Introduction to the COMBINE Programme
The European Union has taken a significant step towards streamlining combined studies involving medicinal products, medical devices, and in vitro diagnostics (IVDs) through the COMBINE Programme. Endorsed by national authorities across Member States, the programme aims to address long-standing challenges that hinder the efficiency of clinical trials and regulatory approvals under the Clinical Trials Regulation (CTR), Medical Device Regulation (MDR), and In Vitro Diagnostic Regulation (IVDR).
The Need for Streamlined Combined Studies
Combined studies, which investigate the use of multiple healthcare products—such as a medicinal product with a medical device or companion diagnostic—are essential for advancing patient care and supporting innovative treatments. However, the fragmented regulatory processes across the CTR, MDR, and IVDR create significant hurdles:
- Administrative Complexity: Sponsors face parallel and often redundant assessment processes across Member States, leading to delays.
- Ambiguities in Regulation: Overlapping requirements on reporting and classification of studies often result in confusion.
- Harmonisation Gaps: Diverging approaches among national competent authorities slow down multi-country studies.
These challenges risk delaying the development and availability of critical healthcare solutions, impacting patients and stifling innovation.
The COMBINE Programme: A Collaborative EU Initiative
To overcome these challenges, the European Commission launched the COMBINE Programme, a cross-sector initiative designed to foster collaboration between regulatory authorities, ethics committees, and stakeholders. By unifying processes and addressing gaps at the interface of CTR, MDR, and IVDR, the COMBINE Programme sets out to:
- Simplify and harmonise the approval of combined studies across the EU.
- Improve collaboration between national competent authorities, the European Medicines Agency (EMA), ethics committees, and sponsors.
- Enhance Europe’s competitiveness in clinical research, aligning with the recommendations of the Draghi Report.
A Phased Approach to Change
The COMBINE Programme will be implemented over the coming years through seven cross-sector projects that focus on key areas such as piloting single assessment processes, harmonising serious adverse event (SAE) reporting, and enhancing advisory services for sponsors. The programme reflects a shared commitment to supporting innovation while ensuring patient safety and regulatory efficiency across the EU.
The Seven Cross-Sector Projects of the COMBINE Programme
The COMBINE Programme will be implemented through seven cross-sector projects, each addressing specific challenges in the regulatory landscape of combined studies. These projects represent a collaborative effort between national competent authorities, ethics committees, the European Medicines Agency (EMA), and other stakeholders to streamline processes, harmonise reporting, and improve advisory services for sponsors.
1. Piloting a Single Assessment Process for Multi-Country Combined Studies
- Objective: Introduce a coordinated, unified assessment process for combined studies involving medicinal products, medical devices, and in vitro diagnostics across multiple EU Member States.
- Why It Matters: Current processes require separate national submissions under different frameworks (CTR, MDR, and IVDR). This pilot project aims to reduce duplication, align timelines, and ensure a single, streamlined review process.
- Outcome: A harmonised approach that accelerates study approvals, reduces administrative burden, and improves efficiency for sponsors conducting multinational combined studies.
2. Harmonisation of Serious Adverse Event (SAE) Reporting Processes
- Objective: Align the reporting requirements for Serious Adverse Events (SAEs) across the CTR, MDR, and IVDR frameworks.
- Challenges Addressed: SAEs are reported differently under each regulation, creating confusion and inefficiencies for sponsors and regulators. Lack of harmonised processes delays decision-making and impacts patient safety monitoring.
- Outcome: A unified, consistent SAE reporting process that improves clarity, facilitates timely reporting, and ensures compliance across sectors.
3. Clarifying the Interface Between Clinical Trials and Medical Device Regulations
- Objective: Resolve regulatory ambiguities where the Clinical Trials Regulation (CTR) intersects with the Medical Device Regulation (MDR) and IVD Regulation (IVDR).
- Key Questions Addressed: When does a study require a Clinical Trial (CT), a Clinical Investigation (CI), or a Performance Study (PS)? How should combined studies be classified and approved under multiple regulatory frameworks?
- Outcome: Clear, harmonised guidelines for sponsors and regulators to navigate the interface between these regulations, ensuring smoother approvals and regulatory compliance.
4. Enhancing Advisory Services for Sponsors
- Objective: Explore new opportunities for providing coordinated, cross-sector advice to sponsors conducting combined studies.
- Why It Matters: Sponsors often face uncertainty when designing combined studies due to fragmented regulatory advice. A lack of centralized guidance increases the risk of regulatory non-compliance and delays.
- Outcome: Improved advisory mechanisms, such as coordinated pre-submission meetings, that help sponsors navigate regulatory complexities, streamline submissions, and accelerate study timelines.
5. Facilitating Knowledge Exchange Between National Authorities
- Objective: Promote collaboration and knowledge sharing among national competent authorities, ethics committees, and regulatory bodies.
- Key Actions: Establish platforms for cross-sector dialogue and exchange of best practices. Encourage joint discussions on shared challenges, such as study assessments, adverse event reporting, and ethical considerations.
- Outcome: A stronger, more unified regulatory network capable of addressing challenges efficiently and supporting the successful implementation of combined studies across the EU.
6. Aligning Regulatory Timelines and Approval Processes
- Objective: Harmonise the timelines and approval procedures for combined studies under the CTR, MDR, and IVDR frameworks.
- Challenges Addressed: Variations in national processes and timelines result in delays, particularly for multi-country studies. Sponsors face inconsistent requirements, creating additional administrative burden.
- Outcome: A coordinated approach that aligns national approval processes, ensures predictable timelines, and fosters greater consistency across Member States.
7. Strengthening Stakeholder Engagement for the COMBINE Programme
- Objective: Foster open dialogue and collaboration with key stakeholders, including sponsors, clinicians, patient representatives, and ethics committees.
- Why It’s Important: Involving stakeholders ensures that the solutions developed under the COMBINE Programme are practical, efficient, and patient-centric. Enhanced engagement helps address real-world challenges faced by industry and clinicians in conducting combined studies.
- Outcome: Improved stakeholder collaboration that ensures the programme’s goals align with industry needs, supports innovation, and prioritises patient outcomes.
Driving Regulatory Innovation Through the COMBINE Programme
The seven cross-sector projects under the COMBINE Programme address the core challenges of combined studies by streamlining processes, clarifying regulatory requirements, and fostering collaboration across the EU. These efforts are essential for improving efficiency, reducing delays, and enabling the development of innovative treatments that combine medicines, medical devices, and diagnostics.
Why the COMBINE Programme Matters
The COMBINE Programme represents a pivotal step toward addressing the regulatory inefficiencies that have long challenged combined studies involving medicinal products, medical devices, and diagnostics. By introducing streamlined processes, harmonising reporting requirements, and fostering collaboration, the programme delivers tangible benefits for all stakeholders.
For Sponsors and Manufacturers: Streamlined Approval Processes
- Simplified Submissions: The COMBINE Programme eliminates duplication by piloting a single assessment process for multi-country combined studies.
- Reduced Administrative Burden: Sponsors will no longer have to navigate fragmented processes under the CTR, MDR, and IVDR, reducing time spent on regulatory paperwork.
- Faster Approvals: Harmonised timelines and improved coordination across Member States will accelerate approvals for combined studies, enabling quicker market entry for innovative products.
For a sponsor conducting a clinical trial of a medicinal product alongside a performance study of an IVD, the single assessment process reduces redundant national submissions, ensuring a smoother and faster pathway to approval.
For National Competent Authorities and Ethics Committees: Improved Collaboration and Efficiency
- Unified Approach: The programme fosters collaboration between national authorities, ethics committees, and the EMA, ensuring consistency in study evaluations.
- Knowledge Sharing: By facilitating the exchange of best practices, authorities can address common challenges, such as adverse event reporting and interface ambiguities, more effectively.
- Efficient Use of Resources: Coordinated assessment processes streamline workflows, reducing the strain on regulatory bodies and ensuring a more efficient allocation of resources.
For Patients: Faster Access to Innovative Treatments
- Accelerated Innovation: By simplifying regulatory pathways, the COMBINE Programme ensures that groundbreaking treatments—such as combined therapies and diagnostics—reach patients more quickly.
- Improved Safety: Harmonised serious adverse event (SAE) reporting enhances patient safety by ensuring timely and consistent monitoring across all regulatory sectors.
- Personalised Medicine: Combined studies enable the development of advanced solutions, such as companion diagnostics paired with targeted therapies, leading to more tailored and effective treatment options.
In diseases like cancer, where combined studies often involve companion diagnostics and therapies, delays in approval can mean a delay in access to life-saving treatments. The COMBINE Programme aims to eliminate these delays, prioritising patient needs.
For the EU: Enhancing Global Competitiveness
- Addressing Recommendations from the Draghi Report: The Draghi Report underscored the importance of regulatory efficiency in maintaining the EU’s leadership in clinical research and innovation. The COMBINE Programme aligns directly with these goals, strengthening Europe’s position as a global hub for clinical trials.
- Attracting Global Studies: A streamlined, harmonised approach makes the EU more attractive for multinational combined studies, encouraging sponsors to invest in research within Europe.
- Supporting Innovation Ecosystems: By addressing regulatory hurdles, the programme fosters an environment conducive to innovation, benefiting SMEs, manufacturers, and healthcare systems.
The COMBINE Programme positions Europe as a leader in integrated clinical research, ensuring the EU remains competitive in the rapidly evolving MedTech and pharmaceutical industries.
Driving Real-World Impact Across Sectors
By addressing the challenges of combined studies, the COMBINE Programme delivers a balanced solution that benefits all stakeholders. For sponsors, it reduces complexity and accelerates approvals. For regulators, it ensures efficiency and collaboration. Most importantly, for patients, it enables faster access to innovative treatments that improve healthcare outcomes.
The COMBINE Programme and EU Competitiveness
The COMBINE Programme is not only a solution to regulatory complexity but also a cornerstone of the EU’s broader strategy to maintain global competitiveness in clinical research and medical innovation. By streamlining processes and fostering collaboration, the programme positions Europe as a leading region for conducting combined studies that integrate medicinal products, medical devices, and diagnostics.
Addressing the Recommendations of the Draghi Report
The Draghi Report, which outlines key priorities for strengthening Europe’s economic and technological competitiveness, highlights the importance of a streamlined regulatory environment for innovation in clinical research. The COMBINE Programme directly supports these recommendations by:
- Reducing Regulatory Complexity: Simplifying combined studies ensures a faster path from research to patient access, allowing Europe to stay ahead of global competition.
- Promoting Innovation: A harmonised and efficient system encourages sponsors and manufacturers to invest in research and development within the EU.
- Improving Market Access: By removing administrative barriers, new treatments can reach the market sooner, boosting Europe’s role as a leader in health innovation.
Strengthening the EU as a Global Hub for Clinical Research
1. Attracting Multinational Studies
Global sponsors often face challenges when navigating fragmented regulatory systems in the EU. The COMBINE Programme resolves these issues by:
- Offering single, coordinated assessments for multi-country studies.
- Harmonising timelines and reporting requirements under the CTR, MDR, and IVDR frameworks.
This streamlined approach makes the EU a more attractive destination for conducting global clinical studies, ensuring sponsors can leverage Europe’s vast expertise, resources, and patient access.
2. Fostering Cross-Sector Innovation
The growing trend of personalised medicine relies on combining medicinal products with diagnostic devices. The COMBINE Programme removes regulatory hurdles that delay the integration of:
- Companion diagnostics: Ensuring that innovative treatments are paired with advanced diagnostics for targeted patient care.
- Advanced therapies: Supporting innovative combined treatments for diseases such as cancer, cardiovascular conditions, and rare diseases.
By addressing these challenges, the EU fosters a dynamic environment where innovation can thrive across sectors, benefiting both industry and patients.
3. Supporting Small and Medium Enterprises (SMEs)
The COMBINE Programme simplifies regulatory pathways, which is particularly critical for SMEs in the MedTech and pharmaceutical sectors. These companies often face resource constraints when navigating complex regulations. By providing:
- Clear guidance on the interface between CTR, MDR, and IVDR.
- Access to advisory services for combined studies.
- Predictable timelines through harmonised processes.
The programme ensures SMEs can bring innovative products to market faster, strengthening Europe’s innovation ecosystem.
Delivering Economic and Healthcare Benefits
The successful implementation of the COMBINE Programme will not only drive regulatory efficiency but also deliver far-reaching benefits across Europe:
Economic Growth:
- Attracting more clinical trials and combined studies generates investments in research and development, boosting the EU economy.
- Improved innovation pathways strengthen the global competitiveness of EU-based manufacturers and sponsors
Healthcare Advancements:
- Patients benefit from accelerated access to cutting-edge treatments that combine medicinal products, medical devices, and diagnostics.
- A harmonised system ensures safer, more effective healthcare solutions reach the market efficiently.
For a European SME developing an innovative therapy paired with a diagnostic IVD, the streamlined approval process reduces delays, allowing faster market entry and broader patient access.
The EU’s Vision for Clinical Research Leadership
Through the COMBINE Programme, the European Union reaffirms its commitment to fostering innovation, supporting collaboration, and maintaining its position as a global leader in clinical research. By addressing regulatory inefficiencies and harmonising processes, the programme ensures that Europe remains an attractive hub for sponsors, manufacturers, and researchers driving the next generation of medical advancements.
Key Takeaway
The COMBINE Programme is a critical initiative that strengthens Europe’s competitive edge in clinical research. By simplifying pathways for combined studies, fostering innovation, and aligning with strategic goals outlined in the Draghi Report, the programme sets the stage for economic growth, global leadership, and improved patient outcomes across the EU.
Implementation and Next Steps for the COMBINE Programme
The successful roll-out of the COMBINE Programme requires a structured, phased approach to ensure that its ambitious goals are achieved efficiently and effectively. By leveraging cross-sector collaboration, pilot projects, and continuous evaluation, the programme sets the stage for lasting regulatory improvements across the EU.
COMBINE Programme Phased Rollout
The COMBINE Programme will be implemented in three key stages over the coming years:
1. Stage 1: Pilot and Early Initiatives (2024–2025)
Key Focus:
- Launch the pilot for a single assessment process for combined studies involving medicinal products and medical devices across multiple Member States.
- Initiate harmonisation efforts for Serious Adverse Event (SAE) reporting, streamlining processes under the CTR, MDR, and IVDR
Actions:
- Identify candidate combined studies for the single assessment pilot.
- Establish cross-functional task forces to develop and test harmonised SAE reporting frameworks.
Outcome: Early learnings from pilot initiatives will inform best practices and provide actionable insights for scaling solutions across the EU.
2. Stage 2: Scaling and Integration (2025–2026)
Key Focus:
- Expand successful pilot initiatives, integrating the single assessment process into broader multi-country studies.
- Strengthen cross-sector collaboration by enhancing knowledge exchange between national authorities and ethics committees.
Actions:
- Roll out the harmonised assessment framework to additional Member States.
- Launch training programmes to support national authorities, ethics committees, and sponsors in implementing new processes.
- Develop and publish clear interface guidance to resolve ambiguities between CTR, MDR, and IVDR.
Outcome: A more unified and harmonised approach to combined studies across Member States, improving regulatory efficiency and reducing delays.
3. Stage 3: Full Implementation and Evaluation (2026–2027)
Key Focus:
- Achieve full implementation of the programme’s objectives, ensuring long-term sustainability and continuous improvement.
- Monitor progress and evaluate the impact of the COMBINE Programme on EU clinical research and innovation.
Actions:
- Conduct comprehensive evaluations of the programme’s milestones, assessing its success in streamlining combined studies and supporting stakeholders.
- Strengthen engagement with sponsors, clinicians, and patient representatives to identify opportunities for further refinement.
- Publish progress reports to share achievements, challenges, and next steps.
Outcome: A fully harmonised regulatory framework that makes the EU a global leader in supporting combined studies of medicinal products, medical devices, and diagnostics.
Key Stakeholders Driving Implementation
The successful implementation of the COMBINE Programme depends on collaboration among a wide range of stakeholders, including:
- National Competent Authorities (NCAs): Leading the development and execution of pilot initiatives and harmonised frameworks at the Member State level.
- European Medicines Agency (EMA): Providing regulatory expertise, scientific consultation, and coordination for multi-country studies.
- Ethics Committees: Aligning ethical review processes with the programme’s streamlined assessment objectives.
- Sponsors and Manufacturers: Engaging in pilot studies, providing feedback, and adopting new processes to improve study timelines and regulatory compliance.
- Clinicians and Patient Representatives: Contributing real-world perspectives to ensure that the programme prioritises patient safety and healthcare innovation.
Monitoring Progress and Ensuring Accountability
To ensure the COMBINE Programme delivers its objectives, robust monitoring and evaluation mechanisms will be implemented:
- Regular Progress Reports: Published at key milestones to assess the programme’s impact, identify challenges, and showcase achievements.
- Feedback Loops: Stakeholder input, including sponsors, NCAs, and ethics committees, will be collected to refine processes and address emerging issues.
- Performance Metrics: Defined to measure success, including:
- Reduction in approval timelines for multi-country combined studies.
- Increased consistency in serious adverse event reporting.
- Improved clarity on the interface between clinical trials and medical device regulations.
Building a Sustainable Future for Combined Studies
The COMBINE Programme is not just a short-term solution but a long-term framework for driving innovation and efficiency in EU clinical research. By fostering collaboration, aligning processes, and prioritising continuous improvement, the programme ensures that Europe remains at the forefront of healthcare innovation.
What’s Next for Stakeholders?
As the COMBINE Programme progresses, stakeholders can expect:
- Opportunities to Participate in Pilots: Sponsors and manufacturers are encouraged to engage with pilot projects for the single assessment process.
- Clearer Guidance: Publication of harmonised frameworks and interface clarifications to reduce regulatory ambiguity.
- Improved Communication: Enhanced dialogue between regulators, sponsors, ethics committees, and patient representatives.
By working together, all stakeholders can contribute to the success of the COMBINE Programme, ensuring it delivers its vision of a harmonised, streamlined regulatory environment for combined studies.
Key Takeaway: The phased implementation of the COMBINE Programme marks a transformative shift in the EU’s approach to combined studies. Through pilots, collaboration, and continuous evaluation, the programme sets the foundation for faster, more efficient approvals that benefit sponsors, regulators, and—most importantly—patients.
Conclusion: A Unified Vision for Combined Studies
The COMBINE Programme marks a pivotal step in the European Union’s commitment to creating a harmonised, efficient, and collaborative regulatory framework for combined studies. By addressing long-standing challenges at the intersection of the Clinical Trials Regulation (CTR), Medical Device Regulation (MDR), and In Vitro Diagnostic Regulation (IVDR), the programme sets a clear path toward innovation, competitiveness, and improved patient care.
Transforming Regulatory Efficiency
Through its seven cross-sector projects, the COMBINE Programme delivers concrete solutions to streamline combined studies:
- Simplifying approvals with a single assessment process for multi-country studies.
- Aligning serious adverse event (SAE) reporting across sectors to ensure safety and consistency.
- Clarifying regulatory interfaces to resolve ambiguities between clinical trials and device regulations.
- Fostering collaboration among national competent authorities, ethics committees, and stakeholders to promote knowledge exchange and efficiency.
These efforts reduce administrative burdens, harmonise timelines, and improve access to clear, actionable regulatory guidance.
COMBINE Programme Supporting Innovation and Competitiveness
By eliminating regulatory fragmentation and ensuring consistent, coordinated processes, the COMBINE Programme positions the EU as a global leader in clinical research and medical innovation.
- Sponsors and manufacturers benefit from faster approvals and streamlined pathways, enabling them to bring innovative treatments to market more efficiently.
- Patients gain quicker access to integrated healthcare solutions, including advanced therapies, medical devices, and companion diagnostics.
- National authorities and ethics committees operate within a more efficient, harmonised framework, reducing duplication and ensuring safety.
In alignment with the Draghi Report recommendations, the COMBINE Programme strengthens Europe’s competitive edge, attracting global investment and driving economic growth in the MedTech and pharmaceutical sectors.
Looking Ahead: A Future of Innovation and Collaboration
The COMBINE Programme is more than a regulatory initiative; it is a transformative vision for the future of clinical research in the EU. By fostering collaboration, harmonising processes, and streamlining combined studies, the programme paves the way for a new era of healthcare innovation.
As Europe continues to lead the charge in medical and clinical advancements, the COMBINE Programme will play a critical role in ensuring that innovative treatments reach patients faster, safer, and more effectively.
Key Takeaway: The COMBINE Programme unifies the efforts of regulators, stakeholders, and innovators to streamline combined studies, strengthen Europe’s leadership in clinical research, and deliver groundbreaking healthcare solutions to patients across the EU.
Call to Action for the COMBINE Programme
Are you planning or conducting a combined study involving medicines, medical devices, or diagnostics? The MDx team is here to help you navigate the complexities of the COMBINE framework. Contact us today to streamline your regulatory strategy and ensure the success of your combined study.
Get in touch with the MDx team now to accelerate innovation and bring your study to life!
