Author: Stuart Angell

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The Notified Body Conundrum: Navigating Regulatory Challenges in the IVD Industry

In the complex landscape of In vitro diagnostic regulation (IVDR), the role of Notified Bodies is crucial yet often misunderstood. These organisations are responsible for assessing the conformity of certain products before they can be marketed in the European Union (EU). However, the system is fraught with challenges.

Understanding Notified Bodies

Notified Bodies are independent organisations designated by EU member states to assess the conformity of products with the applicable regulatory requirements. They play a pivotal role in ensuring that products are safe and effective for use. Their responsibilities include conducting audits, reviewing technical documentation, and performing product testing. Notified Bodies are used for a wide range of European Regulations, including for medical devices and IVDs. This is important to note if a device comes under a number of Regulations, the EU AI Act for example, where an NB is required not just for the IVDR.

Notified Bodies are assigned a Notified Body Code which should be included next to the CE mark of a device placed on the EU market under IVDR (e.g. NB 0123 TUV SUD Product Service GmbH). This way the user can easily identify who has completed the conformity assessment for the device.

In my experience, engaging with a Notified Body is a positive experience, if you plan correctly. Let’s face it, we all want the same thing: to bring safe and effective IVDs to market within an efficient process compliant to the regulation.

The Conundrum

The conundrum arises from several interrelated issues:

1. Limited Capacity

Although the number is increasing, there is still a limited number of Notified Bodies, and their capacity is often stretched thin. This can lead to delays in the certification process, impacting the time it takes for new medical devices to reach the market.

2. Stringent Requirements

The introduction of the In Vitro Diagnostic Regulation (IVDR) has significantly increased the regulatory requirements. Notified Bodies must now adhere to more stringent criteria, which has further strained their resources.

3. High Demand

The demand for Notified Body services has surged, partly due to the increased regulatory requirements and partly due to the growing number of medical device manufacturers seeking certification. This high demand exacerbates the capacity issues.

4. Complexity of Assessments

The assessments conducted by Notified Bodies are complex and require a high level of expertise. This complexity can lead to longer assessment times and higher costs for manufacturers.

Impact on the Industry

The Notified Body Conundrum has several implications for the medical device industry:

Market Delays

Delays in the certification process can slow down the introduction of innovative medical devices, potentially impacting patient care and the competitiveness of manufacturers.

Increased Costs

The complexity and length of the certification process can lead to higher costs for manufacturers, which may be passed on to consumers.

Regulatory Uncertainty

The evolving regulatory landscape and the challenges faced by Notified Bodies can create uncertainty for manufacturers, making it difficult to plan and execute product development strategies.

Potential Solutions

Addressing the Notified Body Conundrum requires a multifaceted approach:

1. Harmonising Assessment Approach

Greater harmonisation of conformity assessment across the EU NB could help reduce the complexity of assessments and improve efficiency.

2. Leveraging Technology

The use of advanced technologies, such as artificial intelligence and machine learning, could help streamline the assessment process and reduce the burden on Notified Bodies.

3. Structured Dialogue

The utilisation of Structured Dialogue before and during the conformity assessment process improves the efficiency and predictability of the conformity assessment process. From my experience, this offers valuable insights into the expectations of the NBs as part of the conformity assessment journey. Note: this dialogue should not be used for getting consultancy from the NBs.

UK Approved Bodies

The UK follows a similar approach where the MHRA recognise a series of Approved Bodies. The list of approved bodies can be found on the MHRA website. While many EU Notified Bodies have a UK Approved Body, there are less ABs to choose from. At the time writing, there are 6 IVD UK Approved Bodies under the UK Medical Device Regulations (2002).

Note: This applies to Great Britain only, Northern Ireland come under the EU IVDR.

My top tips on engaging with a Notified Body

When preparing for conformity assessment, I would recommend the following:

  • Early engagement with a notified body is key.
  • Understand your device and its intended purpose before you make the NB application. They will want to know what the device is as part of the initial discussion.
  • Don’t expect a quick turnaround. While initial engagement is generally quick and positive, most of the time is spent by the manufacturer understanding the device and gathering information (see bullet point 2)
  • Be aware of costs and budget properly. The process isn’t cheap and requires significant investment of time.
  • Don’t rush the technical documentation. The technical documentation you provide should be your best work, not throw it in and see.

Conclusion

The Notified Body Conundrum presents significant challenges for the medical device industry, but it also offers an opportunity for innovation and improvement. Don’t be afraid of engaging with a Notified Body but take your time to find the best fit for your organisation and product. There is more choice available, with a greater amount of information and guidance to support the industry bring new products to market or maintain market access for legacy products.

If you need support, selecting, engaging, or building documents ready for conformity assessment, IVDeology is well placed to support you and your organisation bringing devices onto the EU and UK market.

Contact us for more information [email protected].

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Building an IVD regulatory strategy that scales – from start up to enterprise

Creating a scalable In Vitro Diagnostic (IVD) regulatory strategy is crucial for companies aiming to transition from startup to enterprise. This journey involves navigating complex regulatory landscapes, ensuring compliance, and maintaining flexibility to adapt to evolving requirements.

Also read: Regulatory Strategy, what is it and why do you need one?

Understanding IVD Regulatory Landscape Early

In Vitro Diagnostics (IVDs) are medical devices used to perform tests on samples taken from the human body, such as blood or tissue. These devices are essential for diagnosing diseases, monitoring health conditions, and guiding treatment decisions. The regulatory landscape for IVDs varies significantly across regions, with stringent requirements in place to ensure safety and efficacy.

In many cases with our IVDeology customers, the regulatory pathway is only considered part way through the development process. This is especially true for combination or companion diagnostics (CDx). The reality is, the earlier the path to compliance is understood and planned, the greater chance of success.

Figure 1 Considerations for building an effective regulatory strategy

Building a Scalable Regulatory Strategy

1. Early Engagement with Regulatory Authorities/Notified Bodies

Engaging with regulatory authorities and or Notified Bodies early in the development process is crucial. This helps in understanding specific requirements, obtaining guidance, and identifying potential challenges. Early engagement can also facilitate smoother approval processes and reduce time-to-market. For the US market, the FDA Q-Submission or Pre-Sub process, allows direct communication with the regulator to discuss your regulatory journey.

2. Risk-Based Classification

Understanding the risk classification of your IVD is fundamental. Different classes have varying requirements for clinical evidence, manufacturing practices, and post-market surveillance. Accurately classifying your IVD ensures that you meet the necessary regulatory standards without overburdening your resources.

In cases of a software as a medical device (SaMD) or IVD, you may have different components of the software which are IVDs, Medical Devices, or none of the above, so effective classification based on the intended purpose is key.

3. Robust Quality Management System (QMS)

Implementing a robust Quality Management System (QMS) is essential for ensuring compliance and scalability. A QMS should cover all aspects of the product lifecycle, from design and development to manufacturing and post-market activities. ISO 13485 is the internationally recognized standard for QMS in medical devices, including IVDs.

4. Clinical Evidence and Performance Evaluation

Generating clinical evidence and conducting performance evaluations are critical components of the regulatory strategy. This involves designing and executing clinical studies to demonstrate the safety and efficacy of the IVD. The data collected should be comprehensive and meet the requirements of the relevant regulatory jurisdictions.

5. Regulatory Submissions and Documentation

Preparing regulatory submissions and documentation is a meticulous process. This includes compiling technical documents, clinical study reports, risk management documents, and labeling information. Ensuring that all documentation is clear, organised, readily searchable and unambiguous is vital for successful approval.

6. Post-Market Surveillance and Vigilance

Post-market surveillance is an ongoing process that involves monitoring the performance of the IVD after it has been launched. This includes collecting and analyzing data on adverse events, product complaints, and other relevant information. Implementing a robust vigilance system helps in identifying and addressing issues promptly, ensuring continued compliance and patient safety.

Scaling from Startup to Enterprise

Building a scalable IVD regulatory strategy requires a comprehensive approach that encompasses early engagement with regulatory authorities, robust quality management systems, clinical evidence generation, meticulous documentation, and ongoing post-market surveillance.

By investing in scalable infrastructure, staying informed about regulatory changes, fostering cross-functional collaboration, and prioritizing training and development, companies can successfully transition from startup to enterprise while ensuring compliance and patient safety.

This journey is complex but achievable with the right strategy and commitment to excellence. As the IVD industry continues to evolve, staying proactive and adaptable will be key to long-term success.

Our approach

We believe that the regulatory strategy is the beginning of our customers journey in developing a rounded, and critical assessment of the regulatory landscape specific to the devices they are intending to place on the market. While in most case, the output in provided in a report, this should be considered a live document, with frequent review and update. This step is critical as the device performance, intended purpose or safety may change, and the regulatory environment may shift requiring a realignment of the strategy for regulatory success.

For further information contact [email protected]

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The Medical Devices (Amendment) (Great Britain) Regulations 2025: The status quo continues

The UK Medical Device Regulation (MDR) 2002 is undergoing a number of incremental changes (rather than publishing a full new regulation) to update how medical devices and in vitro diagnostic medical devices (IVDs) are regulated. These amendments are designed to ensure the continued availability and safety of medical devices in Great Britain while fostering innovation and market stability.

The latest SI relates to the continued use of existing elements of the regulation, which were due to stop being used this month (the revocation date).

These Regulations amend the Medical Devices Regulations 2002 (S.I. 2002/618) (“the 2002 Regulations”) by removing the 25th and 26th May 2025 revocation dates of the following pieces of assimilated EU law:

  • Commission Decision 2002/364 (on common technical specifications for in vitro medical devices),
  • Commission Regulation (EU) No 207/2012 (on electronic instructions for use of medical devices),
  • Regulation (EU) No 722/2012 (concerning particular requirements as regards the requirements laid down in Council Directives 90/385/EEC and 93/42/EEC with respect to active implantable medical devices and medical devices manufactured utilising tissues of animal origin) and
  • Regulation (EU) No 920/2013 (on the designation and the supervision of notified bodies under Council Directive 90/385/EEC on active implantable medical devices and Council Directive 93/42/EEC on medical devices).

The SI came into force on 24th May 2025 and apply to England, Wales, and Scotland.

Common Technical Specifications

The EU Common Technical Specifications (TS) for In Vitro Diagnostic Medical Devices (IVDs) provide detailed rules for certain high-risk IVDs, including those detecting or quantifying infectious agents like HIV, hepatitis, and SARS-CoV-2, as well as blood grouping tests. The specifications outline performance, safety, and quality requirements that these devices must meet to ensure they are safe and effective for use.

While the is additional burden required for Class D devices, the provision of common specifications allow manufacturers to greater understand the strategy for demonstrating safety and performance requirements, which can become challenging for lower risk class C devices.

eIFUs

Commission Regulation (EU) No 207/2012 focuses on the provision of electronic instructions for use of medical devices. It applies to manufacturers of IVDs and medical devices who opt to provide instructions for use in electronic form instead of paper if applicable. The manufacturers must meet specific conditions, including ensuring the electronic instructions are accessible and reliable, and have a clear indication that instructions are provided electronically must be included with the device. The electronic instructions must be easily accessible to users, including healthcare professionals and patients.

By removing these revocation dates, the amendments aim to allow the continuation of use of these regulations for the UK market access. This approach marks a common-sense approach in the short term, the alternative would have been to have UK specific requirements on the above, with possible divergence from the EU. The outcome of the continued use supports the aim to safeguard public health and ensure that the benefits of these regulations continue to outweigh any potential risks.

For further information on the transitional process for UK MDR, Common Technical Specifications, or the use of electronic IFUs, please contact [email protected]

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Building IVD Compliance Pathways Through Effective Regulatory Strategies

Introduction

In vitro diagnostic (IVD) medical devices play a critical role in healthcare decision-making, influencing approximately 70% of all clinical decisions. As these technologies advance and global markets expand, navigating the complex regulatory landscape has become increasingly challenging for manufacturers. The path to compliance requires strategic planning, thorough understanding of regulatory frameworks, and implementation of robust quality management systems.

Effective regulatory strategies for IVD manufacturers seek to navigate compliance pathways efficiently and successfully bring their products to market across global jurisdictions, including UK, EU and USA.

The Evolving IVD Regulatory Landscape

IVDR in Europe: A Paradigm Shift

The European Union’s In Vitro Diagnostic Regulation (IVDR 2017/746) marked a significant evolution from the previous In Vitro Diagnostic Directive (IVDD 98/79/EC). This transition brought more stringent requirements, including:

  • Risk-based classification system (Classes A, B, C, and D)
  • Enhanced clinical evidence requirements
  • Increased post-market surveillance
  • Greater involvement of Notified Bodies
  • Unique Device Identification (UDI) implementation

The IVDR’s phased implementation continues to present challenges for manufacturers, particularly those with legacy products requiring recertification or first-time market entrants.

FDA Approach to IVDs

In the United States, the Food and Drug Administration (FDA) regulates IVDs as medical devices, categorizing them primarily through:

  • Class I: General controls (lowest risk)
  • Class II: Special controls and often 510(k) premarket notification
  • Class III: Premarket Approval (PMA) for highest risk devices

Global Harmonization Efforts

The International Medical Device Regulators Forum (IMDRF) continues to work toward harmonizing regulatory approaches worldwide. However, significant differences remain among jurisdictions, creating challenges for manufacturers pursuing global market access. The utilisation of IMDRF can be a valuable tool to develop a ‘one size fits all’ technical file – although this doesn’t quite work in practise. The Uks indication of using IMDRF principles is a welcome signal which may support future international recognition.

Building Strategic Compliance Pathways

1. Early Regulatory Strategy Development

Successful IVD manufacturers integrate regulatory planning into their product development lifecycle from inception. Key elements include:

  • Regulatory roadmapping: Documenting intended markets, timelines, and certification requirements
  • Classification determination: Early assessment of product risk classification across target jurisdictions
  • Regulatory intelligence gathering: Monitoring evolving requirements and guidance documents
  • Stakeholder alignment: Ensuring business, R&D, quality, and regulatory teams share understanding and objectives

Early strategic planning significantly reduces time-to-market and development costs by avoiding regulatory surprises and rework. It is important to consider the end goal – market access, and work backwards, when developing your design and development strategies.

2. Risk-Based Approach to Compliance

Implementing a risk-based approach aligns with modern regulatory frameworks and optimizes resource allocation:

  • Product risk classification: Understanding how regulatory bodies will classify your device
  • Risk management process: Implementing ISO 14971 principles throughout the product lifecycle
  • Benefit-risk analysis: Documenting how benefits outweigh residual risks
  • Risk-based quality management: Focusing QMS efforts proportionally to risk areas

This approach ensures compliance while maintaining operational efficiency. While this is a requirement to meet regulatory requirements, done right, this can add real value to the development and operational efficiency of IVD manufacturing in conjunction with ISO 13485

3. Building Robust Clinical Evidence

Enhanced clinical evidence requirements represent one of the most significant challenges in modern IVD regulation:

  • Scientific validity: Establishing the analyte’s association with clinical condition
  • Analytical performance: Demonstrating technical performance characteristics
  • Clinical performance: Providing evidence of clinical utility and outcomes
  • State-of-the-art analysis: Comparing performance against current alternatives
  • Literature-based strategies: Leveraging existing scientific literature effectively

For novel IVDs, well-designed clinical performance studies with clearly defined endpoints are increasingly essential.

4. Comprehensive Quality Management Systems

A robust QMS serves as the foundation for sustainable compliance:

  • ISO 13485:2016 implementation: Adopting the international standard for medical device QMS
  • Process approach: Defining interconnected processes with clear ownership
  • Design controls: Implementing systematic design and development procedures
  • Supplier management: Controlling purchased components and services
  • Post-market surveillance: Establishing vigilance and feedback systems

Integrated QMS software solutions can streamline documentation and enhance traceability across regulatory jurisdictions.

For the European Union (IVDR), Manufacturers are expected to have a compliant QMS to IVDR from June 2025.

5. Documentation and Technical File Preparation

Strategic documentation management is critical for efficient submissions:

  • Common Technical Documentation (CTD): Organizing technical files in internationally recognized formats
  • Modular approach: Designing core documentation adaptable to different jurisdictions
  • Traceability matrices: Ensuring regulatory requirements are comprehensively addressed
  • Gap analysis tools: Identifying and addressing documentation deficiencies

Electronic document management systems with regulatory intelligence capabilities can significantly enhance efficiency.

For the EU, many Notified Bodies provide guidance and template structures for how they expect to see Technical Documentation to be constructed. For classes B to D, it is recommended to engage with your NB early and understand their expectations of the conformity assessment process.

Advanced Regulatory Strategies for Complex Challenges

Companion Diagnostics

As precision medicine advances, companion diagnostics face unique challenges requiring coordinated regulatory strategies:

  • Drug-diagnostic co-development: Aligning timelines with pharmaceutical partners
  • Combined submissions: Navigating coordinated reviews between device and drug divisions
  • Harmonized clinical studies: Designing trials that satisfy both diagnostic and therapeutic endpoints

Early engagement with regulatory authorities through pre-submission meetings is particularly valuable for companion diagnostics.

Software as a Medical Device (SaMD)

IVDs increasingly incorporate software components or exist entirely as software, requiring specialized regulatory approaches:

  • SaMD framework implementation: Applying IMDRF risk categorization principles
  • Cybersecurity considerations: Addressing security by design principles
  • Artificial intelligence/machine learning: Navigating evolving regulatory expectations for adaptive algorithms
  • Agile development: Reconciling iterative development with regulatory requirements

The FDA’s Digital Health Software Precertification Program signals evolving approaches to software regulation that may influence other jurisdictions.

Point-of-Care and Self-Testing IVDs

Decentralized testing presents unique regulatory considerations:

  • Usability engineering: Demonstrating safe use by intended users
  • Human factors studies: Collecting evidence in simulated use environments
  • Simplified instructions: Developing clear usage guidance for lay users
  • Risk mitigation: Implementing safeguards against user error

Regulatory expectations for usability have increased significantly, particularly for tests intended for self-administration.

Creating Sustainable Compliance

Regulatory Intelligence Systems

Maintaining current regulatory intelligence is essential for sustainable compliance:

  • Monitoring mechanisms: Establishing systems to track regulatory changes
  • Gap assessment processes: Evaluating impact on existing products and pipelines
  • Strategic response planning: Developing action plans for significant regulatory shifts
  • Knowledge management: Maintaining institutional regulatory expertise

Subscription services and industry associations can provide valuable regulatory intelligence resources. Examples include our partners Medboard.

Post-Market Compliance Strategies

Regulatory responsibility extends well beyond initial approval:

  • Post-market surveillance planning: Designing proportionate monitoring systems
  • Real-world evidence collection: Gathering data on performance in clinical settings
  • Periodic safety update reports: Preparing comprehensive safety summaries
  • Change management: Navigating modifications to approved devices

Proactive post-market strategies can identify issues early and support expanded indications.

Building Regulatory Partnerships

Successful manufacturers view regulatory bodies as partners rather than obstacles:

  • Pre-submission consultations: Engaging early with authorities on novel technologies
  • Scientific advice meetings: Seeking input on clinical evidence plans
  • Regulatory inspections: Approaching audits as improvement opportunities
  • Transparent communication: Maintaining open dialogue about challenges

Building positive regulatory relationships creates pathways for more efficient future submissions.

Conclusion

The evolving IVD regulatory landscape presents significant challenges but also opportunities for manufacturers who implement strategic approaches to compliance. By integrating regulatory considerations throughout the product lifecycle, adopting risk-based methodologies, generating robust clinical evidence, and maintaining adaptable quality systems, manufacturers can navigate compliance pathways more efficiently.

Success in today’s regulatory environment requires not just understanding current requirements but anticipating future developments. Organizations that view regulatory strategy as a competitive advantage rather than a necessary burden are better positioned to bring innovative diagnostic solutions to patients while maintaining compliance across global markets.

As the diagnostic landscape continues to evolve with technological advances in digital health, precision medicine, and point-of-care testing, regulatory strategies must likewise adapt. By building sustainable compliance systems and fostering positive relationships with regulatory authorities, IVD manufacturers can create pathways to market that support innovation while ensuring safety and efficacy.

How can we help?

IVDeology has a long history of working with IVD manufacturers to define their regulatory strategy based on their company goals and objectives. We establish long term partnerships with our customers to ensure they meet the regulatory requirements for market access, and through the post market phase. To learn more about how we can help, contact [email protected].

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How to Get Your QMS Ready for IVDR (25 May 2025)

With less than a month to go before the requirement kicks in for a valid Quality Management System (QMS) complaint to the EU IVD Regulation (IVDR), most IVD manufacturers who have placed IVDs on the European market (or any region where you are using the CE mark, including the UK) should be ready for the change.

If you are not one of them, you need to start thinking about the below very quickly!

A Strategic Approach for IVD Companies
The IVDR represents one of the most significant regulatory shifts for IVD manufacturers in recent history. With stricter requirements for quality management systems, technical documentation, and post-market surveillance, achieving IVDR compliance demands a comprehensive transformation of your existing quality processes. Here’s how to prepare your QMS effectively.


Understand the IVDR QMS Requirements
The IVDR significantly enhances the QMS expectations compared to the previous IVD directive (IVDD).


The regulation specifically references ISO 13485:2016 as a presumption of conformity, making this standard the foundation for IVDR-compliant quality systems. The EU harmonised version of this standard, EN ISO 13485:2016A11:2021, includes the handy Annex Z correspondence between the IVDR and ISO 13485


Gap Analysis: Your First Critical Step
Before implementing changes, conduct a thorough gap analysis of your current QMS against IVDR requirements:

  • Review existing procedures against IVDR Article 10 (manufacturer obligations), Annex I (general safety and performance requirements), and Annex IX (QMS and technical documentation assessment)
  • Assess your product classifications under the new risk-based system (Classes A through D)
  • Identify documentation gaps, particularly around clinical evidence and performance evaluation
  • Evaluate your post-market processes for alignment with intensified surveillance requirements

A structured gap analysis provides a clear roadmap of required changes and helps prioritize critical areas.


Key QMS Modifications for IVDR Compliance

1. Risk Management Integration
The IVDR requires risk management to be integrated throughout your QMS, not just during design phases:

  • Update your risk management procedure to align with ISO 14971:2019
  • Establish risk controls that span the entire product lifecycle
  • Implement benefit-risk analysis methodologies
  • Create documentation that demonstrates continuous risk assessment


2. Performance Evaluation System
Develop a robust performance evaluation system that includes:

  • Scientific validity assessment for each analyte
  • Analytical performance verification
  • Clinical performance studies (where applicable)
  • A performance evaluation plan and report (PER)
  • Documented procedures for updating performance evaluation throughout the product lifecycle


3. Post-Market Surveillance System
Strengthen your post-market surveillance (PMS) system to include:

  • A PMS plan specific to each device
  • A PMS report (for Class A and B devices) or periodic safety update report (PSUR) for Class C and D devices
  • Trend reporting for incidents
  • Processes for implementing field safety corrective actions (FSCAs)
  • Integration of PMS data into risk management and performance evaluation.

4. Supply Chain Oversight
The IVDR places greater responsibility on manufacturers for supplier and distributor oversight:

  • Develop procedures for qualifying and monitoring critical suppliers
  • Implement appropriate supplier agreements covering IVDR requirements
  • Establish clear roles and responsibilities for economic operators
  • Create systems for verifying unique device identification (UDI) implementation across the supply chain

5. Person Responsible for Regulatory Compliance (PRRC)
Designate a qualified person responsible for regulatory compliance who will:

  • Ensure product conformity is appropriately verified
  • Maintain technical documentation and EU declarations of conformity
  • Fulfill post-market surveillance obligations
  • Ensure reporting requirements for serious incidents are met

6. Documentation Strategy for IVDR
Documentation requirements under IVDR are extensive. Implement a systematic approach:

  • Update your quality manual to reflect IVDR-specific requirements
  • Revise existing internal procedues to incorporate new requirements and references
  • Develop new procedures for gaps identified in your analysis
  • Create templates for technical documentation aligned with Annexes II and III
  •  Implement document management systems capable of maintaining the necessary documentation throughout the product lifecycle


Conclusion: A Transformed Approach to Quality
IVDR compliance isn’t simply about updating documents, it represents a fundamental shift in how IVD manufacturers approach quality management. By systematically addressing each aspect of the regulation, you can transform your QMS from a documentation-focused system to a truly integrated approach that enhances product safety and performance.

It is recommended that you liaise with your certification/notified body, they may have further guidance on what they would like to see, and how to lay out specific documents and QMS infrastructure before any auditing takes place. Remember it is in everyone’s best interest to ensure manufacturers are compliant, including notified bodies and competent authorities. If you don’t have a notified body, this is a great place to start!


The investment in your QMS now will not only ensure regulatory compliance but also strengthen your market position through improved product quality and enhanced patient safety. Begin your IVDR transformation today to ensure continued access to the European market and position your organization for future growth in an increasingly regulated industry.

You can speak to us by booking in our calendar here, or email [email protected] to discuss investing into your QMS, whether that be QMS hosting or uplifting, IVDeology can support.

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Exploring the EU COMBINE Programme

Understanding and Bridging the Gap in Clinical Research


The European Union’s (EU) healthcare landscape is continuously evolving, driven by the need to integrate
innovative treatments and technologies. One of the most ambitious initiatives in this realm is the EU
COMBINE Programme, launched in June 2023. This programme aims to address the complexities
and challenges at the intersection of three critical regulations: the Clinical Trials Regulation (CTR),
the Medical Devices Regulation (MDR), and the In Vitro Diagnostic Medical Devices Regulation
(IVDR).


Understanding the Need for COMBINE
In the EU, clinical trials of medicinal products, clinical investigations of medical devices, and
performance studies of in vitro diagnostics (IVDs) are governed by distinct regulatory frameworks.
These regulations, while comprehensive, often create operational challenges when combined
studies are required. Combined studies involve:

  • A clinical trial of a medicinal product alongside a performance study of an IVD
  • A clinical trial of a medicinal product alongside a clinical investigation of a medical device

    The COMBINE Programme was initiated to streamline these processes, ensuring that innovative
    treatments combining medicinal products with medical devices or IVDs can be developed more
    efficiently.

    One of the challenges presented by the stakeholders, was the duplication of work by submitting
    combined study application across multiple countries within the EU. Studies spanning multiple
    countries require multiple applications to each competent authority. In some cases, the information
    required, and outcome can vary depending on the country. Not only is this a duplication of work, it
    can put clinical study progression at risk.




The Goals of the COMBINE Programme
The primary objectives of the COMBINE Programme are to:

  1. Analyse Challenges: Identify and understand the root causes of difficulties faced by sponsors
    in conducting combined studies.
  2. Propose Solutions: Develop practical solutions to address these challenges, facilitating
    smoother regulatory processes.

Key Phases of the Programme
The COMBINE Programme is structured into two main phases:

  1. Analysis Phase: This initial phase involved collecting and analysing feedback from various
    stakeholders, including competent authorities, medical research ethics committees, and the
    European Medicines Agency (EMA). The findings were published in an analysis report in May
    2024, highlighting the primary issues and proposing potential solutions.
  2. Implementation Phase: Following the analysis, the Member States endorsed a strategy for
    the second phase in December 2024. This phase focuses on implementing the proposed
    solutions through a series of projects. These projects aim to align the regulatory frameworks
    and simplify the processes for combined studies.

Stakeholder Involvement
The success of the COMBINE Programme hinges on the collaboration of a diverse group of
stakeholders, including:

  • Competent Authorities: National bodies responsible for overseeing clinical trials and
    medical devices.
  • Medical Research Ethics Committees: Groups ensuring that clinical studies meet ethical
    standards.
  • European Medicines Agency (EMA): The agency providing scientific evaluation, supervision,
    and safety monitoring of medicines in the EU.
  • Industry Representatives: Stakeholders from the pharmaceutical and medical device sectors, including associations like the European Federation of Pharmaceutical Industries and Associations (EFPIA) and MedTech Europe.

Progress and Future Directions
As of early 2025, the projects within the COMBINE Programme are progressing according to the
established timelines. Regular reviews and updates ensure that the programme remains on track
and responsive to emerging challenges.


The ultimate goal is to create a more cohesive and efficient regulatory environment that supports
the development of innovative treatments, benefiting patients across the EU

The role of EUDAMED
EUDAMED (European Database on Medical Devices) is an IT system developed by the European
Commission to implement the Medical Devices Regulation (MDR) and the In Vitro Diagnostic Medical
Devices Regulation (IVDR). With the transition to the new regulations, EUDAMED will be enhanced
to create a more transparent and efficient regulatory tool for all industry stakeholders. However, the
implementation of EUDAMED has seen a number of delays, largely due to the complexity of the
system and resources required to implement. The result has been a lack of coordination between
competent authorities, this can be attributed to some of the challenges identified as part of the
COMBINE programme.

Conclusion
The EU COMBINE Programme represents a significant step forward in harmonizing the regulatory
landscape for combined studies. By addressing the complexities at the intersection of CTR, MDR, and
IVDR, the programme aims to foster innovation and improve patient access to cutting-edge
treatments.

The eventual roll out of EUDAMED will enable greater transparency and communication between
member states, and regulatory authorities.

As the projects within the programme continue to unfold, the healthcare community remains
optimistic about the potential for streamlined processes and enhanced collaboration.

Stay tuned for more updates on the progress and impact of the COMBINE Programme as it continues
to shape the future of clinical research in the EU.

How IVDEOLOGY is supporting the industry
The IVD regulation is a key cog in the mechanism for combined studies. We work with a number of
manufactures developing Companion Diagnostic medical devices, or clinical trial assays which fall
under this regulation. We help build regulatory strategies, and technical documentation to support
regulatory submissions.

Book a call with us to discuss your regulatory challenges or questions and see how IVDeology can
help you

References:

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What Are EU Reference Labs for IVDs?

EU Reference Labs for IVD’s – explained

In vitro diagnostic medical devices (IVDs) play a vital role in providing essential information for the diagnosis, monitoring, and treatment of diseases.  IVDs must comply with the In Vitro Diagnostic Medical Device Regulation (IVDR – Regulation (EU) 2017/746) to be placed on the European Union (EU) market.

The IVDR introduced the concept of EU Reference Laboratories (EURLs) for IVDs. EURLs are specialised laboratories designated by the European Commission, to provide scientific and technical expertise for specific types of high-risk IVDs. The designation and responsibilities of EURLs are outlined in Article 100 of the IVDR and more details are laid out in Commission Implementing Regulation (EU) 2022/944.

Designation & Responsibilities of EURLs

For a laboratory to be designated as an EURL by the European Commission, it must:

  • Demonstrate appropriate expertise and experience in the relevant field
  • Have adequate staff with appropriate qualifications
  • Possess necessary equipment and reference materials
  • Show impartiality and independence from commercial interests
  • Comply with ISO/IEC 17025 and other relevant standards
  • Have appropriate quality management systems in place

Once designated, EURLs’ tasks include the following:

  • Performance Verification – EURLs verify the performance claims of class D IVDs by conducting laboratory tests on samples provided by manufacturers i.e., EURLs carry out tests on each manufactured batch of devices.
  • Common Specifications Development – EURLs contribute to the development of common specifications and technical guidance for specific types of devices.
  • Technical Assistance – EURLs provide scientific advice and technical assistance to national authorities, notified bodies and manufacturers.
  • Reference Materials Management – EURLs establish, manage, and make available reference materials and methods for high-risk IVDs.
  • Coordination Role – EURLs coordinate a network of national reference laboratories to harmonize testing methodologies and practices across the EU.
  • Research and Innovation – EURLs contribute to research and innovation in their specific areas of expertise.

Types of IVDs Subject to EURL Assessment

The EURLs verify the performance claims and carry out batch testing on high-risk (Class D) IVDs:

  • Devices which detect the presence of / exposure to, a transmissible agent in blood / blood components / cells tissues / organs / any of their derivatives, to assess their suitability for transfusion / transplantation / cell administration.
  • Devices which detect the presence of / exposure to, a transmissible agent that causes a life-threatening disease with high propagation risk.
  • Devices which determine the infectious load of a life-threatening disease, where monitoring is critical in the process of patient management.
  • Devices for blood grouping, which determine any of the following markers:
    • ABO system [A (ABO1), B (ABO2), AB (ABO3)]
    • Rhesus system [RH1 (D), RHW1, RH2 (C), RH3 (E), RH4 (c), RH5 (e)]
    • Kell system [KEL1 (K)]
    • Kidd system [JK1 (Jka), JK2 (Jkb)]
    • Duffy system [FY1 (Fya), FY2 (Fyb)]

Impact on the Industry

EURLs for IVDs have an impact on both IVD manufacturers and notified bodies.

Manufacturers of class D IVDs must submit samples of their device to an appropriately designated EURL for the EURL to verify performance claims and compliance to any common specifications. Manufacturers must then incorporate any feedback into their technical documentation. Prior to release of a batch of any Class D IVDs, manufacturers must wait for EURLs to confirm they have completed their tests.

Notified bodies will need to consult with EURLs when assessing certain high-risk IVDs and factor in EURL’s opinions into their assessment decisions. Notified bodies will also have to maintain communication with EURLs for post-market surveillance.

Implementation Challenges

Although the IVDR became fully applicable on 26 May 2022, implementation of the regulation has not necessarily been smooth. The timelines to which certain devices must be compliant to the IVDR have been extended more than once and establishing a EURL network has been challenging. Resources have been restrained, as building the necessary infrastructure and hiring the appropriate expertise has required significant investment and coordination.

As a result, the European Commission adopted a phased approach to EURL designation and until EURLs are fully operational for all relevant device categories, interim procedures have been established for the conformity assessment of class D IVDs. MDCG 2021-4 provides guidance on how EURLs should be integrated into the conformity assessment process when designated.

Current State of Play

The European Commission have designated the following 5 EURLs by the implementing act Commission Implementing Regulation (EU) 2023/2713

Designated EU reference laboratoryScope of designation Class D devices intended for detection or quantification of markers of:
Consortium managed by Servicio Madrileño de Salud (SERMAS), Spain and composed of: Hospital General Universitario Gregorio Marañón, Spain Hospital Universitario la Paz, Spain Hospital Universitario Ramón y Cajal, SpainHerpesvirus infection Infection with bacterial agents
Consulting Químico Sanitario SLU (CQS), SpainHerpesvirus infection Infection with bacterial agents
EU Referenzlabor für In-vitro-Diagnostika am Paul-Ehrlich-Institut (PEI-IVD), Germany Hepatitis or retrovirus infection Respiratory virus infection
Instituto de Salud Carlos III (ISCIII), SpainHepatitis or retrovirus infection Herpesvirus infection  Infection with bacterial agents
RISE Research Institutes of Sweden AB (RISE), SwedenRespiratory virus infection

These EURLs took up their tasks in the conformity assessment of devices on 1 October 2024.

In February 2025, the European Commission launched a further call for more applications to be submitted by Member States on behalf of their candidate laboratories for designation of EURLs. This call will be conducted in 2 waves.

The 1st wave is for the following categories of class D devices:

  • detection or quantification of markers of arbovirus infection
  • detection or quantification of markers of parasite infection
  • detection of blood grouping markers

Laboratories must submit applications to their Member State by 15 April 2025 (note: this date is indicative and laboratories should check with their specific Member State).

Member States must forward applications to the Commission by 6 June 2025.

The 2nd wave is for any of the following 8 categories of class D devices:

  • detection or quantification of markers of hepatitis or retrovirus infection 
  • detection or quantification of markers of herpesvirus infection 
  • detection or quantification of markers of infection with bacterial agents
  • detection or quantification of markers of arbovirus infection
  • detection or quantification of markers of respiratory virus infection
  • detection or quantification of markers of infection with haemorrhagic fever viruses or other biosafety level 4 viruses
  • detection or quantification of markers of parasite infection
  • detection of blood grouping markers

Laboratories must submit applications to their Member State by 15 January 2026 (note: this date is indicative and laboratories should check with their specific Member State).

Member States must forward applications to the Commission by 15 April 2026.

Conclusion

EURLs play a critical role in ensuring certain Class D IVDs are safe and effective. Although there are interim procedures in place for the conformity assessment of Class D IVDs, the IVD industry will benefit from the certainty of having enough designated EURLs to cover all categories of Class D devices.

Let’s hope this new call for further applications for designation of EURLs will provide additional resources the EU IVD industry desperately needs.

If you’re looking for a regulatory partner to offer compliance advise and support, get in touch with IVDeology today to begin your new partnership or email us at [email protected]

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A review of the MHRA Fee Consultation

Executive Summary

The MHRA (Medicines and Healthcare products Regulatory Agency) held a public consultation on proposed amendments to its statutory fees, to ensure ongoing cost recovery. The consultation ran from August 29, 2024, to October 24, 2024. The majority of respondents (including stakeholders, from UK Approved Bodies, Trade Associations, Manufactures and the public) disagreed with the new medical devices registration fee, hence the MHRA have decided to proceed with the wider fees uplift and continue exploring options for this fee. The implementation date for the proposed changes to the wider fees uplift is early Q1 2025/26.

Introduction

The MHRA regulates medicines, medical devices, and blood components for transfusion in the UK. It operates on a full cost-recovery basis, ensuring financial sustainability and service delivery. Fees are updated regularly to reflect the cost of regulatory activities, including staff costs and corporate overheads. The MHRA, as a department of the UK government, need to be self-sustaining financially. Any activity they perform, and they are critical to the monitoring of medicines, medical devices and IVDs on the UK market, needs to be paid for by cost recovery initiatives, such as those summarised in the consultation document.

Evaluation of Responses

The document evaluates responses to the five proposals:

  1. Proposal 1: Increase statutory fees to ensure continued cost recovery. Most respondents did not agree, citing high costs and impact on SMEs, particularly in the case of the new proposed medical devices registration fee. The MHRA plans to proceed with the wider fees uplift but did refer to existing payment easements for small companies and payment waivers for SMEs for certain fees. However, this does not apply to medical devices or IVDs.
  2. Proposal 2: Amend the Medical Device Registration fee to include post-market work costs. Most respondents disagreed, citing financial burden on businesses, especially SMEs. The MHRA will continue exploring options for this fee and in the meantime, the existing one-off medical devices registration fee will remain but get the indexation increase being applied to all other existing fees (i.e. raising it from £240 to £261).
  3. Proposal 3: Create a new service for regulatory advice meetings for medical devices. Most respondents agreed, but requested more details on scope, format, and timelines. Questions were also raised with regards to the MHRA’s advice versus that of Notified/Approved Bodies, and the risks if advice was contradictory. The MHRA plans to proceed with this proposal.
  4. Proposal 4: Amend fee models for existing services and remove obsolete fees. Most respondents did not have an opinion but agreed in principle and requested more information be provided. The MHRA plans to proceed with this proposal.
  5. Proposal 5: Update the legal definition of a “standard variation” application for homeopathic products. Most respondents did not have an opinion, and the MHRA plans to proceed with this proposal.

Unintended Impacts on Protected Characteristics

The MHRA assessed the proposals for potential unintended discrimination. Most respondents did not have an opinion, but some raised concerns about the impact on product availability for rare conditions and minority groups. The MHRA believes the risk of unintended discrimination is low.

The implementation of this proposal will also see an increase to UK Approved Body fees, which will increase the financial burden on anyone who potentially uses the international recognition route or UKCA marking for classes B, C and D.

The biggest challenge for IVD manufacturers was the proposal to change how fees were applied for device registrations (proposal 2). In the consultation, a change of fees from £240 (one-off fee) to £210 per GMDN code registration (annually) was originally proposed. This would substantially increase the year on year costs of maintaining IVDs on the UK market (often at an increase of up to 5,000%) Whist the increase continued to be considered, the existing one-off medical devices registration fee will remain but get the indexation increase being applied to all other existing fees (i.e. raising it from £240 to £261) will occur later this year (exact date unconfirmed).

Closing thoughts

In summary, we understand that cost have to be recovered for the services the MHRA provide, and in reality, the fees for the UK are lower than many key regulatory markets (e.g. USA). However, in an aid to ensuring the UK continues to have early access to world leading and innovative products, the UK needs to be shaped into an attractive destination for IVD manufacturers in the short term. A substantial increase in medical devices fees, disproportionate to market size, would not support this message.

We will continue to engage with our customers on the outcome from the consultation and potential impacts of this change, as well as continue to engage with BIVDA, our trade association, to work with the MHRA to find a positive way forward.

IVDeology provides expert regulatory consultancy for anyone taking advantage of the UK’s current regulatory pathway, or planning for UKCA transition. We can help you build your regulatory strategy to consider the impact of UK international recognition, and support non-UK manufacturers place product on market utilising our UKRP service.

Book a call with us to discuss your regulatory challenges or questions and see how IVDeology can help you.

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eQMS is Like a Chocolate Selection box: Choosing the Right Quality Management System

Choosing an electronic Quality Management System (eQMS) might not sound like it has much in common with picking out a chocolate bar, but in many ways, the process is surprisingly similar. Both involve sifting through a variety of options to find the perfect fit for your specific needs and tastes. Just like when you’re deciding between dark, milk, or white chocolate, selecting the right eQMS requires considering your unique preferences, goals, and requirements.

Do you prioritize smoothness and simplicity, or do you need something with a bit more complexity and richness? In this blog, we’ll explore how the decision-making process for an eQMS mirrors the sweet (and sometimes overwhelming) experience of choosing your favourite chocolate bar. So, let’s unwrap the similarities and help you make a decision that’s both satisfying and beneficial

The eQMS Landscape

Here’s an interesting fact, just like chocolate, there are over 100 different versions of eQMS software available today! The remarkable thing is that you can build a compliant quality management system with any of these tools. You could even create one using basic platforms like SharePoint or Google Drive!

What Makes the Difference?

So what separates one eQMS from another? Different systems offer varying functionalities:

  • Some leverage AI (artificial intelligence) capabilities
  • Others focus on simplicity
  • Many interconnect with other business functions

It’s all about understanding what’s right for you and your organization. Quality management system software provides both a tool and a framework to build your QMS around. The work and effort required to build a QMS is largely driven by your specific company needs.

The Value of Expertise

This is where consultants become valuable. Through their careers, consultants experience different types of QMS systems built by different organisations at various stages of development. We can help you determine not only where to begin but also where you may want to go in the future. Our perspective and expertise can support you in developing a long-term strategy for quality planning and QMS implementation.

Our Recommended Options

While hundreds of options exist, here are three QMS software providers we regularly work with:

  1. Cognidox  – This is the system we use to build our own ISO-compliant QMS. It offers simple setup, ease of use, and scalability based on your company’s needs rather than forcing you into a predefined structure.
  2. TraceX – A robust alternative with its own strengths and considerations.
  3. ISMS – Another effective system that works well for certain organizational needs.

Both TraceX and ISMS work excellently, each with positives and negatives. The key is understanding what’s important to you, and we’d be happy to spend time with you to discuss these points. What works wonders for one organisation might not be suitable—or even detrimental—for another. This largely depends on each organisation’s unique needs, processes, and goals – just like how someone absolutely adores a coconut Bounty, whereas someone else, not so much!

Finding Your Perfect Match

Sometimes you want a Bounty, sometimes a Snickers, and sometimes you’re not even sure what you’re craving. But what you don’t want to do is settle for something medicore.

For more information on what’s right for you and how to effectively build a quality management system, get in touch with us on [email protected]. We can discuss these processes in more detail and help build you an effective, right-first-time quality management system tailored to your needs, after all, we maintain and work within our own QMS and know that a quality management system is for life, not just for your audits!

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Understanding Companion Diagnostics: A Key to Personalised Medicine

The first companion diagnostic (CDx) was approved by the US Food and Drug Administration (FDA) in 1998 with the European Medicines Agency (EMA) following with approval 2 years later focussed on the cancer treatment drug Herceptin. Since then, the rise of precision medicine has played an increasing part in eliminating the trial-and-error approach to identifying effective treatments for individual patients ensuring that therapies are tailored to their unique biological characteristics.

What Are Companion Diagnostics?

Companion diagnostics are in vitro diagnostic (IVD) tests (or may be an imaging tool), that provide critical information for the safe and effective use of a corresponding drug or biological product. These tests are co-developed with a therapeutic drug and are essential in determining whether a patient will benefit from a specific treatment, be at risk for severe side effects, or require adjustments in their therapy to achieve optimal results.

The labelling of a CDx must include the specific drug it was developed for and likewise the labelling of the drug must indicate the use of the CDx for prescription of the drug.

The US FDA approach to CDx Submission

In the US, the FDA is the central authority and requires that the drug and device are submitted for review and approval at the same time. Thus, the device and drug are developed at the same time and if possible, the device should be used as the Clinical Trial Assay (CTA). The therapeutic drug and it’s proposed CDx need Investigational Drug Application (IND) and Investigational Device Exemption (IDE) submissions and approvals before investigational clinical studies can commence.

During the development process the drug developer will be able to request meetings with the Centre for Drug Evaluation and Research (CDER) and the device developer will be able to meet with the Centre for Devices and Radiological Health (CDRH) via the Q-Submission process. For each of these meetings the respective developer should make it clear that they are co-developing the CDx and it is always useful to request a representative from the other centre to attend for awareness.

In the past the majority of CDx have been submitted and approved via the Pre-Market Approval process (PMA) and are classified as Class III devices. However, in 2024, the FDA announced plans to reclassify many Class IIIs to be Class II and enable manufacturers to submit for market authorisation via the 510K route.

The EU approach to CDx submission

In the EU, CDx are Class C following the classification rule 3(f) under the IVD Regulation 2017/746 and the key difference to the US process is the consultation process between the Notified Body of the device manufacturer and the EMA. The Notified Body will assess the technical documentation of the CDx and when that is complete, they will then consult with EMA for the final assessment alongside the drug file. This secondary process can add around 6 to 8 months to the approval process and needs to be planned carefully to allow sufficient time for market authorisations.

As with the US process, the CDx should be used as the CTA as early as possible, and the clinical use of the assay is often seen as an interventional clinical study requiring complex and lengthy applications to the separate member state competent authorities for approval.

The Future of Companion Diagnostics

Since the first CDx was approved by the FDA in 1998, there are now over 200 cleared or approved listed by the FDA. IVDeology Ltd is seeing the development of companion diagnostics growing alongside advancements in genomics and biotechnology. As our understanding of the genetic and molecular basis of diseases expands, manufacturers have the ability to create more precise and effective diagnostic tests, leading to better patient outcomes and more efficient healthcare systems.

Conclusion

Companion diagnostics are leading the way in the field of personalized medicine. By ensuring that treatments are tailored to the individual needs of patients, these diagnostics not only improve the efficacy and safety of therapies but also pave the way for a more personalized approach to healthcare. As technology continues to evolve, the role of companion diagnostics will undoubtedly become even more integral to modern medicine.

IVDeology Ltd can support small pharmaceutical developers understand the CDx requirements to enable clear and concise discussions with your identified device developers. Likewise we can support CDx developers understand the requirement for consultation with the FDA and the pathway to market approval.