Understanding MDCG 2021-6 Rev. 1: A Comprehensive Guide for Clinical Investigations under EU MDR

March 16, 2024

The Medical Device Regulation (MDR) 2017/745 has transformed the EU’s regulatory landscape for medical devices. It aims to boost patient safety and transparency. The regulation sets strict criteria for clinical investigations. In this context, MDCG 2021-6 Rev. 1 is key. Issued by the Medical Device Coordination Group (MDCG), it underwent a revision in December 2023.

This update offers valuable insights. It addresses common questions about clinical investigations under MDR. The impact is wide-reaching. Manufacturers, sponsors, competent authorities, research centers, ethics committees, legal representatives, and CROs are all affected. This guide explores MDCG 2021-6 Rev. 1’s vital aspects. Moreover, it highlights its implications for these stakeholders.

Introduction to MDCG 2021-6 Rev. 1

MDCG 2021-6 Rev.1 is a cornerstone document for those embarking on clinical investigations of devices within the scope of the Medical Device Regulation (EU) 2017/745 (MDR). Designed for sponsors, this evolving guide may expand with more questions and answers over time. It clarifies the use of the term ‘device’ in line with MDR. This includes medical devices, their accessories, and specific products listed in Annex XVI.

The guide also standardizes the definition of “clinical investigation.” It aligns with Article 2(45) of the MDR, focusing on investigations aimed at assessing a device’s safety or performance. Moreover, it introduces the broader concept of “clinical study.” This encompasses a range of research activities within medical science. It includes clinical trials of medicines, device investigations, and in vitro diagnostic studies. These elements are vital for understanding the full scope of clinical research.

This document touches on key topics crucial for navigating the regulatory landscape:

Proof of Concept Studies: Offering insights into the initial stages of device development.
Article 82 Clinical Studies: Clarifying the scope of broader research activities under MDR.
Pilot Stage Investigations: Defining early feasibility and its regulatory implications.
Regulatory Pathways: Shedding light on navigating clinical investigations amidst the interplay of MDR, the Clinical Trial Regulation (CTR), and local laws.
Combined Trials: Addressing the complexities of studies involving both medicinal products and medical devices.
Invasive or Burdensome Considerations: Guiding sponsors on ethical and participant safety considerations.
Usability Testing: Outlining when such tests are considered clinical investigations.
Retrospective Testing: Distinguishing between prospective data collection and the analysis of existing data.
Submissions and Modifications: Offering guidance on navigating regulatory submissions and changes during the clinical investigation process.
Legal Representation: Emphasizing the role of legal representatives in ensuring compliance.

Some of the Key Highlights of MDCG 2021-6 Rev. 1

MDCG 2021-6 Rev. 1 offers an in-depth exploration into the clinical investigations aspects under the Medical Device Regulation (EU) 2017/745 (MDR). This document is instrumental in bridging the regulatory gaps and ensuring a harmonized approach across the European Union. Here are the refined key highlights based on the updated request:

Regulatory Pathways and Documentation

The document elaborates on navigating the regulatory landscape for conducting clinical investigations. It includes guidance on choosing the correct regulatory pathway, be it for a novel device entering early-stage clinical investigation or for further assessment of a CE-marked device. Detailed documentation requirements facilitate sponsors in preparing comprehensive applications, streamlining the approval process.

Legal Representative’s Role and Responsibilities

The document provides clarity on the responsibilities of the sponsor’s legal representative, which is pivotal for non-EU manufacturers. It underlines the need for a legal representative within the EU to ensure compliance with MDR requirements. This representative acts as a point of contact between the non-EU sponsor and the EU regulatory authorities, facilitating the submission and communication processes.

Substantial Modifications

Understanding what constitutes a substantial modification is crucial for the continuity and compliance of clinical investigations. MDCG 2021-6 Rev. 1 details the criteria for identifying substantial modifications that could impact the safety, health, or rights of subjects, or the reliability and robustness of the clinical data.

This guidance aids sponsors in navigating the process for notifying competent authorities about such modifications, ensuring that the integrity and validity of the investigation are maintained.

Relationship with the CTR, Combined Trials, and Combination Products

The document delves into the interplay between medical device regulations and the Clinical Trials Regulation (CTR), particularly in the context of combined trials and combination products. It highlights the importance of navigating both regulatory frameworks when a study involves medical devices and medicinal products. This includes guidance on conducting clinical studies that collect data for both devices and associated medicinal products, ensuring compliance with the MDR and CTR. The document’s insights into handling combination products—where devices and medicinal substances are integrated—are crucial for sponsors planning such studies.

Clarifications on Specific Aspects of Clinical Investigations

MDCG 2021-6 Rev. 1 sheds light on several nuanced areas of clinical investigations:

Usability Testing: It clarifies when usability tests are considered clinical investigations.
Invasiveness Considerations: The document defines what constitutes invasive procedures and the implications for clinical investigations, emphasizing the importance of assessing the invasiveness level when planning studies.
Retrospective Studies: Insights are provided on the role of retrospective studies within clinical investigations, delineating when such studies fall under the scope of clinical investigation definitions and how they contribute to clinical evaluations.
Proof of Concept Studies: Guidance on conducting proof of concept studies is highlighted, including their significance in the early stages of device development and their regulatory considerations under the MDR.

In-Depth Highlights of MDCG 2021-6 Rev. 1 for Specialized Clinical Investigations

Proof of Concept Studies according MDCG 2021-6 Rev. 1

Proof of Concept (PoC) studies are instrumental in the nascent phases of medical device development. These studies aim to demonstrate the feasibility and potential clinical benefits of a device, laying the groundwork for subsequent development stages. MDCG 2021-6 Rev. 1 provides comprehensive guidance on PoC studies, emphasizing their critical role in validating device concepts and navigating the regulatory framework of the MDR.

PoC studies serve as a foundational element in device development, enabling sponsors to assess a device’s early clinical viability and address potential design modifications before advancing to more comprehensive clinical trials. The guidance from MDCG 2021-6 Rev. 1 ensures that these studies are conducted within a framework that prioritizes patient safety, scientific validity, and regulatory compliance.

By focusing on detailed planning, ethical conduct, and adherence to specified regulatory pathways, PoC studies under the guidance of MDCG 2021-6 Rev. 1 facilitate a smoother transition through the early stages of device development.

MDCG 2021-6 Rev. 1 delineates the regulatory pathways essential for conducting PoC studies that support the conformity assessment of the device under investigation. It specifies the need for a meticulously detailed Clinical Investigation Plan (CIP), ensuring that PoC studies are grounded in solid scientific rationale and ethical considerations. This guidance is particularly highlighted in:

Question 7, which discusses the regulatory pathways for clinical investigations aimed at supporting device conformity assessments.
Question 11, focusing on the investigational use of CE-marked devices for new potential applications or further PoC studies.
Question 8, which identifies clinical investigations considered at the pilot stage, setting the stage for PoC studies.
Question 9, providing a roadmap for conducting early feasibility and first-in-human studies under the MDR, underscoring the importance of thorough risk assessment and ethical considerations.

Combined Trials

Combined Trials represent a pivotal area of focus within the regulatory landscape of clinical investigations, particularly when these involve both medical devices and medicinal products.

The MDCG 2021-6 Rev. 1 and MDCG 2022-10 documents offer a comprehensive overview of the complexities and regulatory pathways for conducting such trials, highlighting the necessity for compliance with the Medical Device Regulation (EU 2017/745, MDR) and the Clinical Trials Regulation (EU 536/2014, CTR), as well as with the In Vitro Diagnostic Regulation (EU 2017/746, IVDR).

Questions 15 and 16 in MDCG 2021-6 Rev. 1 and the detailed guidance in MDCG 2022-10 illuminate the pathway for combined trials involving medical devices and medicinal products. This guidance is crucial for sponsors planning studies that bridge the gap between medical devices and pharmaceuticals, offering clear directives on navigating combined trials.
The concept of “combined trial” is further elaborated to include simultaneous investigation of a medicinal product (clinical trial authorized under the CTR) and an IVD (clinical performance study), subject to the requirements of both the CTR and IVDR.
Sponsors are encouraged to thoroughly understand and comply with both MDR/IVDR and CTR requirements, ensuring that all aspects of the combined trials are adequately addressed.

Usability Studies

Usability studies are paramount in ensuring that medical devices meet the highest standards of safety and performance through effective user interface design. The MDCG 2021-6 Rev. 1 document, alongside the EN 62366-1:2015 standard, provides comprehensive guidance on when and how usability studies are considered within the scope of clinical investigations under the MDR.

It emphasizes the crucial role of usability studies in integrating user feedback into the device design and development processes. This aligns with the focus of EN 62366-1:2015 on user interface characteristics that foster both safety and user satisfaction, highlighting the importance of these studies in enhancing device usability and overall patient care.

Usability testing evaluates how well users can interact with a device within specified environments, aiming to enhance the user interface to promote performance, safe, and satisfying use.

Question 17 of MDCG 2021-6 Rev. 1 clarifies when usability studies are regarded as clinical investigations under the MDR. The classification hinges on the study’s scope, purpose, and the extent to which users are exposed to the device.
Usability testing that exposes users to device-related risks or where poor usability could impact patient or user safety is more likely to fall under the definition of a clinical investigation. Manufacturers must document their rationale for classifying a usability test as outside the scope of a clinical investigation when human subjects are involved.
Manufacturers should strategically design usability tests to limit human exposure to risks before investigating device performance and safety in clinical investigations.
Documentation of usability considerations, as part of the technical documentation, is critical. This includes justifying why certain usability tests do not constitute clinical investigations, ensuring compliance with both MDCG 2021-6 Rev. 1 guidance and EN 62366-1:2015 requirements.

Invasive or Burdensome Considerations in MDCG 2021-6 Rev. 1

Question 13 is particularly relevant for ensuring the ethical conduct and safety of participants in clinical investigations. It delves into what is considered burdensome or invasive, guiding sponsors in designing studies that minimize discomfort or risk to participants. This question is vital for maintaining ethical standards and participant welfare in both medical device and in vitro diagnostic studies under IVDR.

Impact on Medical Device Stakeholders

The MDCG 2021-6 Rev. 1 document significantly influences the medical device sector. It offers pivotal guidance that extends well beyond the regulatory framework to affect various stakeholders involved in the lifecycle of a medical device within the European Union.

Manufacturers and Sponsors

Manufacturers and sponsors find in MDCG 2021-6 Rev. 1 an essential roadmap. This guidance provides clarity on regulatory requirements, helping to streamline clinical investigations, mitigate risks, and shorten the time-to-market for innovative solutions.

Strategic Planning and Execution: The document outlines regulatory pathways for different types of clinical investigations, facilitating better planning and execution.
Risk Management: Emphasizes the importance of safety reporting and ethical considerations, aiding in the development of comprehensive risk management strategies.

Competent Authorities and Ethics Committees

Competent authorities and ethics committees are crucial in the regulatory oversight of medical devices. MDCG 2021-6 Rev. 1 enhances their ability to assess and ensure compliance with the MDR, promoting a unified application across the EU.

Streamlined Review Processes: Provides clear guidelines that support more efficient review and approval processes, contributing to quicker decision-making.
Enhanced Transparency and Consistency: Promotes transparency and consistency in the review of clinical investigations, bolstering the collaborative effort across Member States.

Research Centers and CROs

Research centers and Contract Research Organizations (CROs) play a vital role in conducting clinical investigations. The document offers them detailed guidance on designing and implementing studies that align with regulatory expectations and scientific rigor.

Design and Conduct of Studies: Facilitates the incorporation of ethical considerations and safety reporting in study designs, ensuring the generation of reliable and meaningful data.
Collaboration Enhancement: Aids in fostering collaborations between industry and research entities, ensuring that studies are conducted efficiently and effectively.

Legal Representatives

Legal representatives are instrumental in ensuring that the sponsor’s obligations under the MDR are met, particularly for non-EU sponsors. MDCG 2021-6 Rev. 1 clarifies their roles and responsibilities, ensuring compliance across the board.

Regulatory Compliance: Guides legal representatives in navigating the MDR requirements, ensuring sponsors fulfill their regulatory duties.

Patients and the General Public

The ultimate beneficiaries of the MDCG 2021-6 Rev. 1 are patients, who gain access to safer and more performance-oriented medical devices.

Access to Innovative Treatments: Enhances patient access to new and innovative medical devices, improving treatment options and patient care.
Enhanced Patient Safety: Prioritizes patient safety through rigorous clinical investigation standards.

Conclusion

The MDCG 2021-6 Rev. 1 marks a significant stride in the EU’s approach to medical device regulation. This document is vital for navigating the complexities of the Medical Device Regulation (EU 2017/745, MDR). It offers a roadmap that impacts a wide range of stakeholders, from manufacturers to regulators and researchers.

Guidance and Collaboration MDCG 2021-6 Rev. 1 details the path for clinical investigations under MDR. It covers regulatory pathways, changes in trials, and usability considerations. This guidance is crucial. It ensures that devices entering the market are both innovative and safe. The document encourages collaboration across the sector, highlighting the shared goal of enhancing patient care.
Impact Across the Board Manufacturers, competent authorities, ethics committees, and others find value in this guidance. It clarifies MDR compliance, aiding in the efficient development and evaluation of medical devices. The emphasis is on using feedback, ensuring ethical conduct, and strategic planning. This collaborative effort advances medical device safety and innovation.
Benefiting Patients and the Public Ultimately, patients and the public stand to gain the most. They benefit from safer, more performance-oriented medical devices. The document fosters an environment where patient care is at the forefront. Innovations in device technology directly enhance patient outcomes and treatment options.
Moving Forward As the regulatory landscape evolves, staying informed and adaptable is key. Stakeholders must use MDCG 2021-6 Rev. 1 insights to meet the MDR’s demands. This commitment to high standards in device development and evaluation will continue to benefit European healthcare.

Written by:

David Tomé

President

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

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Understanding the MDCG 2023-4 Guidance on Medical Device Software and Hardware Combinations

October 20, 2023

The world of medical device regulation is constantly evolving, with regulatory bodies introducing new guidances to keep up with the technological advances in the sector. One such pivotal guidance is the MDCG 2023-4, focusing on Medical Device Software (MDSW) intended to work in combination with hardware or hardware components.

What is MDCG 2023-4?

The Medical Device Coordination Group (MDCG) released the guidance MDCG 2023-4. This document provides detailed insights into the considerations and regulatory requirements for MDSW that is intended to be used in combination with hardware or its components.

Key Highlights of MDCG 2023-4

1. The Prominence of Hardware in MDSW

For many MDSW, hardware components directly link their effectiveness by feeding them with necessary data. Devices such as wearables, smartwatches, or augmented reality goggles utilize sensors and cameras to collect data. This data is then processed by MDSW applications for medical outcomes.

In some cases, these hardware components are crucial to general consumer electronics, emphasizing the importance of convergence between MDSW and hardware. Especially with integrated sensors, understanding their qualification and the suitable regulatory pathways becomes essential.

2. Regulatory Scope of MDCG 2023-4

Hardware components significantly contribute to the medical functionality of specific MDSW through data and signals. Understanding the regulatory implications when combining MDSW with associated hardware is essential. This guidance sheds light on the regulatory considerations for hardware components when they either function as medical devices or their accessories. However, it’s crucial to note that areas like clinical evaluation or cybersecurity are not covered by this guidance.

3. MDSW-Hardware Synergy

The medical intent of numerous MDSW apps is closely tied to the data from the associated hardware. This hardware serves as data input sources and occasionally even controls the MDSW. For optimal functionality, the hardware must guarantee precision, reliability, and performance. There are various scenarios, such as:

A single manufacturer producing both a dermal patch with sensors and a corresponding MDSW app.
A wearable device, like a watch with sensors, requiring a user to download a corresponding MDSW app from the same manufacturer.

However, situations where the hardware and MDSW app manufacturers differ introduce complex interoperability considerations.

4. Regulatory Considerations

As per MDR’s Article 2 and MDCG 2023-4, a medical device’s purpose can either be achieved independently or in conjunction with other devices or accessories. From the scenarios provided, it’s evident that the MDSW and hardware components are interdependent for medical functionality. If a manufacturer claims a medical purpose for the software, they need to provide evidence of compliance with the MDR, ensuring that the interaction between the MDSW and hardware produces safe and effective results.

5. Market Placement

For the initial scenarios, where both the MDSW and hardware are categorized as medical devices or their accessories, MDR compliance is crucial, focusing on safety, interoperability, and performance. This involves comprehensive clinical evaluations and post-market surveillance. However, if the hardware isn’t MDR compliant, the responsibility of ensuring safety and performance lies with the MDSW manufacturer.

Frequently Asked Questions (FAQ)

Is the MDCG 2023-4 guidance binding for manufacturers? The guidance offers insights and best practices. However, always consult with specific regulatory authorities for mandatory requirements.
Does this guidance apply to software-only medical devices? The primary focus is on software working with hardware. Some sections might still be relevant for software-only devices in terms of risk management.
What penalties are in place for non-compliance? Penalties vary based on regional regulations. It’s essential to stay updated with regional medical device regulatory guidelines.

Conclusion

The MDCG 2023-4 guidance is a significant step in clarifying the regulatory framework for medical device software and hardware combinations. Adhering to the guidance ensures innovations in the field are both groundbreaking and compliant, safeguarding patient welfare. Stakeholders and manufacturers are encouraged to familiarize themselves with the MDCG 2023-4 document to stay ahead in the ever-evolving medical device industry.

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Andre Moreira

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FDA Laboratory Developed Tests (LDTs) Regulation

October 4, 2023

The FDA Laboratory Developed Tests regulation marks one of the most significant shifts in U.S. diagnostic oversight in decades. The FDA’s new rule phases in full regulation of LDTs over four years, with no grandfathering. This change elevates the importance of IVD CROs, whose regulatory and clinical expertise will be critical as laboratories adapt to stringent new requirements. The rule represents a major transformation in the U.S. IVD landscape and will reshape how laboratories develop, validate, and maintain LDTs.

Introduction

On September 29, 2023, the FDA released a groundbreaking proposed rule that fundamentally redefines how the agency regulates Laboratory‑Developed Tests (LDTs). This proposal shifts LDTs out of decades of enforcement discretion and brings them fully under the FDA’s medical device framework.

Because LDTs are a subset of in vitro diagnostic products (IVDs), the new rule has sweeping implications for clinical laboratories, manufacturers, and the broader diagnostics industry. Under the FDA Laboratory Developed Tests regulation, LDTs will now be treated like other medical devices—requiring quality systems, medical device reporting, registration, listing, and in many cases, premarket review.

For stakeholders across the IVD sector, this change is significant.

Key Points to Consider as the FDA regulates LDTs

Expanded Definition of IVDs
The FDA proposes to explicitly classify LDTs as IVDs under 21 CFR 809.3.
This means LDTs will now fall under the same requirements as traditional IVD medical devices.
Phased, Four‑Year Implementation
The FDA will remove enforcement discretion in five stages over a four‑year timeline.
Each stage introduces new regulatory obligations for laboratories.
No Grandfather Clause
The proposal does not exempt existing LDTs. All LDTs (old and new) must eventually comply.
Test Categories Exempt from Enhanced Oversight
Certain test types, including forensic tests and HLA assays, are proposed for exemption.
Public Comment Period
Stakeholders were invited to submit comments through December 4, 2023.

Background on FDA Regulation for LDTs and IVDs

IVDs have traditionally been subject to rigorous regulatory scrutiny under various heads:

510(k) premarket notification or premarket approval (PMA)
Quality system regulation
Medical device reporting
Registration and listing
Labeling

LDTs, however, historically operated under enforcement discretion, receiving minimal oversight. This approach was based on the assumption that LDTs were low risk and used primarily within single laboratories.

That landscape has changed.

The Evolving Landscape of LDTs

Over the last 50 years, LDTs have become increasingly complex, widely used, and technically sophisticated. This evolution has driven demand for stronger oversight in areas such as:

Clinical validity
Analytical performance
Manufacturing consistency
Patient safety

The new FDA Laboratory Developed Tests regulation directly responds to these gaps. By redefining LDTs and removing enforcement discretion, the FDA aims to strengthen public health protections.

The Road Ahead: Key Regulatory Impacts

The phased implementation timeline will introduce major compliance requirements:

Medical Device Reporting

The first enforcement area to take effect.

Quality Systems Regulation

Expected three years after publication of the final rule.

Premarket Review

Introduced 3.5 to four years after the final rule, starting with high‑risk LDTs and expanding to moderate-and-low risk tests.

Labs performing LDTs must begin planning now. Clinical and analytical validation, documentation systems, and regulatory processes will all require upgrades.

Alignment With Europe’s IVDR Rollout

The FDA’s new approach mirrors developments in Europe under the In Vitro Diagnostic Regulation (IVDR). The IVDR already applies strict rules to in‑house tests and LDTs, requiring:

Complete Technical Documentation
A compliant Quality Management System
Performance evaluation and validation
Adherence to Article 5.5 requirements for in‑house devices

çUnder IVDR, an LDT cannot be used if an equivalent CE‑marked test exists. This forces laboratories to justify in‑house development and meet near‑manufacturer‑level standards.

Conclusion: An Industry in Transition

As experts in IVD quality, regulatory, and clinical operations, MDx CRO encourages laboratories and manufacturers to prepare now for the FDA Laboratory Developed Tests regulation. Although legal challenges may influence the timeline, increased oversight is inevitable, and already fully established within Europe under the IVDR.

Stakeholders should submit comments to the FDA by December 4, 2023, and begin strengthening their regulatory systems immediately.

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Carlos Galamba

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Monkeypox Diagnostic Test Specifications: Navigating WHO’s TPPs

August 24, 2023

WHO publishes specifications for monkeypox tests

The World Health Organization (WHO) has recently unveiled two pivotal Target Product Profiles (TPPs) for monkeypox diagnostic test specifications. As the diagnostic landscape evolves, it becomes imperative for diagnostic manufacturers to align with these international benchmarks. MDx CRO stands at the forefront as a strategic CRO and regulatory consulting partner to navigate these benchmarks with precision and compliance.

Deciphering WHO’s TPPs

The intended patient population in both TPPs are individuals suspected of monkeypox infection, including children and adults, TPP1 is tailored for NAAT (nucleic acid amplification tests) qualitative diagnostic test applications within healthcare settings and laboratories. TPP1 is directed towards laboratories or point of care facilities, such as a outpatient or STI clinics, emergency units or other settings near patient care. It mandates a test that boasts high diagnostic sensitivity (≥95%), specificity (≥97%) when compared to a reference molecular method.

Sample type: lesion material or mucosal swabs (excluding saliva).
The test’s intended user is typically laboratory personnel or a trained healthcare professional (when used near-patient).
Closed molecular systems and tests that do not require extraction prior to amplification/detection are preferred.
Test design: 2 independent target regions with at least one target that is monkeypox specific. The IFU should specify the assay’s target region.
Results should be obtained in under 4 hours and preferable under 1 hour.

In contrast, TPP2 should be used for tests that aid the diagnosis of orthopoxvirus antigens, such as qualitative lateral flow immunoassays tailored for decentralized used, including in the community, rural environments and low-resource settings. Results should be interpreted visually and/or through digital readout via smartphone. Tests should demonstrate adequate diagnostic sensitivity (≥80%), specificity (≥97%) for community based settings when compared to a reference molecular method.

Sample type: lesion material, mucosal swabs or saliva. When present, lesions are the preferred sample type.
The test should be designed for use by non-lab trained intended users.
The target analyte is the monkeypox virus antigen/protein. Tests targeting antibody detection are not acceptable.
Results should be obtained quickly in under 40 minutes and preferable under 20 minutes, a crucial feature for time-sensitive environments such as outbreak regions or remote settings

The creation of WHO monkeypox diagnostic test specifications was underpinned by a comprehensive process, involving myriad experts from fields such as science, public health, and regulation. A crucial step involved a public consultation phase, ensuring the TPPs were refined with broad feedback before finalization. This initiative by WHO is a hallmark in the trajectory of creating robust diagnostic tools for monkeypox and related orthopoxviruses.

Partnering with MDx CRO for your monkeypox test development

MDx CRO is unwavering in its commitment to support the development and clinical trials that meet monkeypox diagnostic test specifications. Our services, fortified by vast expertise, encompass areas such as meticulous IVD clinical performance study design, efficient sample collection and analysis, and stringent regulatory compliance across multiple jurisdictions, with an emphasis on CE marking under the IVDR.

While the TPPs provide an essential blueprint, the diagnostic journey also demands attention to several critical facets:

Study Populations: Defining the optimal study population is paramount. Such a population should encompass individuals potentially benefiting from the test, including those suspected of monkeypox or those at elevated risk of exposure.
Reference Standards: Leveraging appropriate reference standards ensures validation of the test’s accuracy and reliability, forming the backbone of its developmental and evaluative processes. Samples should cover a range of clinically relevant viral loads as per the reference method used.
IVD Clinical Study Design of monkeypox tests should include prospective or leftover specimens, covering a clinically relevant viral load. MDx CRO can help design and execute clinical performance studies in alignment with the WHO TPP and IVDR CE mark expectations.

With the scientific acumen and regulatory insights of MDx CRO, diagnostic manufacturers can confidently navigate the intricacies of the WHO’s TPPs and other global benchmarks.

Planning to develop an IVD monkeypox test or to conduct an EU based clinical trial? Contact us today to find out how MDx CRO can accelerate your development journey.

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Influenza Assays: Risk Classification Under IVDR

July 27, 2023

New position statement published by the IVD expert panel on influenza viruses

MDx CRO, an IVD consultancy and CRO company, reviews the latest position paper published by the EU Commission IVD Expert Panel. The publication discusses the risk classification of influenza assays under the In Vitro Diagnostic Regulation (IVDR) and focuses on whether influenza viruses should be considered as high-risk Class D pathogens or fall under other risk categories.

Background

Influenza viruses, like many respiratory viruses, have the potential to cause life-threatening diseases with a high or suspected high risk of propagation. The severity and transmissibility of an influenza virus strain depend on various factors, including virus-specific, host-specific, and environmental factors. Seasonal influenza strains undergo antigenic drift, while antigenic shift can result in new influenza A subtypes, potentially leading to pandemics.

Transmissibility and Severity

Transmissibility is a key indicator of the ease of movement of the influenza virus between individuals and communities. It is influenced by the virus’s ability to spread from person to person, transmission dynamics, and population susceptibility. Influenza viruses can be transmitted not only between humans but also from animals to humans and vice versa, posing public health risks.

Disease Severity of Influenza A(H1N1)pdm09

The A(H1N1)pdm09 strain, responsible for the 2009 pandemic, was remarkably different from seasonal influenza strains, leading to a higher fatality rate and impacting younger populations more severely. Since the pandemic, A(H1N1)pdm09 has continued to circulate, causing significant disease burden globally. Despite available vaccines, their effectiveness remains a concern, and oseltamivir-resistant variants have been reported. Ongoing global surveillance and analysis of antiviral susceptibility are crucial for public health and patient care.

Other Circulating Influenza Virus Strains

Various seasonal influenza viruses, both type A and B, have the potential for high transmissibility and severe disease. An unusual and severe epidemic was observed during the 2017-2018 season, primarily dominated by influenza B virus, while influenza A(H3N2) and A(H1N1)pdm09 also caused severe cases in older adults. Additionally, zoonotic transmission of novel influenza strains, like H3N2, H7N9, and H5N6, has been reported, highlighting the importance of global surveillance and early warning systems.

Feasibility of Developing General Common Specifications for influenza assays

Given the unpredictable changes in influenza strains and the potential for novel variants to emerge, it is challenging to develop general common specifications with minimum performance requirements for class D devices. Assays for seasonal influenza detection, intended for individual infection detection, may not be suitable for detecting emerging strains with pandemic potential or from non-human origins. Such assays may require different safety protocols and risk assessments, and rapid confirmatory real-life performance evaluation studies should be considered.

Risk classification of influenza assays under the IVDR

Influenza viruses, particularly A(H1N1)pdm09, have demonstrated the potential for high transmissibility and severe disease, leading to significant public health consequences. The development of general common specifications for all influenza strains is challenging due to the varying risks and objectives associated with different assay types. With regards to the risk classification of influenza assays under the IVDR, the Commission’s position paper points out that seasonal influenza assays should be classified as class C devices, while class D devices may be necessary for assays intended to detect strains with pandemic potential or from non-human origins. This position statement may contradict some of industry’s initial assumptions on the classification of devices for seasonal influenza. V2 of the MDCG guidance on classification rules for IVDs originally stated that a “device intended for the detection of influenza A/B virus (non pandemic)” was a class B device according to rule 6.

Implications for manufacturers of influenza assays

The classification of IVDs can be highly intricate, and determining whether a device should be classified as Class B or Class C (and even D) often presents challenges. This complexity is particularly evident in devices where the associated risk level varies between low, moderate, and high, depending on factors such as circulating strains and the intended use of the device.

Notified Bodies have been adhering to the MDCG classification guidance to classify these devices and grant appropriate certification according to the risk class. For instance, assays designed to detect seasonal influenza were typically considered Class B devices, following examples provided in the guidance. On the other hand, assays intended for detecting high-risk strains would be classified as Class D (also according to the guidance).

This classification approach seemed logical until the latest advice from the expert panel was published. According to this updated advice, seasonal influenza assays could potentially be reclassified as Class C devices. This reclassification would have significant implications for manufacturers, as it would require the creation of Periodic Safety Update Reports (PSURs), Summary of Safety and Performance (SSP) documents, and other additional scrutiny throughout the entire process.

Given these potential changes, MDx CRO and relevant stakeholders are intrigued to learn how Notified Bodies will respond to this new development and what their expectations will be moving forward. Manufacturers may need to adapt their strategies to comply with a potential revised classification and the increased requirements, which may present both challenges and opportunities in the IVD industry.

Ongoing global surveillance, international collaboration, and data sharing are essential for effective influenza control and preparedness.

MDx CRO has extensive experience in conducting clinical performance studies and providing regulatory support for high-risk infectious disease IVDs.

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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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MDR Transition Period: Updated Q&A Document, Changes & Clarifications

July 20, 2023

The recent amendment of the Medical Devices Regulation (MDR) and In Vitro Diagnostic Medical Devices Regulation (IVDR) through Regulation (EU) 2023/607 has introduced crucial changes to safeguard public health, prioritize patient safety, and prevent disruptions in healthcare services. The Q&A document regarding the extension of the MDR transition period and removal of the “sell-off” periods has been updated (July 2023) in response.

Key Changes to the Q&A Document on the MDR Transition Period

MDx CRO had previously published a comprehensive summary of the European Commission’s Q&A document.

The following questions in the Q&A document have undergone significant changes:

Q&A no 1: The Commission will provide flowcharts to assist manufacturers and other relevant parties in determining whether a device falls under the extended transitional period specified in Article 120 MDR.
Q&A no 2: Clarifies that a letter from a notified body regarding the certificate’s expiry or a controlled phase-out of production, mutually agreed upon by the notified body and the manufacturer before 20 March 2023, is not considered a certificate withdrawal.
Q&A no 7: Manufacturers need to provide a self-declaration confirming their compliance with the extension conditions and stating the end date of the transition period. They can include a “confirmation letter” from the notified body, which identifies the devices and certificates covered. Templates for the self-declaration and notified body’s confirmation letter are available at this link. Furthermore, an updated factsheet for competent authorities in non-EU/EEA countries explains the functioning of the extended transition period.
Q&A no 8: Clarifies that that when submitting information, notified bodies (as per Article 36(2) MDR) must have the capability to include the relevant (digital) document(s) in their own records. Simply having ‘read-only’ access to the manufacturer’s electronic data platform is not considered sufficient.
Q&A no 17: Manufacturers must inform the notified body about devices that require surveillance, especially if surveillance activities were discontinued due to certificate expiration before 20 March 2023. This information allows the notified body to conduct proper surveillance and make necessary arrangements with the manufacturer.

New Additions to the Q&A Document

The following questions have been newly introduced in the MDR Transition Period Q&A document:

Q&A no 6.1: If a competent authority grants a national derogation under Article 59 MDR or requires a manufacturer to follow the applicable conformity assessment procedure as per Article 97 MDR after 20 March 2023, the extended transitional period specified in Article 120(3a) MDR does not apply.
Q&A no 6.2: If the removal of the CE marking is a condition or consequence of the derogation granted by the competent national authority according to Article 59 of the MDR, the device may still be placed on the market with a CE marking, provided that all other conditions are met.
Q&A no 9.1: If a manufacturer withdraws the conformity assessment application or terminates the written agreement with the notified body after the deadlines, the extended transitional period ends. However, if the manufacturer switches to another notified body and fulfills all conditions, the transitional period continues. Updated documentation is necessary after the change, except when changing notified bodies due to non-compliance.
Q&A no 9.2: The manufacturer’s organization may undergo administrative changes, such as changes in name, address, or legal form, which generally do not impact the transitional period during the extended transition period. However, the transfer of devices from a manufacturer certified under MDD/AIMDD to another manufacturer intending to market them under MDR is not covered by the transitional period, unless both manufacturers are part of the same larger organization.
Q&A no 11.1: Legacy devices are not required to comply with the Unique Device Identification (UDI) requirements of the MDR during the extended transitional period. Even after May 26, 2024, when the manufacturer of the legacy device must have an MDR-compliant Quality Management System (QMS), UDI requirements will only apply if UDI assignment is necessary for those devices according to Article 10(9), point (h), of the MDR.

MDR Transition with MDx CRO

In conclusion, these recent changes and additions to the medical device regulations are significant milestones that harmonize industry standards and ensure a smooth transition for legacy devices, prioritizing safety and public health. The Q&A document serves as an essential tool for manufacturers, notified bodies, and competent authorities navigating the evolving regulatory landscape within the European Union.

Take advantage of MDx CRO’s expertise to ensure MDR compliance and meet transitional period requirements. Partnering with MDx CRO empowers manufacturers to meet safety standards, unlock opportunities in the European healthcare market, and contribute to healthcare advancements.

Contact us today!

Industry Insights & Regulatory Updates

EU AI Act and Medical Devices: What SaMD Developers Need to Know (2026)

FDA QMSR: How the 2026 Regulation Shift Transforms MDSAP Audits and FDA Compliance Inspections

Navigating the IVDR CDx Certification Pathway

ISO 20916:2024 What You Need to Know for Clinical Performance Studies in 2026

IVDR Lab Readiness: Step-by-Step Transition Checklist