Team-NB clarifies CDx changes under IVDR Annex IX 5.2

November 11, 2025

What the new Team-NB paper covers

Team-NB has adopted an updated position paper (Version 2, 22 Oct 2025) clarifying which changes to companion diagnostics (CDx) under IVDR Annex IX, section 5.2 must be reported to the Notified Body (NB) and when consultation with the medicinal products authority (EMA or relevant national authority) is required. Under Annex IX 5.2(f), manufacturers must inform their NB before making changes that affect performance, intended use, or suitability of the device in relation to the medicinal product. The NB then decides whether a new conformity assessment is needed or a supplement to the EU technical documentation certificate is sufficient, and whether consultation with the medicinal products authority is required.

The paper also notes that manufacturers are responsible for determining if a change requires consultation and must document and justify a decision not to consult; justifications must be available to competent authorities on request. In general, a change that requires consultation should be considered reportable to the NB.

Legacy CDx under Article 110(3)

For legacy CDx (per MDCG 2022-8), significant changes to design or intended purpose cause loss of legacy status (per MDCG 2022-6) and trigger a new IVDR conformity assessment involving a NB and a consultation with the medicinal products authority.

How Team-NB categorizes changes (with examples)

The annex introduces a practical flow that first asks: Does the anticipated change affect the CDx’s suitability for the medicinal product? Depending on the answer, changes fall into three groups.

1) No EMA/National authority consultation required

(“NO” path in the flow; changes out of scope of medicinal product authority consultation)
Examples:

Change in critical raw material or its supplier
Platform transfer (e.g., validation on a new NGS platform)
Extension of CDx shelf-life
New supplier for a reagent
New place of market in distant sales

2) Follow-up consultation (supplement) — change within the scope of the original consultation

Examples:

New limitation in use of the CDx (e.g., cross-reactivity)
Medicinal product restriction impacting the CDx claim
Large-panel NGS tumour profiling device: addition of tissue type for an existing INN
Changes to analytical parameters of the CDx
Change in reagent presentation (e.g., liquid vs lyophilized) that impacts the CDx claim

3) Initial consultation (new conformity assessment) — change outside the scope of the original consultation

Examples:

Medicinal product extension impacting the CDx claim
Addition of a new sample type that changes intended purpose
Addition of a new/expanded target patient population
Large-panel NGS tumour profiling device: additional INNs after initial certification
Addition of additional mutations with outcome data

Important: Team-NB stresses that the annex examples are illustrative, and final determinations are case-specific based on detailed evaluation.

Practical takeaways for CDx teams

Treat changes that likely affect design or intended purpose as reportable and assess them with supporting evidence.
Document your consultation decision (including rationale for no consultation) and keep it ready for competent authorities.
For legacy CDx, avoid significant changes to design/intended purpose unless you’re prepared for loss of legacy status and a new IVDR assessment with consultation.
Refer to the EMA homepage (or relevant EU/EEA medicinal product authority) for process details on consultations.

Why this matters

This Team-NB paper gives CDx manufacturers and their partners a shared interpretation baseline with Notified Bodies and medicinal product authorities, reducing ambiguity around when to notify the NB and when to seek EMA/national consultation after a change. The included flow and examples help teams pre-classify changes and plan evidence/consultation pathways efficiently.

Need a CDx-focused partner?

If you’re planning or assessing CDx changes under IVDR and want a clear pathway through NB reporting and EMA/national consultations, talk to MDx CRO—a consultancy dedicated to companion diagnostics strategy, clinical evidence, and regulatory execution.

Written by:

Carlos Galamba

CEO

Senior regulatory leader and former BSI IVDR reviewer with deep experience in CE marking high-risk IVDs, companion diagnostics, and IVDR implementation.

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September 28, 2025

The IVDR Shift and What It Means for Clinical Laboratories

The in Vitro Diagnostic Regulation (IVDR) (EU) 2017/746 came into force on 26 May 2022, representing a paradigm shift for diagnostic testing in Europe. Its purpose is clear: ensure safety, traceability, and performance of all in vitro diagnostic devices (IVDs). Unlike its predecessor, the IVDD (98/79/EC), the IVDR applies far-reaching obligations not only to manufacturers but also to clinical laboratories that develop and use their own in-house IVDs (IH-IVDs).

A cornerstone of this new landscape is Article 5(5), which sets conditions under which health institutions may continue manufacturing and using in-house devices without CE marking. While this exemption acknowledges the clinical need for tailored diagnostics, it also imposes new responsibilities.

This blog provides a step-by-step readiness checklist for laboratories to guide you through the transition.

Step 1: Do You Know What Counts as an In-House IVD?

What exactly is an in-house IVD under the IVDR?

An in-house IVD (sometimes called a laboratory-developed test or LDT) is any in vitro diagnostic device manufactured and used only within a health institution, not supplied to another legal entity, and not manufactured on an industrial scale

Examples include:

PCR assays where the lab develops its own probes.
Custom-developed software tools for diagnostic interpretation.

Excluded are:

General laboratory supplies.
RUO (research use only) products – unless repurposed for diagnostic use. If an RUO product is used for diagnostic purposes (i.e., results are communicated to the patient for medical decision-making), it ceases to be RUO and must comply with IVDR Article 5(5), thereby becoming subject to the same obligations as an in-house IVD/LDT.
Commercially available CE-marked IVDs (which must be purchased and used as intended) – unless it is modified, combined or used outside it’s intended purpose.

Takeaway:

You must determine whether you are using an in-house IVD. If you are modifying, combining, or using CE-marked diagnostic tests outside their intended purpose, or if you are repurposing RUO products for diagnostic use, you must ensure compliance with Article 5(5).

Step 2: Is Your Laboratory Recognized as a Health Institution?

Who is entitled to the Article 5(5) exemption?

Only health institutions may use in-house IVDs. According to the IVDR, a health institution is an organization whose primary purpose is patient care or public health. This includes:

Hospitals
Clinical laboratories
Public health institutes

Importantly, the recognition of health institutions may depend on national legislation. For instance, some countries require formal registration or accreditation to benefit from Article 5(5).

Takeaway:

Always check your national laws to confirm whether your laboratory qualifies as a “health institution” and whether additional national restrictions or obligations apply.

Step 3: CE-Marked or In-House? Make a Strategic Choice

Should your lab buy CE-marked tests or continue with in-house ones?

Under IVDR, labs face a strategic decision:

Purchase CE-marked IVDs: These carry regulatory assurance but may not always exist for niche diagnostic needs, and market withdrawals could limit supply.
Develop and use in-house IVDs: Allowed under Article 5(5) if your lab demonstrates compliance with conditions (e.g., GSPR, QMS, technical documentation).

From 31 December 2030, labs must justify why an equivalent CE-marked device is not suitable if they want to continue using their in-house test (article 5(5)(g))

Takeaway:

Begin analyzing your portfolio now. Which tests could be replaced by CE-IVDs, and which must remain in-house due to clinical need?

Step 4: Do You Comply with General Safety and Performance Requirements (GSPR)?

What technical documentation requirements already apply?

Since 26 May 2022, all in-house devices must comply with Annex I of the IVDR (GSPR). This includes:

Risk management system covering patient, user, and use error risks.
Performance evaluation based on scientific validity, analytical performance, and clinical performance.
Traceability and identification (lot numbers, production dates).
Appropriate instructions for use and safety information

Takeaway:

Treat your in-house tests with the same rigor as CE-marked devices. Maintain documentation to always prove compliance with the GSPRs.

Step 5: Have You Implemented an Appropriate QMS?

What does IVDR require for quality management when operating under article 5.5?

Since 26 May 2024, labs must manufacture and use in-house devices under an appropriate Quality Management System (QMS). For in-house IVDs, this generally means compliance with EN ISO 15189 or equivalent national provisions

However, note:

ISO 15189 covers quality in medical laboratories but not necessarily manufacturing processes.
Therefore, supplement with elements of ISO 13485 for design and production control.
In addition, laboratories must address the QMS requirements described in Article 10(8) IVDR, which outline the minimal aspects of a system covering risk management, manufacturing documentation, monitoring, corrective actions, and communication with authorities.

Takeaway:

Expand your QMS to cover risk management, manufacturing documentation, monitoring, and corrective actions, and the additional QMS obligations set out in Article 10 IVDR. Note that ISO 15189 alone is not sufficient; relevant elements of design and manufacturing from ISO 13485 must also be considered, as the IVDR introduces further QMS requirements that must be fulfilled.

Step 6: Can You Provide a Public Declaration?

Do labs need to publish information about their in-house devices?

Article 5(5)(f) IVDR requires health institutions to draw up and make publicly available a declaration for each in-house device. This obligation has applied since 26 May 2024, following the end of the initial transition period.

What must the declaration contain? At minimum:

Name and address of the health institution manufacturing the device.
Details necessary to identify the device (e.g., designation, type, internal code).
A declaration of compliance with Annex I (GSPR), or where full compliance is not possible, a reasoned justification explaining the deviations.
Confirmation that the device is manufactured under an appropriate QMS.

This declaration must be kept up to date and made easily accessible, typically via the laboratory or hospital’s website This transparency ensures accountability and facilitates oversight.

Takeaway:

Prepare standardized declarations for each in-house device. A practical tool exists: the IVDR Taskforce Guidance on LDTs (2020) provides a template (Appendix B) for the declaration that can be directly adapted by laboratories.

Step 7: Are You Ready for Competent Authority Oversight?

What role do regulators play?

Competent authorities may request documentation or even audit your lab to verify compliance. Labs must be prepared to show:

Design, manufacturing, and performance documentation of their in-house devices.
Clinical justification for developing or using the test instead of a CE-marked alternative.
Ongoing performance review and vigilance records, including corrective actions and monitoring of clinical use.
Evidence of an appropriate Quality Management System (QMS), as required since 26 May 2024.

The degree of oversight varies across Member States. For example, Belgium and Ireland already operate registration portals where laboratories must register their in-house tests. In other countries, legislation is still under development (Spain) or practices remain vague.

Takeaway:

Anticipate audits. Keep a compliance file for each in-house IVD.

Step 8: How Will You Justify Non-Equivalence? (2030 Requirement)

What happens in 2030?

From 31 December 2030, labs must justify why the specific needs of their target patient group cannot be met by a CE-marked device – Article 5(5)(g).

This justification may be based on:

Technical aspects (e.g., higher sensitivity).
Biological aspects (e.g., pediatric vs adult reference ranges).
Clinical needs (e.g., unmet diagnostic gaps).

Takeaway:

Start now by mapping your portfolio and identifying tests likely to face challenges in proving non-equivalence.

Step 9: Do You Have the Resources?

Why are many labs struggling?

Challenges highlighted in recent analyses include:

Lack of dedicated regulatory staff.
Limited time and budget for documentation.
Unfamiliarity with regulatory terminology.

Takeaway:

Seek structured support, whether through consultants, digital tools, or peer networks, to avoid non-compliance.

Step 10: Checklist. Is Your Lab Ready?

Step 1: Perform a GAP Assessment

Map your current situation: List all in-house IVDs and how they are used in your lab.
Check national status: Verify if your institution qualifies as a “health institution” under national law, and review whether national legislation imposes additional obligations such as mandatory QMS accreditation (e.g., ISO 15189), registration of in-house IVDs with competent authorities, or other reporting requirements that go beyond the IVDR.
Compare requirements vs. practice: Review the IVDR Article 5(5) obligations and identify where your lab already complies (e.g., risk management, traceability) and where gaps exist (e.g., QMS documentation, technical documentation).
Prioritize risks: Highlight critical areas (such as missing QMS procedures or incomplete Annex I documentation) that could block compliance in an inspection.

Step 2 – Take Action to Close the Gaps

Strategic choice: Decide whether to replace tests with CE-IVDs or maintain in-house versions. Document the rationale.
Annex I (GSPR): Ensure all in-house IVDs comply with General Safety and Performance Requirements (effective since 26 May 2022).
Quality Management System: Implement or update your QMS to align with ISO 15189, supplemented with elements from ISO 13485 and Article 10(8) IVDR.
Compliance documentation & oversight readiness: Compile and maintain a compliance file for each in-house IVD, including full technical documentation (design, manufacturing, risk management, and performance evaluation). Ensure these files are audit-read and can be provided upon request by competent authorities.
Vigilance & corrective actions: Set up procedures for monitoring performance, handling incidents, and implementing corrective/preventive measures.
Public declaration: Draft and publish a declaration for each in-house device (mandatory since 26 May 2024). Use available templates from guidance.
2030 justification: Start documenting why no equivalent CE-IVD meets the needs of your patient population to support continued in-house use after 31 December 2030.

Closing Thoughts

The IVDR sets high expectations for laboratory-developed in-house IVDs, transforming informal diagnostic practices into rigorously controlled processes. While compliance requires effort, resources, and cultural change, it also strengthens quality, safety, and patient trust. For laboratories, the transition is not optional, it is an opportunity to embed regulatory excellence into daily operations and secure the future of innovative diagnostics. Are you ready for the IVDR transition? Start today with a gap analysis, QMS reinforcement, and documentation plan. The earlier you act, the smoother your path to compliance will be.

At MDx CRO, we specialize in helping clinical laboratories navigate the IVDR, from gap assessments to QMS implementation and technical documentation. We support laboratories in demonstrating compliance with Article 5(5) for in-house IVDs by assisting with:

Gap assessments: Mapping all in-house IVDs, comparing current practice with IVDR Article 5(5) requirements, and identifying compliance gaps.
QMS alignment: Extending ISO 15189-based systems with manufacturing and design elements from ISO 13485, plus additional QMS obligations under IVDR.
Technical documentation: Preparing complete compliance files per device.
Public declarations: Drafting and publishing Article 5(5)(f) declarations using recognized templates, ensuring accessibility and consistency.
Regulatory readiness: Preparing for competent authority oversight, including audits and requests for documentation.
Strategic portfolio decisions: Advising whether to replace tests with CE-IVDs or justify continued in-house use, including preparing 2030 equivalence justifications.
Vigilance systems: Setting up monitoring, incident reporting, and corrective/preventive actions in line with IVDR obligations.

Our team knows the pitfalls and the solutions. Let us support you in achieving full compliance. Contact us today to discuss how we can help.

Written by:

Hugo Leis, PhD

Training & Quality Manager

Quality & Training Manager and Senior IVDR consultant with expertise in CE marking, Clinical Laboratories, SaMD, Precision Medicine, Quality Assurance, and academic lecturing.

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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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MDCG 2020-16 Rev.3: IVDR Classification Rules

July 9, 2024

MDCG 2020-16 is a key document outlining the classification rules for in vitro diagnostic medical devices (IVDs) under the EU IVDR. Revision 3 of this guidance document introduces specific changes aimed at improving clarity and compliance within the IVD sector, thereby ensuring the safety and performance of devices placed on the market. By detailing the classification rules set out in Annex VIII of the IVDD, the document helps to resolve potential ambiguities, thereby facilitating a more effective application of the regulations.

This article is structured into two main sections: the first part outlines the specific updates and clarifications introduced in Rev.3 of the guidance; the second part provides an analysis of significant IVD categories including Companion Diagnostics (CDx), Next-Generation Sequencing (NGS), self-testing, and Near-Patient Testing (NPT) in the MDCG 2020-16.

Key Updates in MDCG 2020-16 Rev.3

Definition of ‘Kit’

A significant addition in Rev.3 is the formal definition of a ‘kit’, which states: “‘Kit’ means a set of components that are packaged together and intended to be used to perform a specific in vitro diagnostic examination, or a part thereof.”

Rule 3(a)

Now includes Monkeypox Virus in the list of examples.

Rule 4(a)

The MDCG 2020-16 rev.3 includes clarifications for self-testing IVDs.

Clarification in the classification for self-testing.

Devices for detecting pregnancy, fertility, and cholesterol levels in any specimen, along with those for glucose, erythrocytes, leukocytes, and bacteria in urine, are classified as Class B.
If a device detects both a Class C marker and a marker listed as an exception (Class B), the device will be classified as Class C according to implementing rules 1.8 and 1.9.
Devices meeting certain criteria under implementing rules 1.8 and 1.9 are classified as Class D, including self-testing kits for HIV detection from a fingerprick blood sample.

Information Society Services:

The updates clarify the role of information society services in self-testing, stating that devices intended for such services are considered self-testing devices when lay persons perform part of the testing procedure, like adding reagents or placing the specimen on a test cassette. Importantly, actions solely required for collecting the specimen or ensuring its integrity and stability do not qualify the device as for self-testing.

Standalone Specimen Receptacles:

The revisions specify that standalone specimen receptacles and kits intended solely for specimen collection by laypersons, even those offered through information society services, are not considered devices for self-testing.

Clarification in the examples

Meters and strips with integrated testing reagents for self-testing of capillary blood glucose are classified in Class C.
Devices intended to measure levels of calprotectin, where the lay person collects the stool specimen, performs the testing procedure using the test cassette, and sends an image of the result for interpretation by a healthcare professional, are also in Class C.
Self-testing kits for the detection of HIV antibodies from a fingerprick blood sample are classified in Class D.

Rule 5(c)

The guidance includes the rationale and additional examples.

Classification and Definition:

Specimen receptacles are defined as containers or tubes (evacuated or non-evacuated), which may be empty or prefilled with a fixative solution or other general reagent. These are intended for primary containment, preservation, transport, and storage of biological specimens such as cells, tissues, urine, and feces for the purpose of in vitro diagnostic examinations.
These receptacles are classified as Class A under IVDR, highlighting their fundamental role in sample collection without any integrated testing functions, ensuring the integrity and stability of the specimens.

Integration in Kits:

Specimen receptacles can be marketed as standalone devices or as components of kits intended for specimen collection or testing.
Kits intended for specimen collection must include at least one IVD component (the specimen receptacle) and may contain other non-IVD components. Such kits are typically classified as Class A, in alignment with the classification of the included specimen receptacle.

Actions by Users:

The use of these devices or kits may require actions by the user, such as mouthwash, gargling, pipetting, or buffer addition to ensure specimen integrity. These actions are defined in the instructions for use (IFU) and are not considered part of the testing procedure.

Market Placement and Combination Use:

Specimen receptacles and kits intended for specimen collection can be marketed separately but are intended to be used in combination with another IVD. In such cases, implementing rule 1.2 applies, and both the receptacle and the other IVD should be classified independently.
If a specimen collection kit is used by lay persons and includes steps that are part of the testing procedure, then the entire kit is considered a device for self-testing as per Rule 4. However, the specimen receptacle itself, within such a kit, is not considered a device for self-testing.

Examples Clarifying Usage and Classification:

Standalone Devices: Examples like a urine collection cup, stool container, saliva collection tube, or a blood spot collection card are all classified as Class A.
Kits for Lay Use: Standalone kits for layperson use, such as those for collecting saliva for SARS-CoV-2 detection or stool for fecal occult blood testing in colorectal cancer screening, are also in Class A. These kits may include additional components like a plastic stick for sample collection and a pre-filled tube for conservation and transport, yet still retain a Class A classification.

Rule 6

Includes a change in the example of the device intended for the detection of Influenza A/B virus, from non-pandemic to highly virulent.

Classification of Key Diagnostic Tools in the MDCG 2020-16 Rev.3

Next Generation Sequencing (NGS)

NGS technology plays a central role across various diagnostic applications within the MDCG 2020-16 Rev.3 document:

Companion Diagnostics (CDx) (Rule 3(f), Page 24): NGS is essential for identifying genetic variants that influence the efficacy of specific medical treatments, thereby supporting personalized medicine by enabling tailored therapeutic strategies.

Cancer Diagnostics and Staging (Rule 3(h), Page 27): NGS is utilized for comprehensive cancer screening, diagnosis, and staging. This involves detailed analysis of cancer-related genes, which is crucial for developing precise treatment plans and managing patient care effectively.

General Laboratory Use (Rule 5(a) and 5(b), Pages 40-41):

Rule 5(a): NGS is specifically mentioned in the context of “Library Prep reagents for the preparation of DNA for downstream analysis by NGS sequencing.” This example highlights the role of NGS in preparing genetic material for detailed analysis, reflecting its importance in the preliminary steps of genetic testing.
Rule 5(b): Instruments that enhance the utility of NGS, such as “PCR thermocyclers, sequencers for NGS applications, and clinical chemistry analyzers,” are listed. These devices are integral to executing NGS procedures, demonstrating the technology’s critical role in performing complex genetic analyses within laboratory settings.

Companion Diagnostics (CDx) in the MDCG 2020-16 Rev.3

Rule 3(f), Page 22: Companion diagnostics are defined as essential devices for the safe and effective use of corresponding medicinal products. These devices are crucial for:

Identifying patients who are most likely to benefit from a specific therapeutic product, thereby optimizing treatment efficacy.
Detecting risks of adverse reactions, crucial for minimizing potential negative effects from treatments.

CDx must be explicitly linked to a medicinal product identified by an International Non-proprietary Name (INN), emphasizing their integral role in targeted therapy regimes.

Rule 3(f), Page 22: This rule outlines the regulatory framework for CDx, highlighting their use before or during treatment. This flexibility allows for adjustments in therapy based on patient responses and biomarker changes over the course of treatment, ensuring ongoing efficacy and safety.

CDx have transformative implications across various medical fields:

Oncology: Tests like those for ALK protein or PD-L1 expression determine eligibility for targeted cancer therapies, significantly improving outcomes in conditions like NSCLC.
Chronic and Genetic Diseases: Genetic tests for mutations in genes such as DPYD help predict metabolism of drugs like fluorouracil, preventing severe side effects in metabolically compromised patients.

Page 24, Rule 3(f): MDCG 2020-16 Rev.3 provides several examples:

Genetic Variants: Devices that detect KRAS/NRAS variants are crucial for colorectal cancer treatment decisions.
Biomarker Detection: Immunohistochemical devices for PD-L1 help determine eligibility for immunotherapy in cancer treatment.
Next-Generation Sequencing (NGS): NGS-based CDx assess multiple genetic variants, aiding in comprehensive treatment decisions for multifactorial diseases.

Annex II: Decision Flowchart Rule 3(f): Includes a flowchart to assist in determining whether an IVD qualifies as a CDx. This tool is vital for navigating the regulatory landscape, ensuring correct classification and utilization in line with therapeutic contexts.

Self-testing references in the MDCG 2020-16

Rule 4(a) on Page 37: Self-testing devices are intended for use by laypersons and require designs that ensure ease of use, reliability, and accuracy. This rule ensures that these devices, used outside traditional clinical settings, meet rigorous safety standards to prevent misuse and potential harm.

Near-Patient Testing references in the MDCG 2020-16

Rule 4(b) on Page 39: Near-patient testing devices are classified distinctly to ensure they provide rapid and reliable results essential for immediate clinical decision-making. These devices are crucial in settings like emergency rooms or clinics where quick diagnostic information is vital.

Conclusion

MDCG 2020-16 Rev.3 introduces clarifications that enhance the regulatory framework for IVD devices within the EU.

By refining the definitions and classifications of key diagnostic tools, including Companion Diagnostics, Next-Generation Sequencing, self-testing, and Near-Patient Testing devices, this guidance ensures guidance for manufacturers and stakeholders.

Written by:

Alice Toomey-Smith

Regulatory Director, IVD

Quality & Regulatory Affairs leader with global IVD expertise, guiding products to compliance across EU IVDR, FDA & beyond.

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Clinical Evaluation of Orphan Devices: Navigating MDCG 2024-10

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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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IVDR Performance Studies and the ISO 20916:2024 Revision

April 2, 2024

ISO 20916: Introduction

ISO 20916, “Clinical performance studies using specimens from human subjects – Good study practice” was first published in 2019 and recently released as EN ISO 20916:2024 (European Standard) at the end of March 2024, harmonizing IVDR Performance Studies with this latest revision.

In the rapidly evolving landscape of in vitro diagnostic (IVD) medical devices, maintaining the highest standards of safety and performance is paramount. ISO 20916 stands as a cornerstone in this endeavor, providing a framework for the quality and reliability of IVDs used in clinical performance studies employing human subject specimens.

This standard encapsulates comprehensive practices for planning, designing, conducting, recording, and reporting clinical performance studies for IVD devices. It lays down the foundational principles and specifies general requirements aimed at assessing clinical performance and safety for regulatory purposes. It has been meticulously designed to ensure that IVDs meet stringent criteria, thereby safeguarding public health and enhancing patient outcomes. It is intended to aid regulatory compliance, ensuring studies yield robust, ethical, and reliable results.

MDx will host a live free webinar on “Preparing for IVDR Clinical Performance Studies under ISO20916 and the new annex ZA” on the 30th April 2024 at 5pm CET. Register here.

The importance of Annex ZA of ISO 20916:2024 in IVDR performance studies

At the end of March 2024, the IVD community witnessed a significant milestone with the publication of a new revision of ISO 20916 which harmonizes IVDR performance studies. While the standard was already referenced in the text of the IVDR, this revision is particularly notable for the inclusion of Annex ZA, which finally harmonizes the standard with the In Vitro Diagnostic Regulation (IVDR) (Regulation (EU) 2017/746).

This harmonization of performance studies marks a critical step in aligning the standard with the comprehensive requirements set forth by the IVDR, thus facilitating a more streamlined regulatory pathway for IVD manufacturers. The significance of Annex ZA cannot be overstated. It bridges the gap between ISO 20916 and the IVDR, providing a clear and actionable framework for manufacturers to achieve compliance.

The text of ISO 20916:2019 has been approved by CEN (the European Committee for Standardization) as EN ISO 20916:2024 without any modification. This inclusion is a strategic enhancement, reinforcing the standard’s relevance and applicability in the regulatory landscape.

Note: As of the date this article was written, the official recognition of ISO 20916:2024 as an IVDR harmonized standard for clinical performance studies in the European Union’s Official Journal was awaiting confirmation.

Success in IVD Clinical Performance Studies with MDx CRO

At MDx CRO, we navigate the complexities of IVDR and the latest ISO 20916 revision for in vitro diagnostic (IVD) studies with unmatched expertise. Our commitment to rigorous clinical operations ensures that every clinical performance study meets all regulatory standards, incorporating strategic risk management and adaptability for maximum compliance and integrity.

Partnering with us offers manufacturers a significant advantage, rigorously evaluating IVDs to ensure adequate performance and safety, a critical component of regulatory approvals.

Choose MDx CRO for excellence in IVD clinical performance studies, driving success and enhancing patient outcomes. Contact us for a discussion today!

Highlights from Annex ZA include:

Presumption of Conformity: Compliance with the normative clauses of ISO 20916, as specified in Table ZA.1, confers a presumption of conformity with the corresponding GSPRs of the IVDR. This presumption is a testament to the robustness of the standard in meeting regulatory expectations.
Definition Clarification: Where differences arise between definitions in ISO 20916 and those in the IVDR, Annex ZA ensures clarity by highlighting these differences. The annex prioritizes the definitions set out in the IVDR, underscoring the regulation’s primacy.
Risk Management Alignment: The annex emphasizes the necessity of aligning the risk management process in EN ISO 20916:2024 with the IVDR. This alignment ensures that risks associated with IVDs are “reduced as far as possible”, in accordance with the regulation’s stringent requirements. In addition, ISO 20916 does not include foreseeable misuse in the risk management process, as required by IVDR.
Manufacturer’s Policy on Acceptable Risk: Annex ZA clarifies that the manufacturer’s approach to determining acceptable risk must adhere to specific GSPRs (i.e. 1, 2, 3, 4, 5, 8, 10, 11, 13, 15, 16, 17, 18 and 19) outlined in the IVDR. Furthermore, when reducing risks, sponsors, CROs, manufacturers and other stakeholders should note that while ISO 20916 does not include user training as a risk reduction measure, this is indeed allowed under IVDR.

Synergies between ISO 20916 and IVDR:

IVDR clinical performance parameters: Generally aligned between ISO 20916 and IVDR, however note that ISO 20916 does not mention “expected values in normal and affected populations” as a clinical performance parameter.
Ethical considerations: Generally aligned but ISO 20916 is a lot more prescriptive when compared to IVDR, defining ethical considerations and responsibilities for all parties involved, including principal investigators and sponsors.
Measures to minimise bias in study design: ISO 20916 further defines specific areas that should be considered when avoiding bias, including population bias, bias in the test protocol, bias in the reference measurement procedure, etc.
Site qualification: ISO 20916 provides a more detailed framework for site qualification, covering several criteria, including investigator qualifications, adequate resources and facilities, validated equipment , lab’s quality management system etc.
Clinical performance study report (CPSR): ISO 20916 is in general a lot more prescriptive on the contents of the clinical performance study report. Additional requirements are provided for interventional and other performance studies involving risks to the subjects.
Comparator devices used in an IVD performance study: Generally aligned, but ISO 20916 defines further how comparator IVDs should be listed, including their commercial name, manufacturer and catalogue number for example.
Investigators Brochure (IB) for Annex XIV studies: both IVDR and ISO 20916 are aligned. Annex C in ISO 20916 is dedicated to the contents of the IB. In addition ISO 20916 is a lot more prescriptive than IVDR on requirements related to risk management and risk-benefit analysis that need to be described in the CPSP and IB.

Differences to be aware of:

Differences in Annex XIV studies (and IVDR article 58): The definitions of an Annex XIV study in IVDR (i.e. interventional and other performance studies involving risks to the subjects) are different from ISO 20916. Although Annex ZA considers both the standard and regulation to cover the same elements and therefore being aligned, the description of what is in essence an Annex XIV study is different when we look at the detail. For example, the IVDR recognizes surgically invasive sample taking as being an Annex XIV study, while ISO 20916 does not use this terminology.
Adverse events: Although both IVDR and ISO 20916 are considered aligned, there are differences in the categorization of adverse events occurring in clinical performance studies. ISO 20916 provides two main types of events: non-device-related and device-related, and further categorizes this into non-serious and serious, anticipated, and non-anticipated. The IVDR is not as prescriptive in this area.
Clinical performance study plan (CPSP): ISO 20916 is more prescriptive on the specimen details to be listed in the CPSP, including their storage. In addition, ISO 20916 does not require reference to the current state of the art in diagnosis and/or medicine, whereas this is a requirement from IVDR. Last but not least, ISO 20916 has specific requirements for the CPSP synopsis.
Monitoring plan: ISO 20916 is a lot more prescriptive on the requirements for the monitoring plan, including qualification and training of monitors. According to ISO 20916 sponsors can also develop a rationale for remote monitoring. In addition, whereas IVDR requires that sponsors appoint a monitor independent of the investigation site, this point is not mandated by ISO 20916.
Informed Consent: A lot more detail is provided in ISO 20916 when compared to IVDR. The standard offers a detailed framework for obtaining informed consent.

Who Benefits from EN ISO 20916:2024?

Manufacturers of in vitro diagnostic medical devices
In vitro diagnostic clinics and laboratories
Test centres for in vitro diagnostic medical devices
Regulatory authorities
IVDR Notified Bodies
IVD Clinical research organizations (CROs)
Investigators and sponsors

Advantages of Adopting EN ISO 20916 for IVD Performance studies

Robust Results: It ensures high-quality, accurate, and reliable data generation, pivotal for safe healthcare decisions.
Ethical Standards: It upholds the rights, safety, dignity, and well-being of study subjects.
Study Planning and Conduct: It facilitates the meticulous planning and execution of IVD performance studies, ensuring regulatory and ethical compliance alongside scientific validity.
Compliance and Clarity: It provides a framework for compliance with IVDR, clarifying roles and responsibilities of all parties involved.
Risk Management: It emphasizes subject safety, especially regarding specimen collection risks, and ensures data integrity.

Implications for IVD Performance Studies and CRO Services

The integration of ISO 20916 with the IVDR, highlighted by the inclusion of Annex ZA, significantly transforms IVD clinical performance studies and CRO operations. This crucial alignment demands a comprehensive revision in study design, execution, and reporting methodologies, highlighting the importance of compliance with the unified ISO 20916 and IVDR standards. It emphasizes the need for robust quality and risk management systems and ethically responsible study development.

This evolution signifies more than standard adherence; it represents a commitment to elevating IVD performance and efficacy in line with the highest EU regulatory standards. It requires IVD stakeholders, including CROs, sponsors and manufacturers, to deeply understand and agilely apply these standards, not only for compliance but to set new quality and safety benchmarks in diagnostics.

This commitment is fundamental to advancing patient care and public health, marking a significant step forward in regulatory compliance and industry excellence.

Since its foundation, MDx CRO has consistently used ISO 20916 as the benchmark for all our IVD clinical performance studies. The release of Annex ZA and its harmonization with IVDR reinforces our status as the leading CRO for IVD clinical performance studies.

Written by:

Carlos Galamba

CEO

Senior regulatory leader and former BSI IVDR reviewer with deep experience in CE marking high-risk IVDs, companion diagnostics, and IVDR implementation.

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