Exploring the EU COMBINE Project: A Path to Harmonized Regulatory Frameworks

The European Union’s regulatory framework for healthcare innovation is among the most advanced globally, yet its complexity often presents significant challenges.? This is especially true for “combined studies” involving medicinal products, medical devices, and in vitro diagnostics (IVDs).

Recognizing these challenges, the EU launched the COMBINE project in June 2023 to streamline the regulatory landscape for such studies to ensure that innovative treatments reach EU patients while maintaining compliance with high standards.

Understanding Combined Studies and Regulatory Complexity

Combined studies, which involve the simultaneous investigation of one or more medicinal products, IVDs, and/or medical devices must comply with multiple regulatory frameworks:

• Regulation (EU) 536/2014 on clinical trials of medicinal products (CTR)
• Regulation (EU) 2017/745 on medical devices (MDR)
• Regulation (EU) 2017/746 on in vitro diagnostic medical devices (IVDR)

Each framework governs distinct yet interrelated aspects of healthcare product development.? Divergent requirements, documentation, timelines, and processes across these frameworks pose significant barriers, delaying trial initiation and limiting patient access to innovative therapies.

The Impact of IVDR on Using Companion Diagnostics in Clinical Trials

Companion diagnostics (CDx) are often co-developed together with their medicinal product and are evaluated in combined studies.? Previously, under Directive 98/79/EC (IVDD), CDx were not defined and such “biomarker assays” were classified as “IVD other” (not Annex II; low risk).? Regulatory oversite for use of biomarker assays in clinical trials occurred at the Member State level and requirements were not harmonized.?

With the entry into force of the Regulation (EU) 2917/746, a new risk-based classification system (classes A to D) was introduced and a legal definition for CDx established. Companion diagnostics are Class C devices and when used in clinical trials, are now required to be CE-marked for their intended use in the trial, authorized for in-house use, or developed for clinical performance evaluation.

Clinical performance studies (PS) involving CDx must adhere not only to the general requirements for all PS set out in IVDR Article 57 and Annex XIII, but must also be designed, authorised, conducted, recorded and reported in accordance with Articles 58 to 77 and Annex XIV as for “interventional clinical performance studies” as CDx represent a significant level of inherent risk.?

These changes have contributed to significant delays in clinical trial initiation.

A 2023 report by the European Federation of Pharmaceutical Industries and Associations (EFPIA) highlighted that 43% of companies expected delays of 6 to 12 months in starting their trials, with 228 to 410 trials enrolling fewer EU patients. In the context of oncology alone, this could mean delayed access to life-saving treatments for as many as 42,200 patients over the next three years[1].

The COMBINE Project: Finding Solutions to Regulatory Barriers

In response to these growing issues, the COMBINE project established ?a two-phased approach with the goal of first understanding the encountered challenges and then implementing solutions. This involves cross-functional collaboration at the EU level, including experts from the different EU governance structures. Additionally, an external stakeholder group, representing industry, patients, academic research groups, health care professionals, clinicians and notified bodies contributes to the effort.

Phase 1: Analysis – ?Mapping the Challenges and Early Insights

The first phase of COMBINE, conducted between September 2023 and May 2024[2], was dedicated to understanding the challenges sponsors face when conducting combined studies. The analysis phase had four key objectives:

1. Identifying Issues: Stakeholder workshops revealed 78 unique issues, ranging from misaligned regulatory timelines to unclear definitions and procedural inconsistencies.
2. Mapping National Processes: A survey across 24 EU Member States uncovered significant inconsistencies in how national competent authorities (NCAs) and ethics committees (ECs) handle combined studies.
3. Reviewing Ongoing Work: Existing EU-level guidance and activities were assessed for areas of alignment and gaps.
4. Proposing Solutions: The issues were analyzed, and potential solutions were grouped into thematic areas such as coordinated assessments, alignment, and improved communication.

The analysis phase also identified more than 50 proposed actions to address these issues and concluded with a roadmap that emphasized:

• Establishing coordinated assessments for combined studies to reduce duplication and harmonize processes.

• Aligning Member State interpretations and procedures to minimize variability.

• Enhancing communication between stakeholders through training, dialogue forums, and better IT integration.

Phase 2: COMBINE Programme Vision and Strategic Implementation Plan

In December 2024, the EU Member States endorsed the strategy for the second phase: the “COMBINE programme”.?

Building on insights gained from its analysis, the COMBINE programme implementation phase is designed to deliver solutions for challenges facing combined studies in the EU.

The recently published ‘COMBINE’ programme strategy’ document[3], clarifies the vision, its structure and governance, and provides an overall plan of activities.

The COMBINE programme seeks to make the European Union an attractive region to conduct combined studies, envisioning a clear and smoothly functioning regulatory environment for combined studies through broad involvement of regulators, ethics committees and all impacted stakeholders, with the ultimate goal to support availability of innovative treatments for patients.

Structure and Governance

In the EU, there is no single regulatory authority.? Medical devices are governed at a European level by the EU Commission expert groups, organized under the Medical Device Coordination Group (MDCG) while medicines are governed by the Heads of Medicines Agency (HMA), the EU Commission and the European Medicines Agency (EMA).

Further, National Competent Authority (NCA) clinical trial authorization is governed by the Clinical Trials Coordination Group (CTCG) at the HMA and the Clinical Trials Coordination and Advisory Group (CTAG) at the EU Commission.? And the Ethics Committees system is made up of national Research Ethics Committees (RECs) for both medicines and devices, sometimes the same Committees cover both aspects and sometimes the Committees are separate.

This affords unique challenges in solving issues with cross-sectorial relevance.? As such, the COMBINE programme aims to provide a framework for cross-sectorial work in relation to combined studies that cannot be solved by a single sector and is not intended to replace or significantly change already existing structures.

Programme Action Plan Highlights

The programme’s activities are organized into three thematic areas:

1. Coordinated Assessments

This pillar focuses on harmonizing the evaluation of combined study applications by competent authorities, as well as by ethics committees by:

• Exploring coordinating assessments of applications for combined studies among Member States (including competent authorities and ethics committees) and across the CTR and IVDR or MDR.
• Piloting a coordinated assessment procedure for clinical trials involving IVDs as companion diagnostics.
• Integrating learnings into ongoing work on integration between the CTR Clinical Trials Information System (CTIS) and the MDR/IVDR European database on medical devices (Eudamed).

2. Alignment

Efforts under this area aim to align interpretations and procedures across the EU Member States by:

• Providing an aligned approach on the processes for combined studies (e.g., same IVD used in multiple IMPs, procedures for substantial modifications).
• Optimizing serious adverse event reporting in combined studies.

3. Communication and Dialogue

This thematic area emphasizes improving stakeholder exchange of information, advice and training, including:

• Enhancing training for sponsors and assessors.
• Fostering member state collaboration through forums and best practice exchanges.

A Phased Implementation Approach (2024-2027)

To ensure feasibility and effective resource allocation, the action plan is divided into three stages:

• Stage 1 (2024 – Q1 2025): Focus on coordinated assessments and initial alignment activities.
• Stage 2 (Q2 2025 – Q1 2026): Expand alignment efforts and initiate communication and dialogue-focused projects.
• Stage 3 (Q2 2026 – Q1 2027): Sustain communication and dialogue initiatives.

The Road Ahead

The COMBINE project provides a roadmap to address regulatory inefficiencies, ensuring combined studies can progress without unnecessary delays. Its success depends on sustained collaboration and commitment across the EU regulatory ecosystem. As the EU continues to refine its approach to combined studies, the lessons learned, and solutions implemented through COMBINE will serve as a blueprint for future regulatory innovations.

These solutions are essential to reducing the regulatory burden on sponsors, speeding up trial initiation, and ensuring that European patients have access to cutting-edge therapies.

Beaufort’s Commitment to Innovation and Patient Access

As regulatory frameworks evolve, Beaufort’s expertise positions us as a trusted partner for sponsors navigating the complexities of combined studies. By staying abreast of regulatory changes and advocating for streamlined processes, we help our clients succeed and ensure that patients benefit from timely access to innovative treatments. Beaufort remains committed to driving excellence in regulatory strategy, fostering a future where innovation and compliance go hand in hand.

Contact us to learn more about how Beaufort can successfully support your current or future clinical trial.

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[1] https://health.ec.europa.eu/document/download/77e1409a-f4c0-45db-bff1-4873c7a0e7ae_en?filename=md_combined-analysis-phase-report_0.pdf

[2] European Federation of Pharmaceutical Industries and Associations. (2023). Critical Impacts of IVDR Implementation on Patient Access to Clinical Trials. https://efpia.eu/media/677143/efpia_ivdr-survey-slides.pdf

[3] https://health.ec.europa.eu/document/download/c10c325f-ae88-4956-a7eb-f45acc0a9811_en?filename=md_combine_strategy_en.pdf