The European Union (EU) has one of the most advanced regulatory frameworks for healthcare innovation in the world. However, this complexity can pose significant challenges, particularly when clinical studies involve more than one category of health technology. These “combined studies,” which include medicinal products, medical devices, and in vitro diagnostics (IVDs), often require developers to navigate multiple overlapping regulations.
To address these challenges, the European Commission launched the COMBINE project in June 2023. The goal of the project was to simplify and harmonize regulatory processes for combined studies to ensure timely access to innovative therapies for patients across Europe whilst maintaining high safety and ethical standards COMBINE is one of the initiatives highlighted in the Draghi report to support EU competitiveness in clinical research.
What are combined studies?
Combined studies refer to clinical research efforts that investigate a combination of:
- A medicinal product alongside an in vitro diagnostic (IVD) in a performance study, or
- A medicinal product in parallel with a medical device under clinical investigation.
Such studies are highly complex, as they must comply with multiple regulatory frameworks simultaneously, including:
- Clinical Trials Regulation (EU) 536/2014 (CTR)
- Medical Device Regulation (EU) 2017/745 (MDR)
- In Vitro Diagnostic Regulation (EU) 2017/746 (IVDR)
Each regulation addresses distinct but connected aspects of therapy product development. Indeed, the EU regulatory landscape is inherently fragmented: medicines oversight is shared by the European Medicines Agency (EMA), the Heads of Medicines Agencies (HMA), and the European Commission; medical devices and IVDs fall under the Medical Device Coordination Group (MDCG); and clinical trial approvals are granted by NCAs through the Clinical Trials Coordination Group (CTCG) and Clinical Trials Coordination and Advisory Group (CTAG). Meanwhile, Ethics Committees (RECs) operate at the national level, and in some countries, the same committee handles both medicines and devices; in others, they are separate.
As a result, misaligned requirements, inconsistent national processes, and uncoordinated timelines frequently pose significant challenges for trial sponsors, leading to approval delays and, ultimately, hindering patient access.
What is the COMBINE project?
Given this fragmentation, COMBINE aims not to replace existing systems but to create a framework for cross-sector collaboration, addressing challenges that no single regulatory body can solve alone.
The COMBINE project takes a structured, two-phased approach:
Phase 1 (September 2023 – May 2024)
The first phase focused on understanding the practical difficulties in conducting combined studies across EU member states. Key actions included:
- Identifying issues: Through stakeholder workshops, 78 unique regulatory and procedural challenges were documented.
- Mapping national processes: A survey covering 24 EU countries revealed significant variability in how national competent authorities (NCAs) and ethics committees (ECs) approach combined studies.
- Reviewing existing guidance: Ongoing EU-level initiatives were assessed for alignment and gaps.
- Proposing solutions: Potential solutions were categorized into themes such as regulatory coordination, procedural alignment, and enhanced communication.
The analysis produced more than 50 proposed actions, leading to a strategic roadmap emphasizing:
- Coordinated assessments to minimize duplication
- Harmonization across member states
- Improved communication through better training and digital integration
Phase 2 (2024–2027)
In December 2024, the EU Member States endorsed a strategy for implementing the COMBINE programme. This phase focuses on transforming insights into real-world improvements. COMBINE is being rolled out in phases from 2024 to 2027, focusing on three priority areas:
- Coordinated assessments (Q1 2024 – Q1 2025)
- Develop and test procedures for joint evaluation of applications involving multiple product types
- Pilot a coordinated assessment process for clinical trials involving IVDs as companion diagnostics
- Integrate findings into ongoing work linking the Clinical Trials Information System (CTIS) and the Eudamed database for devices
- Alignment (Q2 2025 – Q1 2026)
- Harmonize interpretation and procedures across EU Member States
- Provide consistent guidance on combined studies, including those using the same IVD across different investigational medicinal products (IMPs)
- Refine serious adverse event reporting in multi-technology trials
- Communication and dialogue (Q2 2026 – Q1 2027)
- Improve training for trial sponsors and regulators
- Encourage collaboration and knowledge-sharing among EU Member States via stakeholder forums and best practice exchanges
For more information, head to the European Commission website here.
Get in touch
As the second phase of COMBINE rolls out, the team at Boyds will be keeping a close eye on developments. If you would like to discuss the COMBINE project or would like any advice, please get in touch and a member of our team will be happy to help.
