Running Clinical Studies Under IVDR: What You Need to Know

September 28, 2025

The In Vitro Diagnostic Regulation (IVDR EU 2017/746) has redefined the requirements for bringing invitro diagnostic (IVD) devices to the European market. Compared with the previous IVD Directive, most devices are now subject to higher classification, more rigorous oversight, and stricter evidence requirements.

At the heart of these new obligations lies the clinical performance study. To comply with IVDR, manufacturers must demonstrate that their devices perform safely and effectively in real-world conditions. The standard ISO 20916:2024 sets the benchmark for conducting these studies to recognised international good practice.

In this article, we’ll explore what clinical performance studies are, why they matter under IVDR, the role of ISO 20916, and how manufacturers can successfully run studies to secure CE marking and maintain market access.

What Is a Clinical Performance Study?

A clinical performance study is an investigation carried out to establish how an IVD performs using human specimens. Unlike laboratory-based analytical performance tests, clinical performance studies focus on real-world clinical outcomes:

Does the device detect the intended condition accurately?
Does it provide reproducible and reliable results in the target population?
Is its performance clinically meaningful for diagnosis or monitoring?

In regulatory terms, clinical performance means the device’s ability to yield results that correlate with a specific clinical condition or physiological state. Under IVDR, Clinical Performance Studies provide essential evidence to confirm this performance.

Why Clinical Performance Studies Are Critical Under IVDR

The IVDR dramatically increases the need for robust clinical evidence:

Higher device classification – Many IVDs previously self-certified under the IVD Directive now require Notified Body review.
Performance evaluation requirements – Clinical performance is one of the three pillars of evidence (alongside scientific validity reports for EU IVDR submission and analytical performance) outlined in IVDR Article 56.
Regulatory approval and CE marking – Without a compliant Clinical Performance Study, manufacturers risk delays or refusal of certification.
Market competitiveness – Strong clinical data builds confidence with regulators, clinicians, and end-users.

Put simply: no strong clinical evidence, no EU market access.

The Role of ISO 20916

ISO 20916 provides the internationally recognised framework for running Clinical Performance Study.

The standard sets out requirements across the study lifecycle, including:

Planning: Protocol design, objectives, endpoints, sample size, and bias control
Ethics: Protecting participant rights, safety, and data privacy in line with the Declaration of Helsinki and GDPR
Conduct: Investigator qualification, site selection, specimen handling, and monitoring
Data integrity: Ensuring quality, traceability, and Good Clinical Practice oversight
Reporting: Producing structured, regulator-ready study reports

By following ISO 20916, manufacturers can ensure their Clinical Performance Study meet both IVDR requirements and global best practice. This reduces the risk of regulatory rejection.

Key Components of a Clinical Performance Study

1. Study Planning and Protocol Development

Every Clinical Performance Study begins with a comprehensive study protocol, which must define:

Study objectives and endpoints.
Target population and specimen types.
Statistical methodology and sample size.
Ethical and data protection considerations.

A strong protocol is the backbone of a successful Clinical Performance Study.

2. Regulatory and Ethical Approvals

Before starting, approvals must be obtained from:

Ethics committees – Ensuring participant protection.
Competent authorities – Depending on Member State requirements and risk of the study.

For example, interventional clinical performance studies require competent authority approval, whereas observational, non-invasive studies may only require ethics approval.

Timelines vary across the EU, so early planning is essential. MDx can act as your study legal representative in the EU.

3. Study Design Options

Common approaches include:

Prospective studies – Collecting new samples directly from participants.
Retrospective studies – Using existing, stored, or leftover samples.
Multicentre studies – Increasing robustness and diversity of data.

The chosen design must reflect the device’s intended use and risk class.

4. Specimen Management

The validity of results depends heavily on proper specimen handling. ISO 20916 requires:

Documented collection procedures.
Controlled storage and transport.
Full traceability from donor to result.

5. Data Capture and Monitoring

Accurate and reliable data is non-negotiable. Clinical Performance Study should use:

Validated electronic data capture systems.
On-site and remote monitoring.
Independent oversight where appropriate.

6. Statistical Analysis

Predefined statistical methods must cover:

Sample size calculations.
Handling of missing or invalid data.
Robust evaluation of endpoints.

7. Reporting and Submission

At study close, results are documented in a Clinical Performance Study Report (CPSR). This feeds into the Performance Evaluation Report (PER), a mandatory element of IVDR technical documentation reviewed by Notified Bodies.

Common Challenges in Running a Clinical Performance Study

Acoording to Floella Otudeko, many manufacturers encounter obstacles, including:

Navigating complex approval processes across different EU Member States.
Recruiting enough suitable participants within target populations.
Coordinating specimen collection, transport, and storage logistics.
Addressing GDPR compliance for personal and health data.
Aligning study expectations with Notified Bodies to avoid re-work.

Without careful planning, these issues can lead to costly delays.

Best Practices for Successful Clinical Performance Study

Where possible, engage early with regulators and Notified Bodies to avoid surprises.
Develop a robust protocol that anticipates operational and statistical challenges.
Invest in investigator training to maintain study consistency.
Implement real-time monitoring to catch issues before they escalate.
Document everything thoroughly for audit readiness.
Seek external expertise where internal resources are limited.

How a IVD MedTech CRO Adds Value

Running a compliant Clinical Performance Study is resource intensive. Partnering with a specialist consultancy like MDx CRO can help by:

Designing protocols aligned with ISO 20916 and IVDR requirements.
Managing submissions to ethics committees and competent authorities.
Overseeing study conduct across multiple sites and geographies.
Ensuring GDPR-compliant data management.
Engaging with Notified Bodies through structured dialogues to align on expectations early.

Leading to faster approvals, stronger evidence, and smoother market access.

Concluding Remarks

Running a clinical performance study under IVDR is not just a regulatory box-ticking exercise, it is the foundation of market approval and long-term trust in your device. ISO 20916 provides the global standard for good study practice, ensuring that evidence is ethically gathered, scientifically robust, and regulator ready.

For IVD manufacturers, the journey can be challenging, but with the right planning and support, it becomes an opportunity to demonstrate value, accelerate approvals, and build credibility with clinicians and patients alike.

As an experienced full service IVD MedTech CRO partner, MDx helps companies design, conduct, and report clinical performance studies. We pay special attention to meet both regulatory demands and business objectives. Whether you are preparing your first IVDR submission or adapting existing devices, our team provides the expertise and operational support you need to succeed.

Contact MDx CRO today to discuss your IVD Clinical Study needs.

FAQ

Do all IVDs require a clinical performance study under IVDR?

Not always. The need depends on the device’s risk class, intended use, and existing evidence. However, most devices now require stronger clinical evidence than under the previous directive, and many will need new or updated clinical performance data reviewed by a Notified Body.

What is the difference between analytical performance and clinical performance?

Analytical performance shows how well the test works in controlled laboratory conditions (accuracy, precision, limits of detection). Clinical performance demonstrates that the device’s results correlate with a specific clinical condition or physiological state in the intended population. Both are mandatory components of the IVDR performance evaluation, alongside scientific validity.

When is Competent Authority approval required?

Interventional clinical performance studies generally require approval from both an ethics committee and the relevant Competent Authority. Observational, non-interventional studies may only require ethics approval, depending on the Member State. Early planning is essential because timelines vary across the EU.

How does ISO 20916 support IVDR compliance?

ISO 20916 provides the internationally recognised framework for designing, conducting, monitoring, and reporting clinical performance studies. Following it helps ensure ethical conduct, data integrity, and regulator-ready documentation aligned with IVDR expectations.

What are the most common reasons studies face delays?

Delays often stem from incomplete protocols, misalignment with Notified Bodies, slow ethics or authority approvals, recruitment challenges, and GDPR-related data issues. Clear planning, predefined statistical methods, and strong documentation reduce the risk of rework.

What happens after the study is completed?

Results are compiled into a Clinical Performance Study Report (CPSR), which feeds into the Performance Evaluation Report (PER). The PER forms part of the IVDR technical documentation reviewed by the Notified Body for CE marking.

Can a CRO support the process?

Yes. A specialised IVD MedTech CRO can design IVDR-aligned protocols, manage regulatory submissions, oversee multicentre operations, ensure GDPR-compliant data management, and engage early with Notified Bodies—reducing risk and accelerating time to market.

Written by:

Floella Otudeko

Senior QARA Specialist

Senior QA/RA consultant with MDR, IVDR, Usability/Human Factors and MDSW expertise, supporting MedTech and IVD innovation globally.

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A CRO’s Guide to IVD Analytical Validation: Best Practices & Common Pitfalls

September 28, 2025

Mastering IVD Analytical Validation Under IVDR

Analytical validation is the cornerstone of in vitro diagnostic (IVD) development. Under the European Union’s In Vitro Diagnostic Regulation (IVDR; EU 2017/746), it provides evidence that an IVD device performs as intended—accurately, reliably, and consistently within its defined scope. For both CE-marking manufacturers and laboratories operating under Article 5(5), analytical validation sits at the center of the performance evaluation framework in Article 56 and Annex XIII.

Core Parameters of Analytical Performance

The IVDR requires a full demonstration of the analytical performance characteristics in Annex I, Section 9.1(a). These include:

Trueness (Bias): Closeness of agreement between measured values and a reference (ISO 5725-1; JCGM 200:2012).
Precision: Repeatability and reproducibility across instruments, operators, and time (CLSI EP05-A3; ISO 20776-2).
Accuracy: Combination of trueness and precision; essential for reliable results.
Analytical Sensitivity (Limit of Detection, LoD): Smallest analyte amount distinguishable from background (CLSI EP17; MM06).
Analytical Specificity: Ability to measure only the target analyte, avoiding cross-reactivity and interference (ISO 15193; CLSI MM09, MM26).
Linearity: Proportional response across a defined concentration range (CLSI EP06, EP10).
Limit of Quantification (LoQ): Minimum (and where relevant maximum) concentrations quantifiable with acceptable error.
Cut-off Values: Thresholds separating positive from negative results (CLSI EP12, EP24).
Reportable Range: Span of values that the assay can report reliably.
Metrological Traceability: Link results to references through a documented calibration chain (JCGM 200:2012).
Stability: Shelf-life and in-use stability (ISO 18113-1; EN ISO 23640).
Specimen Type & Stability: Validate all relevant sample types and storage conditions (CLSI M47).

If a parameter does not apply, provide robust justification. Regulators expect clear reasoning. Use harmonized standards and consistent definitions wherever possible. The CLSI Harmonized Terminology Database helps align terminology across documents and communications.

Challenges and Common Pitfalls

Ambiguity in Intended Use: Vague claims misalign studies and weaken evidence.
Suboptimal Study Design: Studies should be statistically powered with predefined acceptance criteria.
Uncontrolled Pre-analytical Variables: Validate collection, transport, and storage; justify them in the Performance Evaluation Plan (PEP).
Software Validation Gaps: Algorithm-driven IVDs require software lifecycle controls (IEC 62304; IEC 82304-1).
Inadequate Traceability: Link raw data to the Analytical Performance Report (APR) and Performance Evaluation Report (PER).
Lifecycle Oversight: Changes to reagents, software, or protocols may trigger revalidation. Maintain PMS and PMPF to stay compliant.

Strategic Solutions

At MDx CRO, teams combine regulatory, scientific, and statistical expertise to streamline analytical validation. Key services include:

Gap assessments against IVDR, MDCG, and CLSI guidance.
Custom analytical study design aligned with ISO 13485 and Annex XIII.
Software validation support with cybersecurity oversight.
Technical file preparation for Notified Body review.
Integration of PMS and PMPF into performance lifecycle management.

Conclusion

Analytical validation is more than a regulatory obligation—it forms the foundation of diagnostic credibility. When executed well, it shows that an IVD is accurate, safe, and clinically effective. With IVDR bringing heightened scrutiny, manufacturers should use clear definitions, rigorous justifications, and harmonized standards to achieve strong validation and long-term market success.

Need help building audit-ready analytical validation under IVDR? MDx CRO designs compliant studies, strengthens traceability, and prepares technical files for faster, smoother reviews. Contact us today.

Written by:

Marketa Svobodova, PhD

Regulatory Director, Precision Medicine

Expert in Precision Medicine, NGS & CDx, combining technical and regulatory expertise to guide IVDs through CE certification

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MDx CRO co-authors Journal of Liquid Biopsy paper on EU–US collaboration for IVDR-ready liquid biopsy validation

August 21, 2025

MDx CRO is proud to have contributed to the peer-reviewed article, “BLOODPAC’s collaborations with European Union liquid biopsy initiatives,” published in The Journal of Liquid Biopsy (Vol. 10, Article 100321; open access). The paper outlines practical pathways to align analytical validation, clinical performance evidence, and data standards that can accelerate European adoption of liquid biopsy under IVDR.

Carlos Galamba (CEO, MDx CRO) is listed among the authors, contributing European IVDR and clinical evidence expertise to this multi-stakeholder effort.

What the paper delivers (and why it matters)

Convergence on validation & evidence: It maps BLOODPAC’s US-developed minimum technical data elements and analytical validation protocols to EU needs—supporting more consistent clinical performance packages for IVDR submissions.
Data standards for reproducibility: The paper emphasizes fit-for-purpose standards and pre-competitive data sharing to improve comparability across clinical research for liquid biopsy, from cfDNA/ctDNA assay development to clinical use.
Practical EU–US collaboration: It proposes guidance and collaboration routes that can reduce variability across Member States and shorten time to patient access—without compromising IVDR rigor.

Read the Article (open access)

A broad coalition behind the work

The author affiliations span leading precision-medicine organizations and networks, including MDx CRO, Labcorp, Tempus AI, Natera, Exact Sciences, AstraZeneca, GSK, Bristol Myers Squibb, Johnson & Johnson, MSD, Thermo Fisher Scientific, TECAN, IQN Path, ELBS, EUCOPE, ISLB, Cancer Patients Europe, and BLOODPAC—a clear reflection of the field’s momentum toward shared, usable guidance.

Author list from the Journal of Liquid Biopsy paper showing MDx CRO (Spain) among affiliations

MDx CRO’s contribution and perspective

Through our CEO, Carlos Galamba, MDx CRO contributed to this multi-stakeholder paper outlining practical EU–US collaboration to accelerate liquid biopsy adoption under IVDR. Our perspective aligns with the paper’s focus on:

IVDR-first evidence architecture that cleanly links intended use → analytical validation → clinical performance requirements for ctDNA/cfDNA assays.
Harmonized validation expectations by mapping BLOODPAC frameworks and data elements to EU evidence needs, supporting consistent submissions.
Clearer regulatory narratives that connect validation outcomes to performance claims and real-world clinical implementation.

“This contribution reflects MDx’s commitment to turning shared frameworks into credible, IVDR-ready evidence that speeds responsible patient access” – Carlos Galamba, CEO

For IVD developers: immediate takeaways

Think trans-Atlantic. Where appropriate, re-use US learnings and BLOODPAC frameworks to reduce duplication—while meeting EU requirements.

Design for IVDR from day zero. Lock pre-analytical variables and analytical validation plans that ladder to clinical performance claims.

Adopt shared data elements. Standardized data models future-proof submissions and enable cross-study comparisons for regulators and payers.

How we execute: turning frameworks into IVDR-ready evidence

1) Study architecture (IVDR-first)

We design from intended use → analytical validation → clinical performance so claims, endpoints, and statistics line up from day one. For liquid biopsy (cfDNA/ctDNA), we predefine fit-for-purpose metrics (e.g., LoD/LoQ, precision, interference) and clinical endpoints (e.g., PPA/NPA, sensitivity/specificity).

2) Multisite execution (ISO 20916 aligned)

Feasibility and qualification of sites/labs, standardized pre-analytical controls (collection tubes, processing windows, storage), specimen logistics and chain-of-custody, risk-based monitoring, and documented deviation/CAPA management across centers.

3) Data you can trust (eCRF + eTMF)

We build validated eCRFs, enforce edit checks and audit trails, and maintain a complete eTMF/regulatory binder. Data dictionaries align with study objectives and, where appropriate, community data elements used in clinical research for liquid biopsy.

4) Analytical validation to clinical performance—without gaps

We run or coordinate liquid biopsy validation workstreams (method comparisons, reproducibility, cross-site concordance) and transition seamlessly into clinical performance studies so the evidence package is coherent under IVDR.

5) Reporting & regulatory narrative

IVDR-compliant documentation (Analytical Performance Report, Performance Evaluation Plan/Report, study reports), plus clear narratives that connect results to performance claims and labeling.

6) Governance & quality

Project governance with milestone dashboards, risk logs, vendor oversight, and audit-ready files under an ISO-driven clinical QMS.

Outcome: faster, cleaner submissions for IVDR liquid biopsy validation—and evidence that stands up to scrutiny.

Plan a study? Let’s map your assay’s intended use to the analytical validation and clinical performance evidence you’ll need.

Contact MDx today

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COMBINE Programme: Streamlining EU Combined Studies for Medicines, Devices, and Diagnostics

December 17, 2024

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!

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Clinical Evaluation of Orphan Devices: Navigating MDCG 2024-10

July 2, 2024

The Medical Device Coordination Group (MDCG) recently released guidance MDCG 2024-10, focusing on the clinical evaluation of orphan medical devices. This comprehensive guidance aims to address the unique challenges and regulatory requirements for orphan devices under the Medical Device Regulation (MDR) 2017/745. Orphan medical devices are intended for rare diseases or conditions, affecting a small patient population. This article delves into the key aspects of the new guidance, emphasizing the clinical evaluation processes and the implications for manufacturers.

Introduction to Orphan Devices

Orphan medical devices play a crucial role in providing diagnostic or therapeutic solutions for rare diseases or conditions, which often lack adequate medical alternatives. The MDR has stringent requirements for clinical evidence, which pose significant challenges for orphan devices due to their limited patient population and the ethical concerns surrounding clinical investigations in vulnerable groups, such as children.

Defining Orphan Devices

Orphan devices (OD) are defined as medical devices or accessories intended for the treatment, diagnosis, or prevention of diseases or conditions that affect no more than 12,000 individuals annually in the European Union. To qualify as an orphan device, the device must meet one of the following criteria:

There is an insufficiency of available alternative options for the treatment, diagnosis, or prevention of the disease or condition.
The device provides an expected clinical benefit compared to available alternatives or the current state of the art, taking into account both device-specific and patient population-specific factors.

Scope of Applicability for MDCG 2024-10

The MDCG 2024-10 guidance does not apply to the following types of devices:

Custom-made devices: According to EU MDR Article 2(3).
In-house devices: According to EU IVDR Article 5(5).
Products without an intended medical purpose: According to EU MDR Annex XVI.
In vitro diagnostic medical devices: Devices covered under the In Vitro Diagnostic Medical Devices Regulation (IVDR) 2017/746.

Evaluating Clinical Data Limitations

For orphan devices, it is acknowledged that the scarcity of available patients and the nature of the conditions often limit the amount of comprehensive clinical data that can be gathered pre-market. Therefore, the MDCG allows for certain limitations in pre-market clinical data under specific conditions:

There must be enough existing non-clinical and clinical data to suggest that the device can perform its intended purpose with an acceptable level of safety.
Any limitations in the clinical data must be transparently communicated to healthcare professionals and users.
The manufacturer must implement an effective post-market surveillance (PMS) strategy and post-market clinical follow-up (PMCF) plan to gather further data and validate the clinical performance and safety of the device post-launch.

Importance of Non-clinical Data for OD

Non-clinical data play a pivotal role in supporting the safety and efficacy of orphan devices, especially when clinical data are limited. This data can include:

Laboratory and animal studies that provide preliminary safety and performance insights.
Engineering and bench tests that demonstrate the device’s mechanical and functional integrity.
Computational modeling that predicts device behavior in various scenarios.

Manufacturers are encouraged to utilize robust non-clinical data to justify the safe use of their devices, reducing the reliance on extensive pre-market clinical trials which may not be feasible for orphan devices.

Expert Panel Consultation: Enhancing the Orphan Device Certification Process

Section 11 of the MDCG 2024-10 guidance outlines the role of expert panels in the evaluation process of orphan medical devices. This section emphasizes the importance of obtaining external expert advice to ensure that orphan devices meet stringent safety and efficacy standards before they reach the market. The involvement of expert panels is particularly crucial given the unique challenges associated with the development and evaluation of devices intended for rare diseases.

Purpose of Expert Panel Consultation

The consultation with expert panels serves multiple purposes:

Verification of Orphan Device Status: Expert panels assist in verifying the orphan status of a device, ensuring that the manufacturer’s justification aligns with the regulatory definitions and requirements.
Assessment of Clinical Evidence: Panels review the sufficiency and appropriateness of both clinical and non-clinical data to support the intended use of the device. This is especially critical when traditional clinical trial routes are impractical due to the rarity of the condition the device is designed to treat.
Guidance on Regulatory Compliance: Expert panels provide guidance on whether the device meets the overall regulatory requirements, including safety and performance standards outlined in the MDR.

Process of Expert Panel Involvement

Early Engagement: It is recommended that notified bodies engage with expert panels as early as possible, ideally during the pre-assessment phase of the device certification process. This early engagement allows for a structured dialogue between the manufacturer, the notified body, and the expert panel, facilitating a thorough and informed evaluation.
Review of Manufacturer’s Submission: The expert panel reviews the documentation provided by the manufacturer, focusing on the justification for the orphan device classification and the adequacy of the clinical and non-clinical evidence.
Issuance of Recommendations: Based on their review, the expert panel issues recommendations that can significantly impact the certification process. These recommendations might pertain to additional data requirements, modifications to the device or its intended use, or specific post-market surveillance strategies.
Influence on Notified Body Decisions: The advice provided by the expert panel is taken into consideration by the notified body in their final decision-making process. While the notified body is not bound to follow the panel’s recommendations, any deviations must be well justified in the assessment report.

Benefits of Expert Panel Consultation

The involvement of expert panels in the certification process of orphan devices brings several benefits:

Enhanced Device Safety and Efficacy: Expert panels contribute to a higher level of scrutiny, potentially increasing the safety and efficacy of devices approved for rare conditions.
Reduced Risk of Post-Market Issues: By addressing potential issues during the pre-market phase, expert panels help reduce the risk of significant complications once the device is in clinical use.
Increased Confidence Among Stakeholders: The input from expert panels can increase confidence among healthcare providers, patients, and regulatory bodies regarding the reliability and effectiveness of orphan devices.

Notified Bodies

Notified bodies play an essential role in determining whether a device qualifies as an orphan device before its certification. This critical initial assessment should be conducted as early as possible to ensure compliance and readiness for market entry:

Verification of Orphan Device Status:

The orphan status of the device should be verified at the earliest opportunity, ideally during a structured dialogue before or during the initial conformity assessment activities. This verification involves a thorough assessment of the evidence provided by the manufacturer, which must justify the classification of the device as an orphan, as detailed in section 4.2 of the guidance.

Assessment of Clinical and Non-clinical Data:

Notified bodies are tasked with evaluating the sufficiency and quality of both clinical and non-clinical data submitted by the manufacturer. This evaluation is crucial to ensure that, despite the acknowledged limitations typically associated with clinical data for orphan devices, there is robust evidence to demonstrate that the device can perform safely and effectively.

Compliance with Regulatory Requirements:

The review process must confirm that the device complies with all relevant regulatory requirements, with a focus on safety and performance standards as specified in the Medical Device Regulation (MDR).

Additionally, if applicable, notified bodies may take into consideration advice provided by an expert panel. This advice can significantly influence the assessment, particularly regarding the device’s status as an orphan and the adequacy of the clinical evidence. This expert input ensures a comprehensive review process, aligning the device assessment with the highest standards of regulatory compliance and patient safety.

Conclusion for the Clinical Evaluation of Orphan Devices

The MDCG 2024-10 guidance provides a structured approach for the clinical evaluation of orphan medical devices, balancing the need for clinical evidence with the practical challenges of studying rare conditions. By allowing for limitations in pre-market clinical data and emphasizing robust non-clinical evidence and post-market follow-up, the guidance aims to facilitate the market access of orphan devices, ultimately improving patient care for rare diseases. Manufacturers must navigate these requirements carefully, leveraging robust non-clinical data and detailed documentation, to ensure that orphan devices meet regulatory standards while addressing the unique needs of patients with rare conditions.

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MDR Investigator´s Brochure

June 22, 2024

Consolidating MDCG 2024-5 and ISO 14155 for Medical Devices

The MDR Investigator’s Brochure (IB) is a foundational document in clinical research for medical devices. Under the EU Medical Device Regulation (EU MDR) 2017/745, preparing an Investigator’s Brochure is a mandatory requirement for any clinical investigation. This document consolidates all relevant clinical and non‑clinical data about the investigational device and serves as the primary reference for investigators responsible for conducting MDR‑compliant clinical studies.

The purpose of the MDR Investigator’s Brochure is to ensure that every clinical investigation is supported by robust, transparent, and scientifically sound information. It provides investigators with the knowledge necessary to evaluate device performance, understand potential risks, and ensure patient safety throughout all study phases.

To meet MDR expectations, the IB must be developed in alignment with ISO 14155, the international standard governing Good Clinical Practice for medical device clinical investigations. ISO 14155 specifies how clinical studies must be designed, conducted, recorded, and reported, and the Investigator’s Brochure plays a central role in ensuring compliance with these principles.

In addition, MDCG 2024‑5 offers further guidance on the structure and content of the MDR Investigator’s Brochure. This MDCG document stresses clarity, completeness, and scientific rigor, ensuring the IB provides a comprehensive overview of the investigational device. It highlights the need for detailed information on device design, intended purpose, manufacturing, prior clinical experience, and risk–benefit considerations, elements essential for informed clinical oversight.

Beyond summarizing design and safety information, the MDR Investigator’s Brochure compiles clinical evidence from previous bench tests, preclinical studies, and human data (where available). This evidence synthesis supports ethical review, risk assessment, and regulatory submission, forming the backbone of a well‑prepared clinical investigations. plan. Ultimately, a high‑quality Investigator’s Brochure strengthens both regulatory compliance and patient protection, ensuring that investigational devices are evaluated responsibly and scientifically.

MDR investigator´s brochure: Regulatory Context and Importance

Regulated by EU MDR 2017/745

The European Union Medical Device Regulation (EU MDR) sets strict requirements for clinical investigations in the EU. Article 71.4 references the Investigator’s Brochure (IB) twice and clearly defines what it must contain.

According to this article, the IB must present comprehensive information about the investigational device. It should also reflect the current state of scientific knowledge. This ensures the device can demonstrate safety, performance, and clinical benefits during the investigation.

Article 71.4 explicitly requires a detailed description of the device. This includes its intended use, risk classification, design features, and manufacturing details. It must also include all necessary clinical and non‑clinical data available at the time of submission.

Together, these elements ensure the investigational device is properly assessed before and during clinical investigations. They also help investigators confirm that the device is used safely, consistently, and in line with MDR expectations.

Standardized by ISO 14155

ISO 14155 mentions the Investigator’s Brochure (IB) four times and sets the standard for good clinical practice in clinical investigations involving human subjects. It defines how studies must be designed, conducted, recorded, and reported.

In Section 6.5 and Annex B, ISO 14155 outlines the core requirements for the IB. It states that the IB must give principal investigators sufficient safety and performance data from pre‑clinical studies and previous clinical investigations. This information helps investigators understand the device and use it safely during the study.

Moreover, ISO 14155 requires that the IB remain continuously updated. As new, relevant information emerges during a clinical investigation, sponsors must revise the IB. This ensures the document stays accurate, current, and comprehensive throughout the study lifecycle.

Detailed in MDCG 2024-5

MDCG 2024‑5 provides detailed guidance on what the MDR Investigator’s Brochure must include to support a clinical investigation application. This document clarifies how sponsors should compile the IB so it fully meets regulatory expectations and facilitates an efficient review by competent authorities.

The guidance also stresses the importance of clear, balanced, and non‑promotional content. Using this approach ensures investigators receive reliable information and can make informed decisions about participating in the clinical investigation.

Structuring the MDR Investigator´s Brochure: A Detailed Approach

1. Device Description and Specifications

The detailed description of the investigational device forms a crucial part of the Investigator´s Brochure (IB). This section must provide a thorough overview of the device, including its design, operational mechanics, and the scientific rationale behind its development. The aim is to furnish investigators with the necessary information to understand the device’s functionality, potential clinical applications, and safety features.

General Information

Device Identification: This includes the official name, model number, and any other identifiers unique to the device. It’s essential to maintain consistency in terminology throughout the IB to avoid confusion.
Regulatory Status: Details about the device’s approval status, including whether it is under investigation or already approved for use in other contexts or regions. This should align with the regulatory requirements of the EU MDR and include any CE marking statuses.

Technical Details

Design Overview: A comprehensive description of the device’s design, highlighting any innovative features. This should cover the underlying technology, operational principles, and any software components integral to the device’s function.
Materials and Components: Detailed information about the materials used in the device’s construction, especially those in contact with patients. Information on biocompatibility must be included as per ISO 10993-1 standards, ensuring that all materials are safe for intended use scenarios.
Manufacturing Process: Insight into the manufacturing processes, including quality control measures and compliance with current good manufacturing practices (cGMP). This transparency helps assure investigators of the device’s reliability and consistency in production.

Operational Mechanics

Mechanism of Action: Explanation of how the device achieves its intended medical purpose. This includes a description of any mechanical, electronic, or biological actions that are central to the device’s operation.
Instructions for Use: Clear, step-by-step instructions on how the device should be operated during the clinical investigations, including setup, usage, and shutdown procedures, if applicable. This section should also address any training requirements for investigators or clinical staff.

Safety Features

Safety Mechanisms: Details of built-in safety features designed to protect the patient and user, such as automatic shut-offs, error alerts, and fail-safes.
Known Risks and Mitigation Strategies: An overview of identified risks associated with the device, along with strategies implemented to mitigate these risks. This should be directly linked to the risk management processes detailed in a later section of the IB.

This section of the IB serves not only to inform but also to build confidence among clinical investigators and regulatory bodies regarding the investigational device’s suitability for clinical investigations. By providing a clear and detailed description of the device, the IB helps ensure that all stakeholders have a deep understanding of the device’s capabilities, safety, and potential impact on patient health.

2. Clinical and Non-Clinical Data

This section of the IB comprehensively details the investigational device’s performance in both pre-clinical and clinical settings. It should offer a thorough summary of all relevant studies, ensuring that investigators have access to comprehensive data that supports the safety and performance of the device.

Pre-Clinical Studies

Overview of Studies: A summary of all pre-clinical studies conducted, including laboratory, in vitro, in vivo (animal studies), and any biomechanical or biochemical research relevant to the device’s intended use. This should include detailed results and interpretations.
Safety and Performance Data: Detailed findings from pre-clinical tests that assess the safety and performance of the device. This includes any biocompatibility testing done in accordance with ISO 10993, mechanical and durability testing, and any other relevant safety evaluations.
Regulatory Compliance: Explanation of how pre-clinical testing complies with relevant regulations and standards, including any deviations from standard protocols and justifications for such deviations.

Clinical Data

Summary of Clinical Investigations: A detailed account of previous and ongoing clinical investigations involving the device, including study design, methodology, sample size, duration, endpoints, and primary outcomes. This should include both published and unpublished data.
Safety and Performance Outcomes: Analysis of data related to the device’s safety and performance from clinical investigations, highlighting any significant adverse events, device deficiencies, and corrective actions taken.
Comparative Analysis: If applicable, comparative data from similar devices or previous versions of the same device, providing a contextual understanding of the investigational device’s performance.

Integration of Data

Data Correlation: Correlate pre-clinical findings with clinical outcomes to illustrate how earlier studies have informed clinical investigation designs and expectations.
Rationale for Clinical Investigation: Based on the integrated data, provide a comprehensive rationale for proceeding with further clinical investigations, outlining expected benefits, potential risks, and overall clinical value of the device.

Justification of Clinical Relevance

Scientific Literature: Review and summarize relevant scientific literature that supports the use, safety, and performance of the device. This should include any meta-analyses, systematic reviews, and key opinion papers.
Regulatory Considerations: Discuss any regulatory feedback or advisories that have impacted the clinical development of the device, including any special designations or regulatory pathways that are being utilized.

This section of the IB is critical for establishing the scientific and clinical foundation upon which the clinical investigation is based. It must convincingly demonstrate that the investigational device has been thoroughly evaluated in non-clinical settings and that the data derived from these evaluations justify its examination in human subjects. By providing clear, comprehensive, and scientifically sound data, this section helps ensure that the clinical investigation proceeds with a well-defined understanding of the device’s potential impacts on patient safety and performance.

3. Risk Management

Overview of Risk Assessment

Risk Identification: Detail all potential risks associated with the use of the device, derived from pre-clinical studies, historical data from similar devices, and initial clinical investigations. This should include both device-specific and procedure-related risks.
Risk Analysis: Evaluate the likelihood and potential impact of identified risks. Use qualitative and quantitative methods to assess how these risks could affect patient safety and the reliability of study results.

Risk Control Strategies

Risk Mitigation Measures: Outline specific strategies and actions taken to minimize identified risks. This includes design modifications, safety features integrated into the device, and specific procedural steps taken during clinical investigations to mitigate risks.
Monitoring and Reporting: Procedures for ongoing monitoring of risks throughout the clinical investigation. Detail how adverse events and device deficiencies will be recorded, analyzed, and reported. Include information on the data monitoring committee’s role and any interim analyses planned.

Documentation and Communication of Risks

Risk Communication Plan: Describe how information about risks is communicated to all stakeholders, including clinical investigation sites, investigators, and participants. Ensure that all parties are aware of potential risks and the measures in place to protect participants.
Training Programs: Detail training provided to clinical staff and investigators to recognize, manage, and report risks effectively. Training should cover the proper use of the device, recognition of adverse events, and emergency procedures.

Benefit-Risk Analysis

Overall Benefit-Risk Profile: Synthesize the benefits and risks of the device to demonstrate that the anticipated benefits outweigh the risks. This analysis should be based on data from pre-clinical and clinical studies and should be updated with new information obtained during the investigation.
Regulatory Compliance: Ensure that the risk management approach complies with ISO 14971, the international standard for the application of risk management to medical devices, and any specific regulatory requirements pertinent to the device.

Continuous Risk Management

Review and Update: Mechanisms for regularly reviewing and updating the risk management plan as new data become available or as circumstances change during the investigation. This includes planned revisions following interim analyses or in response to external factors such as newly published research or changes in clinical practice.

Risk Management Documentation

Documentation Standards: Maintain comprehensive documentation of all risk management activities, including assessments, decisions made, actions taken, and the rationale behind each decision. Documentation should be readily accessible and auditable.

This section of the MDR Investigator´s Brochure is essential for ensuring that all potential and actual risks are adequately managed throughout the clinical investigation. The risk management protects participants and also ensures the integrity of the clinical data and supports the ultimate goal of demonstrating the device’s safety and performance.

4. Regulatory and Compliance Information

Compliance with General Safety and Performance Requirements (GSPRs)

GSPR Alignment: List and describe how the investigational device complies with each of the applicable General Safety and Performance Requirements as outlined in Annex I of the EU MDR. This includes detailing the device’s design, manufacturing processes, and performance characteristics that ensure compliance.
Standards and Specifications: Identify all standards and Common Specifications (CS) applied during the device’s development and testing phases, such as ISO standards for medical devices, IEC standards for electrical devices, etc. Provide a justification for each standard’s application and describe how it contributes to the device’s compliance with the GSPRs.

Documentation of Compliance

Evidence of Compliance: Provide documentation or summaries of test results and analyses that demonstrate the device’s compliance with the aforementioned standards and requirements. This should include both pre-clinical and clinical data, as well as any data related to device modifications.
Notified Body Interaction: Detail interactions with Notified Bodies, including any conformity assessments or certifications obtained. This section should also cover the scope of the assessments, highlighting critical areas reviewed and any recommendations made by the Notified Body.

Regulatory Submissions and Approvals

Regulatory Filings: List all regulatory filings made for the device, including submissions to national and international regulatory agencies. Detail the status of these filings, any approvals received, and pending decisions.
Labeling and Instructions for Use: Ensure that the device’s labeling and instructions for use comply with regulatory requirements. Include information on language requirements, symbols used, and any specific labeling considerations for investigational use.

Compliance with International Guidelines

ISO 14155 Compliance for Clinical Investigations: Demonstrate how the clinical investigations comply with ISO 14155, which outlines good clinical practice for the design, conduct, recording, and reporting of clinical investigations performed on human subjects. Discuss any deviations from these guidelines and provide justifications.
Ethical Considerations: Address ethical considerations in compliance with the Declaration of Helsinki and local regulations where the clinical investigations are being conducted. Include information on ethical review board approvals, informed consent processes, and any other ethical safeguards in place.

Continuous Regulatory Monitoring

Monitoring Changes in Regulations: Establish a process for monitoring and responding to changes in regulatory requirements that could affect the ongoing clinical investigations. This includes updates to laws, guidelines, or standards relevant to the device or its clinical investigation.
Adaptation to Regulatory Changes: Describe the strategies for adapting the clinical investigation and documentation practices in response to regulatory changes. Ensuring ongoing compliance throughout the investigation’s duration.

This section of the MDR IB serves to assure all stakeholders. Including regulatory authorities, ethics committees, and clinical investigators, that the device meets all necessary safety, performance, and regulatory requirements for clinical investigation. It underscores the sponsor’s commitment to adhering to the highest standards of regulatory compliance and patient safety.

5. MDR Investigator´s Brochure Revisions and Updates

Update Procedures

Scheduled Updates: Define a schedule for regular reviews and updates of the IB. These should be strategically timed to follow major study milestones, such as the completion of certain phases or after significant data analysis points.
Trigger Events for Ad-Hoc Updates: Specify conditions or “trigger events” that necessitate immediate updates outside of the regular schedule. These may include significant adverse events, changes in regulatory requirements, or substantial amendments to the clinical investigation protocol.

Document Control and Version Management

Version Tracking: Implement a version control system to track all changes made to the IB. Each version should be clearly numbered and dated, with a summary of changes provided in each new version.
Archiving Procedures: Establish procedures for archiving superseded versions of the IB. This ensures that previous versions are accessible for reference or regulatory review, maintaining a complete history of document changes.

Communication of Updates

Notification System: Develop a systematic approach for notifying all stakeholders, including clinical investigation sites, ethics committees, and regulatory authorities, of updates to the IB. Notifications should detail the nature of the updates and their implications for ongoing clinical activities.
Training on Updates: Coordinate training sessions for all relevant clinical investigation personnel whenever significant updates are made to the IB. This ensures that all team members are informed about the latest device information, safety protocols, and compliance requirements.

Regulatory Compliance of Updates

Regulatory Submission of Updated IB: Outline the procedures for submitting updated versions of the IB to regulatory authorities as required by local regulations or international guidelines. Include timelines for submissions following significant changes or discoveries during the investigation.
Compliance Audits: Regularly audit the update and revision processes to ensure they comply with both internal quality standards and external regulatory requirements. Audits help identify and rectify any discrepancies or inefficiencies in the documentation process.

Feedback Mechanism

Stakeholder Feedback: Establish a feedback mechanism allowing investigators and other stakeholders to provide input on the IB’s content and layout. This feedback can be instrumental in improving the clarity and utility of the document.
Continuous Improvement: Use stakeholder feedback and audit outcomes to continually refine the update and revision processes. This ensures that the procedures remain effective and responsive to the needs of the clinical investigation and regulatory landscape.

This section ensures that the MDR IB remains a living document, reflective of the latest scientific knowledge and regulatory standards. By meticulously managing updates, ensuring comprehensive communication and training regarding these changes. Sponsors can maintain the document’s relevance and utility throughout the clinical investigation process.

In summary, the MDR Investigator´s Brochure must be actively managed to remain a current and compliant resource throughout the study. The processes outlined in this section provide a framework for achieving this, ensuring that the MDR IB continuously supports the safe and performance evaluation of the investigational device.

Key Insights

The Role of the MDR Investigator’s Brochure in Medical Device Research

The MDR Investigator’s Brochure is a central document in any clinical investigation for medical devices. Its purpose goes far beyond regulatory compliance. It equips investigators, ethics committees, and regulatory authorities with the information they need to understand the investigational device. With this shared knowledge base, stakeholders can make informed decisions that protect participants and ensure reliable, high‑quality clinical data.

A Dynamic and Evolving Document

The IB is not static. Instead, it must evolve throughout the clinical investigation. As new data, observations, or safety information emerge, sponsors must update the MDR Investigator’s Brochure accordingly. This continuous revision process ensures the document remains accurate, transparent, and aligned with current knowledge. It also reinforces trust among investigators, ethics committees, and regulators.

Integrating Multidisciplinary Expertise

Developing a robust MDR Investigator’s Brochure requires input from multiple disciplines. Engineering, clinical research, regulatory affairs, quality assurance, and risk management all contribute essential insights. This multidisciplinary collaboration ensures the IB is scientifically sound, comprehensive, and reflective of the latest advancements in both medical technology and clinical practice.

Commitment to Transparency and Investigator Education

The MDR Investigator’s Brochure also serves as a critical educational resource. It explains the device’s development history, intended purpose, mechanism of action, and supporting evidence. By presenting this information clearly and objectively, the IB promotes transparency and strengthens the trust of investigators, clinical staff, participants, and the wider public.

Future Considerations

As regulations and standards continue to evolve, the MDR Investigator’s Brochure must adapt. Future developments may include more accessible digital formats, interactive layouts, and harmonized content that supports multinational studies. Proactive updates will be essential as global regulatory expectations shift and clinical research models become more complex.

Conclusion

The MDR Investigator’s Brochure is more than a regulatory requirement—it is a vital tool that shapes the scientific, ethical, and operational quality of clinical investigations. A clear, current, and compliant IB helps sponsors streamline the investigation process, strengthens regulatory confidence, and ultimately supports the development of safe and high‑performing medical devices.

This article has outlined a structured and practical approach to building an Investigator’s Brochure that meets MDR expectations. By following these principles, sponsors can conduct clinical investigations with the highest standards of safety, performance, and data integrity.

Written by:

David Tomé

President

Clinical research leader and MedTech entrepreneur with deep expertise in medical devices, IVDs & precision medicine, with global study experience.

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