Performance and Clinical Performance which can now be ‘demonstrated and documented in a dedicated section of the performance evaluation report.’ This will be a much needed simplification of the Performance Evaluation process and prevent needless duplication, although it may not have much of an impact for ‘clinical trial assays’ undergoing following the new Combined Study pathway. Clinical performance can now be demonstrated by ‘a device for which equivalence to the device concerned can be demonstrated’ including clinical performance studies, other studies and clinical experience published in literature, clinically relevant post-market information, and experience gained by routine diagnostic testing. A small change is also proposed for Clinical Performance Study Plan (CPSP) requirements regarding the parameters of clinical performance to be determined by the corresponding study – “for combined studies, endpoints reporting on the device and medicinal product together may be used”. The applicability of parameters listed Annex I Section 9.1(b) for CDx devices has been a point of contention for many combined studies, and endpoints are a common subject for NCA questions during the Annex XIV application process. This addition should provide some alignment and clarification for many Sponsors.

The ‘Proposal for a regulation to simplify rules on medical and in vitro diagnostic devices’ is a significant step forward for the EU and shows a willingness from the Commission to both listen and act on stakeholder feedback. The changes for Precision Medicine clinical trials are significant and, on paper, should simplify requirements, reduce administrative burden, costs and timelines, and ultimately help to ensure EU patients continue to have access to IMP Clinical Trials. In particular, the broadening of scope for in-house testing and addition of requirements for Combined Studies will be well received by Sponsors carrying out clinical trials in the EU.

There remains, however, a number of uncertainties around how these changes may be implemented in practice and the Commission should aim to ensure that appropriate resources, infrastructure and guidance are in place to support all stakeholders (Sponsors, Manufacturers and National Competent Authorities) if and when the proposal is adopted. The outcome of the COMBINE pilot will likely help to shape this new process. Sponsors should also be aware that this is a proposal only and is still subject to further change before adoption. Until then, the current regulatory framework still applies!

ARC Regulatory is a partner for the global precision medicine and companion diagnostic industry, providing laboratory, clinical and regulatory support for CDx performance studies. If you’d like to discuss further how ARC can support your precision medicine clinical trial, please contact [email protected]