EUDAMED Mandatory Timelines for MDR and IVDR

November 27, 2025

What the 2026 Deadlines Mean for Medical Device and IVD Manufacturers

EUDAMED mandatory timelines for MDR and IVDR are no longer theoretical. On 27 November 2025, the European Commission published Commission Decision (EU) 2025/2371 in the Official Journal of the European Union. This Decision confirms that four EUDAMED modules are now functional: Actor registration, UDI/Device registration, Notified Bodies and Certificates, and Market Surveillance.

Under the amended transitional rules in Regulation (EU) 2024/1860, that publication starts a six-month transition. As the Commission’s EUDAMED overview explains, from 28 May 2026 these four modules become mandatory to use for both medical devices and IVDs.

For manufacturers, authorised representatives, importers and notified bodies, this creates fixed dates that must now sit inside MDR and IVDR compliance plans.

1. How the EUDAMED Gradual Roll-Out Works

Regulation (EU) 2024/1860 amends the MDR and IVDR so that EUDAMED can go live module by module. Instead of waiting for all six modules, the Commission can audit each module or group of modules, confirm functionality, and then publish a notice in the Official Journal.

Once that notice appears, the rules change in a clear way. According to the Commission’s Q&A on the gradual roll-out of EUDAMED, the obligations and requirements linked to a given module become applicable six months after the notice is published. Until that date, the relevant provisions of the old Directives and their national transposition measures still apply for registration duties.

The same Q&A explains that some modules also come with extra time:

For the UDI/Device module, manufacturers have up to 12 months from the Official Journal notice to register certain devices already on the market.
For the Notified Bodies and Certificates module, notified bodies have up to 18 months from the notice to upload information on existing MDR and IVDR certificates.

Because the notice for the four modules appeared on 27 November 2025, the six-month period runs to 28 May 2026. After that date, the four modules are no longer optional.

2. Module-by-Module Deadlines Under MDR and IVDR

2.1 Actor Registration: SRNs Before Placement on the Market

The Actor module covers registration of economic operators. It applies to manufacturers, authorised representatives and importers that fall under Article 31 MDR and Article 28 IVDR.

The Q&A makes one point very clear. These economic operators must register as Actors and obtain a Single Registration Number before a device is placed on the market. Registration in the Actor module also unlocks other actions in EUDAMED, such as device registration and vigilance reporting.

Because the Official Journal notice for the four modules was published on 27 November 2025, use of the Actor module becomes mandatory from 28 May 2026. Manufacturers and authorised representatives can already register voluntarily and the Commission strongly encourages early registration to avoid a last-minute rush.

2.2 UDI/Device Registration: New vs. Ongoing Devices

The UDI/Device (UDI/DEV) module holds device and system/procedure pack data at the level of the UDI-DI or EUDAMED ID. The Q&A describes how the timelines work for different device situations.

First, if a medical device or IVD under the MDR or IVDR has its first sales unit placed on the EU market on or after the date when UDI/DEV becomes mandatory, the manufacturer must register the device in EUDAMED before that first placement. In practice, this means that any new MDR or IVDR device with a first unit sold on or after 28 May 2026 requires registration in UDI/DEV in advance.

Second, if the first unit of a device entered the EU market before the mandatory date, but the manufacturer will place more units on the market after that date, the device must still appear in UDI/DEV. In this case, the Q&A gives manufacturers 12 months from the publication of the Official Journal notice to register those devices. Because the notice was published on 27 November 2025, this deadline falls on 27 November 2026.

Devices that will not be placed on the market anymore when UDI/DEV becomes mandatory generally do not need registration, unless a specific post-market surveillance or vigilance action for that device occurs.

2.3 Notified Bodies and Certificates: New and Legacy Certificates

The Notified Bodies and Certificates (NB/CRF) module contains MDR and IVDR certificates and related NB decisions. The Q&A again draws a line between future and past certificates.

Once NB/CRF becomes mandatory, notified bodies must register every MDR and IVDR certificate they issue from that date onward, together with updates and certain decisions that affect these certificates. For the four modules declared functional in November 2025, this obligation starts on 28 May 2026.

For certificates that notified bodies issued before that date, the Q&A gives them more time. They must upload information on existing MDR and IVDR certificates within 18 months of the Official Journal notice, provided the related devices need to be registered in UDI/DEV. With a notice date of 27 November 2025, that 18-month period ends on 27 May 2027. Only the latest version of a certificate and the latest relevant NB decision need to appear in EUDAMED.

2.4 Market Surveillance: A New Tool for Authorities

The Market Surveillance (MSU) module supports market-surveillance work by national competent authorities. Manufacturers do not directly enter data into this module. However, they will feel its effects because it strengthens coordination between authorities and gives them a harmonised IT tool for cross-border cases.

The Q&A applies the same six-month rule to the MSU module. As a result, competent authorities must use the MSU module from 28 May 2026.

3. Practical Impact of EUDAMED Mandatory Timelines for MDR and IVDR

3.1 What Changes for Manufacturers and Authorised Representatives

For manufacturers and authorised representatives, EUDAMED becomes a central part of regulatory operations rather than a future project. Several changes now follow from the fixed dates.

First, Actor registration turns into a gatekeeper. From 28 May 2026, manufacturers, authorised representatives and importers in scope of Article 31 MDR and Article 28 IVDR need their Actor registration and Single Registration Number in place before they place devices or IVDs on the EU market. Without this registration, they cannot complete device registration or use other EUDAMED functions.

Second, device master data becomes more strategic. New MDR and IVDR devices must have device records ready before first placement after 28 May 2026. Devices that are already on the market but will continue after that date require registration by 27 November 2026. Manufacturers now need structured UDI-DI hierarchies, clear product groupings and consistent trade names across their documentation.

Third, manufacturers must align device data with certificate data. For many products, public EUDAMED information will combine UDI/device data and NB certificate data. If these do not match, authorities and customers may question the status of a device. Coordination between regulatory, quality and IT teams becomes more important than ad-hoc, product-by-product corrections.

3.2 What Changes for Notified Bodies

Notified bodies also face a significant workload. They must register all MDR and IVDR certificates issued from 28 May 2026 and bring existing certificates onto the NB/CRF module by 27 May 2027.

Because many notified bodies hold large portfolios, they will need efficient tools to manage uploads. The Commission has provided documentation for manual, bulk and machine-to-machine data exchange with EUDAMED. However, each notified body still has to implement and validate its own approach. Manufacturers should talk to their notified bodies early to understand how and when certificate information will appear in EUDAMED and how that timing aligns with their own device registrations.

3.3 Portfolio Planning and Transitional Provisions

The EUDAMED roll-out also interacts with other MDR and IVDR changes. Regulation (EU) 2024/1860 extends some IVDR transitional timelines for certain IVDs, but EUDAMED obligations apply regardless of those extensions. A device might benefit from longer time to move from IVDD to IVDR certification and still require EUDAMED registration within the new deadlines.

At the same time, the amended Articles 123 MDR and 113 IVDR help to avoid double work. Until the EUDAMED deadline for each module, national systems based on the old Directives continue to apply. Once the EUDAMED obligations become mandatory, they replace those older mechanisms and remove the risk of duplicate registrations.

For global organisations, this means EUDAMED is now a core input into portfolio and lifecycle planning, not just a technical IT project.

4. How MDx CRO Can Support EUDAMED Readiness

MDx CRO specialises in supporting medical device and IVD companies through MDR and IVDR. The new EUDAMED mandatory timelines for MDR and IVDR increase the value of structured, data-driven support.

4.1 Strategy and Gap Assessment

MDx CRO can review your product and certificate portfolio and map it against the new deadlines. This includes checking which legal entities need Actor registration, which devices will still be placed on the EU market after May 2026, and where device and certificate data must align.

We can then build a practical roadmap that sequences Actor registration, device registration and interactions with notified bodies. This approach reduces the risk of late surprises when EUDAMED becomes mandatory.

4.2 Data Preparation for UDI/DEV and NB/CRF

We help teams design clear UDI-DI structures and basic device data sets. That work supports both UDI/DEV registration and internal quality systems.

MDx CRO can also support data cleansing and consistency checks so that the information you load into EUDAMED matches your technical documentation, declarations of conformity and certificates. This preparation lowers the chance of errors and reduces back-and-forth with authorities or notified bodies.

4.3 Integration Into Clinical and Regulatory Programmes

EUDAMED should sit alongside performance evaluation, clinical data generation and labelling work, not apart from it. MDx CRO can help you embed EUDAMED milestones into your MDR and IVDR programmes so that regulatory submissions, certificate planning and EUDAMED entries move together.

We also support communication with notified bodies on certificate upload planning and with national competent authorities where clarifications are needed.

5. The Bottom Line: The EUDAMED Clock Is Now Running

With Decision (EU) 2025/2371 published and the Commission confirming that the first four modules will be mandatory from 28 May 2026, the EUDAMED project has crossed a line. The remaining time to prepare is now measured in months, not years.

For medical device and IVD manufacturers, the message is straightforward. The EUDAMED mandatory timelines for MDR and IVDR fix near-term deadlines for Actor registration, device and UDI data, certificate uploads and market-surveillance tooling. Organisations that act now will spread the workload and reduce risk. Those that wait may face crowded registries, limited notified body bandwidth and internal bottlenecks.

If you want to test your EUDAMED readiness or build a structured plan to meet the 2026 and 2027 dates, MDx CRO can support you with strategy, data preparation and regulatory execution.

Read more about IVD clinical studies services.

Read more about regulatory documentation support.

Need help meeting your EUDAMED deadline?

Talk to our regulatory team.

Written by:

Alberto Bardají

Head of Medical Devices

Senior med-tech expert & ex-Notified Body reviewer with deep experience in high-risk implants, orthopedics, dental & neurology.

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FDA Proposes to Down‑Classify Key Oncology Companion Diagnostics to Class II: What CDx Sponsors Need to Know

November 27, 2025

Carlos Galamba

A Structural Shift in FDA Companion Diagnostic Policy

FDA has published a proposed order in the Federal Register to reclassify a major family of oncology companion diagnostics and related molecular tests—from post‑amendment Class III (PMA) devices to Class II with special controls, under a new regulation at 21 CFR 866.6075.

This proposal creates, for the first time, a unified Class II device type for “Nucleic Acid‑Based Test Systems for Use with a Corresponding Approved Oncology Therapeutic Product”. It would move many oncology nucleic‑acid tests (including core companion diagnostics) onto a 510(k) pathway—while maintaining stringent analytical and clinical expectations via special controls.

For CDx sponsors, pharma partners and oncology laboratories, this is more than a technical reclassification. It reshapes how you plan evidence, sequence FDA and EMA/IVDR strategies, budget user fees, and negotiate drug–test labeling.

As an IVD‑focused CRO with deep experience in IVD clinical studies services, IVDR performance studies, EMA CDx consultation and FDA submissions, MDx CRO is already working with sponsors to future‑proof pipelines against this new framework.

What Exactly Has FDA Proposed?

FDA’s proposed order would:

Create a new device type at 21 CFR 866.6075 titled “Nucleic Acid‑Based Test Systems for Use with a Corresponding Approved Oncology Therapeutic Product.”
Reclassify post‑amendment Class III devices in this category—currently approved under product codes OWD, PJG, PQP and SFL—into Class II (special controls), subject to 510(k).
Apply the new regulation to both currently approved devices and future devices that fit this definition.

Under the proposed identification, these devices are prescription IVDs that:

Detect specific genetic variants and/or other nucleic acid biomarkers in human clinical specimens
Use nucleic acid amplification (e.g., PCR) and/or sequencing technologies (e.g., NGS)
Provide information related to the use of a corresponding FDA‑approved oncology therapeutic product

Crucially, the device type covers two sub‑families:

1 – True companion diagnostics – tests essential for the safe and effective use of an oncology therapeutic product, with reciprocal references in both the device labeling and the drug labeling.

2 – “CDx‑adjacent” tests – tests that are not essential for use of the drug, but are referenced in the drug’s labeling because they provide information about known benefits and/or risks (for example, prognostic or response‑enrichment information).

FDA has opened a 60‑day public comment period following publication of the proposed order; if finalized, the new classification would take effect 30 days after the final order is published in the Federal Register.

Why Is FDA Comfortable Moving Oncology NAAT/NGS CDx to Class II?

FDA’s justification rests on a decade‑plus of real‑world experience with these technologies, framed through the statutory reclassification provisions in section 513(f)(3) of the FD&C Act.

1. Extensive PMA Experience

Since the first approval in 2011 (cobas 4800 BRAF V600 Mutation Test), FDA has approved 35 PMAs and 403 PMA supplements for oncology nucleic acid‑based test systems across four product codes (OWD, PJG, PQP, SFL).

For this proposed reclassification, FDA relied on data from 17 original PMAs and one panel‑track supplement, making use of the “six‑year rule” in section 520(h)(4) to draw on PMA datasets once they were sufficiently aged to be used for reclassification.

These submissions include PCR hotspot assays, NGS panels, BRCA and RAS panels, MSI signatures and other archetypal oncology CDx platforms.

2. Post‑market Safety and Recall Data

FDA analysed MDRs (MAUDE database) and recalls for these product codes:

147 MDRs across four product codes, with >80% related to false positives; >95% reported no clinical harm, and the fraction associated with serious health impact was low.
Four Class III recalls and 23 Class II recalls, with root causes concentrated in non‑specific molecular interactions, non‑conforming components, process deviations, labelling errors and off‑label use—not systemic failures of the technology itself.

The conclusion: risk modes are well understood and can be mitigated through defined special controls, rather than case‑by‑case PMA‑level scrutiny.

3. Technological Maturity

FDA explicitly characterises oncology nucleic acid‑based test systems as a well‑bounded technological family, with:

Similar purposes and intended uses
Common analytical principles (PCR and NGS)
Comparable bioinformatics pipelines
No unique, unmitigated risk patterns across product codes

On that basis, FDA finds that Class II with appropriate special controls can provide reasonable assurance of safety and effectiveness.

What Are the Proposed Special Controls?

The special controls in proposed 21 CFR 866.6075(b) fall into two main buckets: design verification/validation and labeling.

1. Design Verification and Validation

Sponsors must provide:

Analytical performance data

Precision, analytical accuracy, analytical sensitivity, analytical specificity
Sample and reagent stability
Evaluation for each gene/variant, or an FDA‑accepted representative strategy

Coverage and limitations

Data showing which genomic regions are targeted and detected
Disclosure of regions not covered or with limited detection

Clinical performance data

Generated using clinical specimens representative of the intended use population
Demonstrating appropriate clinical performance for the intended use (e.g., response‑predictive or risk‑informative claims)

Specimen handling validation

Validation of specimen types, pre‑analytical handling, extraction and preparation as described in the labeling

Biomarker classification / bioinformatics validation

Clear description of the classification pipeline and criteria
Documentation of the basis for biomarker interpretation, with appropriate references

Risk‑mitigation specifications

Controls, procedures and user‑training requirements designed to reduce false results and misinterpretation

In practice, this codifies what high‑quality oncology CDx sponsors already do under PMA—now packaged as device‑type‑level expectations rather than bespoke PMA negotiations.

2. Labeling Controls – Including the New Label‑Alignment Requirement

Labeling must include:

Device description (biomarkers detected, analysis algorithms, quality metrics, detection limitations)
A summary of analytical and clinical performance studies and their results

For essential CDx tests:

Language stating that the test is indicated for use with a specific FDA‑approved oncology therapeutic product, and
A requirement that device labeling be consistent with the corresponding drug’s FDA‑approved labeling.

For non‑essential but drug‑informative tests:

Language summarising known benefits and/or risks of the drug as informed by the test, which also must be consistent with the therapeutic product’s FDA‑approved labeling.

That last element—the requirement that test claims about drug benefit or risk “track” the drug label—is where the most interesting policy tension sits.

Why This Matters Operationally: PMA vs 510(k) for Oncology CDx

If finalized, reclassification would move this family of tests from PMA to 510(k), with important practical effects:

Less burdensome submission type. FDA itself notes that the 510(k) pathway is generally less burdensome and more cost‑effective than PMA, with shorter review timelines.
Lower user fees. In FY 2025, the standard user fee for a PMA‑type application is about $541k, while a 510(k) fee is about $24k—roughly a 20‑to‑1 difference, before small‑business reductions.
More predictable review questions. Instead of re‑litigating the entire benefit–risk story, sponsors will argue substantial equivalence and conformity to codified special controls.
More flexible change control. FDA explicitly points to predetermined change control plans (PCCPs) as a way to implement certain future modifications without a new 510(k) each time, if the change is covered by a cleared PCCP.

For oncology CDx sponsors, that means:

Faster and cheaper routes for follow‑on tests targeting established biomarkers (EGFR, BRAF, BRCA, MSI, etc.).
A clearer template for analytical and clinical evidence packages.
Easier lifecycle management for panel expansions, algorithm updates and bioinformatics refinements—subject to PCCP design.

The Built‑In Ceiling: Test Claims Cannot Outrun Drug Labeling

While the new Class II device type creates a more efficient pathway, it also codifies a strict rule about how far test labeling can go:

For tests essential to a drug’s safe and effective use, device labeling must be consistent with the corresponding drug label.

For tests that merely provide information about known benefits or risks (without being essential), the device can only summarise those benefits/risks in language that is, again, consistent with the drug label.

In practice, this means:

You cannot obtain CDx labeling for a novel biomarker–drug relationship unless the drug’s own labeling acknowledges that relationship.
Independent evidence generated by an IVD sponsor, academic group or cooperative trial cannot, on its own, support drug‑linked claims in device labeling if the corresponding therapeutic product label remains silent or disagrees.

This alignment rule is not new, it has long applied in the PMA CDx world, but the new regulation explicitly extends it to the broader family of “CDx‑adjacent” oncology NAAT/NGS tests.

From a sponsor’s perspective, that creates a structural stalemate scenario:

A test developer may generate high‑quality evidence showing that a biomarker predicts lack of benefit or heightened risk for a widely used oncology drug.
If the drug sponsor declines to pursue a label update, FDA cannot allow device labeling that effectively rewrites the drug’s benefit–risk profile.
The test might still be cleared as a purely analytical device, but it would not carry the clinically meaningful, drug‑linked claims that drive adoption and reimbursement.

For CDx developers, the implication is clear:

Regulatory strategy for these new Class II tests still hinges on drug‑sponsor alignment, not just assay science.

What Should Sponsors Do Now?

Even before the order is final, CDx and oncology test sponsors can act:

Map your pipeline against the new device type: Identify NAAT/NGS oncology tests tied to approved therapies that fall into the new 866.6075 definition.
Re‑think U.S. regulatory roadmaps: For qualifying tests, plan around a 510(k) with special controls instead of a PMA—while recognising that evidence expectations remain high.
Align CDx and drug strategies early: For new biomarkers, ensure drug‑side teams understand that therapeutically meaningful test claims will require corresponding drug‑label changes.
Design performance studies that satisfy both FDA and IVDR: Build analytical and clinical validation packages that can support 510(k) clearance and the IVDR Class C CDx pathway, including EMA consultation.
Leverage PCCPs thoughtfully: Consider where a PCCP can safely cover bioinformatics updates, new variants or refined cut‑offs—without triggering repeated submissions.

How MDx CRO Can Help

MDx CRO is built around IVD and CDx:

We deliver end‑to‑end IVD trial solutions, including delegated sponsor responsibilities, ISO 20916‑compliant clinical performance studies, biostatistics, data management, safety reporting and IVDR‑compliant study reports.
Our regulatory affairs team designs global strategies for IVDR and FDA, including device classification, performance evaluation, technical documentation and regulatory submissions.
We are already supporting IVDR CDx EMA consultation processes, making us well placed to harmonise evidence plans with FDA’s new Class II framework for oncology NAAT/NGS CDx.

If your portfolio includes oncology companion diagnostics, predictive biomarkers or NGS oncology panels, this proposed reclassification is an opportunity to:

Reduce time and cost to achieve an FDA label
Align U.S. and EU strategies more intelligently
Design performance studies that work once and serve both regimes

Contact MDx CRO to discuss how to stress‑test your CDx roadmap against the new 21 CFR 866.6075 framework and build a regulatory plan that works on both sides of the Atlantic.

This article is provided for general information only and does not constitute legal or regulatory advice. Sponsors should consult their own regulatory and legal counsel for device‑specific strategies.

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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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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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 classification rules

July 9, 2024

MDCG 2020-16 Rev.3 classification rules provide essential guidance on how to classify in vitro diagnostic medical devices (IVDs) under the EU IVDR. The latest revision enhances clarity, addresses known ambiguities, and strengthens consistency in how Annex VIII classification rules are applied. For manufacturers, understanding these updates is critical to ensuring correct classification, smoother conformity assessment, and regulatory compliance.

This article covers two areas:

the key updates introduced in Rev.3, and
how the guidance applies to major IVD categories, including Companion Diagnostics (CDx), Next‑Generation Sequencing (NGS), self‑testing, and Near‑Patient Testing (NPT).

Key Updates in MDCG 2020-16 Rev.3 classification rules

New Definition of “Kit”

Rev.3 introduces a formal definition of a kit:
A set of components packaged together and intended for a specific IVD examination or part of it.
This definition improves consistency in how kit-based products are classified.

Rule 3(a) – Updated Examples

Monkeypox Virus has been added to the list of organisms under this rule, reflecting current public‑health priorities.

Rule 4(a) – Clarifications for Self‑Testing IVDs

Rev.3 provides detailed guidance for the classification of self‑testing devices:

Devices for detecting pregnancy, fertility, cholesterol, glucose, erythrocytes, leukocytes, and bacteria in urine remain Class B.
Devices detecting both a Class C marker and an exception marker are Class C, following implementing rules 1.8–1.9.
Devices meeting the criteria under rules 1.8–1.9 can be Class D, including self‑tests for HIV from fingerprick blood.

Information Society Services

Devices used within online services are considered self‑testing devices only when the lay user performs part of the testing procedure.
Specimen-only actions (e.g., stabilizing or collecting the sample) do not make a device self‑testing.

Standalone Specimen Receptacles

Specimen-only collection kits offered online are not classified as self‑testing.

Examples in Rev.3

Glucose meters/strips for capillary blood → Class C
Calprotectin tests with lay interpretation via image upload → Class C
HIV antibody self‑tests (fingerprick) → Class D

Rule 5(c) – Expanded Rationale and Examples

Definition and Classification

Specimen receptacles are defined as containers (evacuated or non‑evacuated, empty or prefilled) for the primary containment and transport of biological specimens.
They are classified as Class A, as they do not perform any analytical function.

Use in Kits

Specimen receptacles included in kits for specimen collection remain Class A, even when accompanied by non‑IVD components.

User Actions

Actions such as gargling, pipetting, or adding buffer—when required solely to maintain specimen integrity—are not considered part of the testing procedure.

Combination Use

Specimen receptacles and the subsequent IVD are classified separately under implementing rule 1.2.

Examples

Standalone urine cups, stool containers, saliva tubes, blood spot cards → Class A
Lay‑use kits for saliva or stool collection for SARS-CoV‑2 or occult blood testing → Class A

Rule 6 – Updated Example

The example for Influenza A/B now refers to a highly virulent strain rather than a non‑pandemic one.

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

Next‑Generation Sequencing (NGS)

Rev.3 highlights the role of NGS across several rules:

Rule 3(f) (Companion Diagnostics) – NGS identifies variants linked to therapeutic response.
Rule 3(h) (Cancer Diagnostics) – Supports cancer staging and genomic profiling.
Rule 5(a)–(b) (General Laboratory Use) – Includes library prep reagents, PCR thermocyclers, NGS sequencers, and other instruments essential for genetic analysis.

Companion Diagnostics (CDx)

Under Rule 3(f):

CDx devices are essential for the safe and effective use of specific medicinal products. They are used to:

Identify suitable patients for targeted therapies
Detect risks of adverse reactions
Support treatment decisions before or during therapy

Examples provided in Rev.3 include:

KRAS/NRAS variant detection for colorectal cancer
PD‑L1 IHC tests for immunotherapy selection
NGS‑based CDx for multi‑gene therapy selection

A decision flowchart in Annex II helps manufacturers determine whether an IVD qualifies as a CDx.

Self‑Testing Devices (Rule 4(a))

Self‑testing IVDs must be usable by laypersons without compromising analytical performance. Rev.3 emphasizes:

Ease of use
Safety
Minimised risk of misuse

Near‑Patient Testing (NPT) Devices (Rule 4(b))

NPT devices are designed for rapid clinical decision-making in point‑of‑care settings.
Rev.3 ensures clear differentiation between self‑testing and near‑patient testing based on user type, setting, and intended use.

MDCG 2020-16 Rev.3 classification rules provide crucial clarifications that support more consistent application of the IVDR. By refining definitions, expanding examples, and clarifying rules for CDx, NGS, self‑testing, and near‑patient testing, the guidance helps manufacturers classify devices accurately and reduce regulatory uncertainty.

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

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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