IVDR Performance Studies and the ISO 20916:2024 Revision

April 2, 2024

ISO 20916: Introduction

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

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

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

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

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

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

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

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

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

Success in IVD Clinical Performance Studies with MDx CRO

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

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

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

Highlights from Annex ZA include:

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

Synergies between ISO 20916 and IVDR:

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

Differences to be aware of:

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

Who Benefits from EN ISO 20916:2024?

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

Advantages of Adopting EN ISO 20916 for IVD Performance studies

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

Implications for IVD Performance Studies and CRO Services

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

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

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

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

Written by:

Carlos Galamba

CEO

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

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FDA Laboratory Developed Tests (LDTs) Regulation

October 4, 2023

FDA’s new LDT regulation underscores the vital role of IVD CROs in compliance and safety. Phased over four years without grandfathering, it highlights the necessity for IVD CROs’ regulatory expertise and their key role in aligning LDTs with stringent standards, marking a significant shift in the IVD landscape.

Introduction

The Food and Drug Administration (FDA) recently released a groundbreaking proposed rule on September 29, 2023, aiming to transform its existing approach toward Laboratory-Developed Tests (LDTs). This paradigm shift directly impacts In Vitro Diagnostic products (IVDs) and their regulation. The proposed rule presents a layered plan for LDTs, phasing out FDA’s longstanding policy of enforcement discretion. For stakeholders in the IVD sector, including clinical laboratories and LDT manufacturers, the implications of this proposed rule are monumental.

Key Points to Consider as the FDA regulates LDTs

Modification to IVD Definition: The FDA aims to explicitly categorize LDTs as IVDs within the scope of 21 CFR Part 809.3, thus making them subject to FDA’s medical device regulations, including premarket review.
Phased Implementation: The FDA proposes to gradually roll back its enforcement discretion policy for LDTs, segmenting the regulatory shifts over five distinct stages across a four-year period.
No Grandfather Clause: Unlike previous considerations, the new proposal doesn’t plan to “grandfather” existing LDTs. Public commentary on this subject is invited.
Test Exemptions: Specific test types, such as forensic and human leukocyte antigen tests, are marked for exemption from enhanced regulatory oversight.
Comment Period: Stakeholders have until December 4, 2023, to submit their feedback on the proposed rule.

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

These IVDs also fall under the Clinical Laboratory Improvement Amendments of 1988 (CLIA). LDTs, a specialized category within IVDs, have long operated under enforcement discretion, essentially receiving less stringent oversight. This approach historically aligned with the perception of LDTs as low-risk products, but the proposed rule acknowledges the evolved complexity and widespread use of LDTs in modern healthcare.

The Evolving Landscape of LDTs

Over the past 50 years, the role of LDTs has changed dramatically, making the FDA regulation of Laboratory Developed Tests increasingly crucial. Their growing prevalence and the technical sophistication involved have prompted calls for stronger regulatory oversight. These significant developments have culminated in the FDA’s renewed perspective on LDTs. Shedding its previous stance of general enforcement discretion, the FDA Laboratory Developed Tests Regulation now aims to redefine LDTs broadly, addressing potential regulatory gaps and emphasizing the need for robust public health protection.

The Road Ahead: Implications and Recommendations

The phased implementation approach impacts various aspects of medical device regulation:

Medical Device Reporting: Will be the first area where enforcement discretion will cease.
Quality Systems: Expected to come under scrutiny three years after the final policy is published.
Premarket Review: To be phased in 3.5 to four years after the final policy, impacting high-risk IVDs first and then trickling down to moderate-risk and low-risk IVDs.

Given these imminent changes, clinical labs offering LDTs must prepare for enhanced regulatory compliance and for increased FDA regulation of Laboratory developed tests. These labs should develop protocols for both analytical and clinical validity, ensuring alignment with new regulatory expectations.

Synergies with the EU’s IVDR roll-out

In Europe, a similar regulation, the In Vitro Diagnostic Regulation (IVDR), is being phased in, emphasizing the importance of compliance for in house developed tests. Under IVDR, laboratories must ensure that their Technical Documentation and Quality Management System are up-to-date and comply with the regulation and the national law. Failure to comply with the IVDR can result in serious consequences, including fines, loss of accreditation, and even closure of the laboratory.

Furthermore, laboratories that develop in-house IVDs will be required to comply with similar requirements for manufacturing as commercial IVD manufacturers. This means that laboratories must ensure that their IVDs meet high standards for safety and performance, which can only be achieved through rigorous testing and validation.

It is important to note that the IVDR specifically includes in-house developed tests, including LDTs and CE marked IVDs modified by laboratories. If an equivalent CE marked device is available on the market or IVD product is manufactured at an industrial scale, the laboratory cannot use exemption for LDT´s provided in the IVDR (Article 5.5) and must CE mark the IVD. MDx CRO has recently published an article assessing the impact of the IVDR on LDTs.

Conclusion: An Industry in Transition

As specialists in quality, regulatory, and clinical consultancy focused on IVDs, MDx CRO advises stakeholders to take proactive measures in anticipation of these sweeping regulatory changes. Judicial challenges and public feedback could alter the timeline for the FDA to start regulating LDTs, but there’s no doubt that enhanced regulation of LDTs is on the horizon, already in full force in Europe.

Comments on the Proposed FDA Rule should be submitted by December 4, 2023, to help shape this crucial regulatory development. It is an opportune time for the industry to engage in open dialogue and to prepare for the inevitable changes that lie ahead.

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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Navigating the IVDR CDx Certification Pathway

August 24, 2023

The evolving landscape of Companion Diagnostics (CDx) introduces complexities in regulatory and certification processes. Engaging in IVDR Companion Diagnostic Consulting is essential to ensure a streamlined and compliant journey.

Deciphering Regulatory Nuances: US vs. EU

Historically, CDx devices in the EU were self-certified under the IVDD. A CDx manufacturer may have had experience with the FDA but the regulatory process in the EU is only now emerging.

The EU IVDR defines a CDx as a device which is essential for the safe and effective use of a corresponding medicinal product to identify, before and/or during treatment:

Patients who are most likely to benefit from the corresponding medicinal product
Patients likely to be at increased risk of serious adverse reaction as a result of treatment with a corresponding medicinal product

The FDA’s definition is similar but extends to devices used for “monitoring treatment responses with a particular therapeutic product”. Unlike in the US such devices are not considered companion diagnostics in the EU. Furthermore, the FDA acknowledges a category of devices termed complementary diagnostics. These diagnostics are characterized as tests that pinpoint a group of patients, identified by specific biomarkers, who respond well to a drug. While they assist in evaluating the risk-benefit ratio for individual patients, they aren’t mandatory for drug administration. Within the IVDR framework, complementary diagnostics aren’t explicitly detailed, nor do they have specific prerequisites for CE certification

These nuances are key for any CDx regulatory strategy and for the planning of CDx clinical trials. A specialized IVDR CDx consulting company like MDx CRO can help diagnostic companies and their pharma partners navigate global differences and ensure CDx regulatory compliance.

The EMA Consultation Process

EMA’s guidance stands as a pivotal component in IVDR Companion Diagnostic Consulting. The EMA CDx Assessment Report Template, publicly available, provides a comprehensive blueprint. It is a great source of information for the expectations in CDx submission content, particularly useful for when drafting SSPs and IFUs.

MDx CRO published a comprehensive guide to the CDx consultation process.

The process encompasses:

Declaration of intent.
EMA Rapporteur appointment.
Optional, but highly recommended, pre-submission meeting.
Application submission.
Interactive Q&A phases.
EMA’s final verdict.

Crafting of SSP & IFU with Detail

For successful IVDR CDx certification, the SSP and IFU documents should be meticulously detailed as they are the 2 key documents used during the EMA consultation process.

Diagnostic manufacturers should ensure they include:

Emphasis on scientific validity of the biomarker
Comprehensive detail on performance evaluation, study design descriptions, encompassing both analytical and clinical performance.
Insight into clinical data, detail on device modifications during or after the clinical performance study, and associated impacts, rationale for cut-off point selection and more.

A deep dive into the risk-benefit analysis is pivotal, concentrating on major residual risks and device limitations.

Time Considerations for IVDR CDx Certification

The certification process for CDx under IVDR is extensive. From the initial 3-month EMA notification to the concluding recommendation, the timeline can span 8-18 months. Such extended durations underline the criticality of early preparations. Engaging early with a specialized CDx consulting company can help avoid surprises and streamline the CDx certification journey.

The expertise offered by the notified body can significantly enrich IVDR Companion Diagnostic certification. Early engagements, prior to document submissions, can provide clarity, ensuring alignment with EMA requirements.

Selecting your IVDR CDx Consulting partner

MDx CRO has published a deep dive into the crucial factors to bear in mind when picking an IVD consultant.

In the dynamic realm of CDx, efficient navigation is paramount. If you’re seeking specialized insights into IVDR certification, explore our IVD services. At MDx CRO, our experts offers tailored IVDR Companion Diagnostic Consulting, ensuring optimal integration of CDx within the regulatory framework.

Contact our team today to discuss your CDx product needs!

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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IVDR Transition: Insights from the Dutch Authority

August 11, 2023

State of play of IVDR Transition:

In the realm of in vitro diagnostics (IVD), a seismic shift is underway as manufacturers grapple with the complexities of transitioning to the new European In Vitro Diagnostic Regulation (IVDR). This transition, necessitated by advancements in technology and evolving patient safety concerns, brings both challenges and opportunities for IVD manufacturers. A recent report by the Dutch Competent Authority (IGJ) delves into the progress, setbacks, and strategies of IVD manufacturers in their journey toward IVDR compliance. Over 40% of respondents raised doubts about whether they will be able to obtain the CE marking for their IVDs before the transition periods expire.

The IGJ Report Findings:

The IGJ report sheds light on the multifaceted landscape of the IVDR transition. Manufacturers are confronted with stringent requirements that demand a paradigm shift in their approach to product development, documentation, quality assurance, and post-market surveillance. The report identifies several key challenges:

Technical Documentation Overhaul: The IVDR mandates comprehensive and meticulously documented technical files and dossiers. This demand presents a considerable challenge as manufacturers strive to align existing documentation with the new regulations. Additionally, the dynamic nature of diagnostic technologies requires continuous updates, further complicating the documentation process. Gathering of IVDR Clinical Evidence is particularly challenging for manufacturers due to lack of guidelines and international coordination. For example, application for clinical performance studies across Member States is not fully harmonised.
Certification Complexities: Acquiring the necessary certification from Notified Bodies is a crucial step in the IVDR transition. However, the IGJ report underscores the intricate nature of the certification process, involving rigorous assessments and evaluations. This complexity can lead to delays in bringing products to market. Notified Bodies have reported delays in the certification process due to lack of information in the IVDR technical documentation and also lack of structure and clarity in the file.
Post-Market Surveillance Emphasis: The IVDR places increased importance on post-market surveillance (PMS) and vigilance. Manufacturers are expected to establish robust systems for monitoring the performance and safety of their products throughout their lifecycle. This shift necessitates a proactive approach to identifying and addressing potential issues. 80% of respondents have adapted their vigilance procedures to IVDR requirements, however compliance to PMS System, PMS plan and PMPF requirements is lower, at 70% of respondents. The IGJ has declared they will promote or enforce compliance through random inspection visits.
Educational Imperative: The IGJ report emphasizes the significance of educating all stakeholders, from manufacturers to regulatory bodies, about the intricacies of IVDR compliance. Adequate training is crucial to ensure that everyone understands their roles, responsibilities, and the broader implications of the new regulation.

The Role of MDx CRO in your IVDR Transition:

Amid these challenges, MDx CRO emerges as a guiding light for IVD manufacturers. As the industry grapples with the transformative implications of the IVDR, MDx CRO stands as a stalwart partner, offering expert guidance and tailored solutions to navigate the evolving regulatory landscape.

Strategic Guidance: MDx CRO’s team of seasoned experts provides strategic advice that empowers manufacturers to make informed decisions. Transitioning to the IVDR isn’t just about compliance; it requires a forward-looking approach that considers the long-term impact on products and business strategies.

Technical Documentation Excellence: The IGJ report highlights the criticality of accurate and comprehensive technical documentation. MDx CRO’s expertise shines in this arena, aiding manufacturers in compiling technical files and dossiers that meet IVDR standards while showcasing the safety and innovation of their products.

Certification Support: With the certification process’s complexities highlighted in the report, MDx CRO’s collaborative approach becomes invaluable. By assisting manufacturers in preparing for interactions with Notified Bodies, MDx CRO streamlines the certification journey, ensuring quicker time-to-market for products. Read about our pre-submission service.

Continuous Partnership: The IGJ report’s emphasis on post-market surveillance aligns with MDx CRO’s commitment to the entire product lifecycle. Beyond the transition, MDx CRO supports manufacturers in establishing robust PMS systems, enabling them to meet ongoing compliance and safety monitoring requirements.

Knowledge Dissemination: As underscored by the report, education is pivotal in a successful IVDR transition. MDx CRO’s training and workshops empower manufacturers with the insights and understanding needed to navigate the new landscape with confidence.

Conclusions:

The IGJ report provides a comprehensive view of the challenges and advancements in the IVD sector’s transition to IVDR compliance. One message is clear, the IGJ unequivocally mandates manufacturers to expedite IVDR certification without delay. This is key to prevent peak in applications when the transition period come to an end. Within this landscape, MDx CRO emerges as a crucial enabler, equipping manufacturers with the tools, expertise, and support needed to thrive in the new regulatory era. By offering strategic guidance, technical excellence, certification support, ongoing collaboration, and knowledge dissemination, MDx CRO paves the way for compliant, innovative, and patient-centered IVD products. As the industry continues to navigate the evolving regulatory seas, MDx CRO stands as a steadfast partner in this transformative journey.

Contact our team today to discuss your IVDR transition needs!

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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Carlos Galamba: Your Trusted IVD Consultant and IVDR Expert

August 10, 2023

Innovative medical professional specializing in MedTech advancements at MDX, focusing on accelerating healthcare innovation and improving patient outcomes through cutting-edge technology. — Carlos Galamba, CEO MDx CRO

Carlos Galamba, IVD Consultant – MDx CRO Founder

In the intricate landscape of In Vitro Diagnostics (IVD) and the evolving In Vitro Diagnostics Regulation (IVDR), one name stands out as a beacon of expertise and guidance – Carlos Galamba. With a wealth of experience spanning over 18 years in the IVD sector, Carlos is a seasoned consultant who has left an indelible mark on the world of diagnostics.

Pioneering Path to Regulatory Mastery

Carlos’s journey commenced as a biomedical scientist, setting the stage for a remarkable career journey. His trailblazing role as the first in-house clinician for IVDs at BSI (British Standards Institution), a renowned Notified Body, played a pivotal role in shaping the clinical oversight process for hundreds of diagnostics. From genetic tests to molecular assays, point-of-care diagnostics, CDx, LDTs / in-house assays, NGS and beyond, Carlos expertise is unrivaled. This groundbreaking contribution has significantly impacted how the industry approaches regulatory compliance.

Mastering the IVDR Landscape

Carlos Galamba’s expertise extends well beyond his role at BSI. His insights have positioned him as a distinguished external expert for the EU Commission, where he provides invaluable guidance in navigating the intricate IVDR terrain. His strategic acumen has propelled prominent companies like Biomerieux, Cepheid, Leica, Hologic, Abbott, Thermofisher, Werfen and more toward achieving excellence in IVDR compliance.

Guiding Innovation in IVD

At the helm of innovation, Carlos Galamba served as the Vice President of IVD Intelligence & Innovation at RQM+. His technical thought leadership encompassed an array of IVD technologies, ranging from immunoassays to more complex next-generation sequencing tests and IVD Software. Carlos’s insights have led to the development of competitive intelligence strategies that drive expansion and commercialization within the IVD consultancy sector.

A Catalyst for Regulatory Success

Carlos’s dedication to simplifying the complex is the cornerstone of his approach. His tailored solutions empower businesses to navigate the evolving regulatory landscape while gaining a competitive edge. His remarkable achievements, including leading the transition to the new EU medical device legislation (IVDR) at several companies and successfully implementing pivotal regulatory changes, position Carlos Galamba as a catalyst for transformative IVD projects.

Connect with MDx CRO for Regulatory Excellence

Whether you’re an IVD startup with ambitious goals or a global diagnostics manufacturer looking to streamline regulatory processes, Carlos Galamba’s expertise is your compass for regulatory mastery. If your company is seeking unparalleled IVD consulting, don’t hesitate to connect with Carlos and his team at MDx CRO. Together, they bring a wealth of knowledge to guide you through the complexities of IVD regulations.

Connect with Carlos on LinkedIn

In the complex landscape of In Vitro Diagnostics and the evolving IVDR framework, Carlos Galamba’s expertise continues to set the standard for regulatory excellence. His extensive experience and leadership exemplify how deep regulatory insight and practical guidance can shape successful IVD strategies and ensure lasting compliance under the IVDR.

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Companion Diagnostics IVD Consultancy within the EMA Framework: Comprehensive Guidance

August 8, 2023

The field of companion diagnostics IVD (CDx) represents a confluence of technological innovation, regulatory compliance, and patient care. As personalized medicine becomes an integral part of healthcare, the regulatory framework governing CDx, including the In Vitro Diagnostic Medical Devices Regulation (IVDR), has become more complex. This scenario calls for a specialized companion diagnostics consultancy. MDx CRO is at the forefront of this arena, offering expertise and guidance in the process for CDx consultation with the European Medicines Agency (EMA), Notified Body preparation and IVDR compliance within the European Union (EU).

Companion Diagnostics IVD and their Role

CDx are in vitro diagnostic (IVD) tests designed to provide information that is essential for the safe and effective use of a corresponding medicinal product. Their applications could include:

Identifying patients who are most likely to benefit from a particular therapeutic product.
Determining patients’ suitability for specific treatments.
Monitoring responses to ongoing treatments.

The Impact of IVDR on Companion Diagnostics

The IVDR sets out robust legal requirements for in vitro diagnostic medical devices, including CDx. Key aspects include:

Enhanced Patient Safety: Ensuring the quality and reliability of CDx IVDs.
Stricter Oversight: Increased scrutiny of the CDx development and approval process. Unlike the previous directive, CDx now require conformity assessment by a Notified Body, an independent organization designated to assess the compliance of medical devices and in-vitro diagnostics. In addition, CDx are also assessed by a medicines authority, most likely the EMA (European Medicines Agency), but a competent authority could also be involved .
Comprehensive Technical Documentation: Increased clinical evidence requirements are particularly notable in the IVDR. MDx CRO can help CDx manufacturers and their drug partners gather the necessary data to support their CDx application. This data may include clinical trial data (clinical performance data), analytical data, and safety data. Manufacturers must provide robust clinical evidence to demonstrate the performance, safety, and clinical utility of the CDx.

There are a number of other factors that can affect the approval process for CDx in the EU. These factors include:

The availability of data: Both the Notified Body and the EMA will need to have access to data from clinical trials that demonstrate the safety and effectiveness of the CDx.
The complexity of the CDx: The more complex the CDx, the more difficult it will be to assess its safety and effectiveness.
The novelty of the CDx: If the CDx involves new technologies or indications, the EMA and the Notified Body will need to take a more cautious approach to its approval. Different scenarios will play a role on the extent of scrutiny involved, including co-developed CDx scenarios, follow-on CDx, and CDx already on the market under the old IVD directive.

Understanding the EMA Companion Diagnostics Consultation Procedure

The consultation procedure is initiated by the notified body when it receives an application from a CDx manufacturer. The medicinal product involved could be a medicine already authorised for marketing in the EU or a medicine undergoing approval. Aligning drug and diagnostic development processes can help to ensure that the results of the clinical trials are accurate and reliable, and that the medicine is safe and effective when used with the CDx.

Aligning timelines in the drug and diagnostic (CDx) development process can help to ensure that the clinical trials for the medicine are conducted in a way that is consistent with the intended use of the CDx.

Upon application for a CDx IVD approval, the notified body will submit a letter of intent to the EMA, along with a technical dossier that describes the CDx and the medicinal product.

The EMA will then appoint a rapporteur, who will be responsible for reviewing the technical dossier and issuing a scientific opinion on the suitability of the CDx for use with the medicinal product. The rapporteur will also consider the views of any other interested parties, such as the applicant for the medicinal product, the manufacturer of the CDx, and patient groups.

The EMA will provide its scientific opinion on the CDx aspects that relate to the medicine to the notified body. The notified body will then use the EMA’s opinion to make a decision on whether to grant the CE mark to the CDx, in accordance with the regulatory requirements of the in vitro diagnostics regulation (EU IVDR).

EMA procedure timetables play a major role in the success of the consultation and turn around times for responses can be extremely short. Manufacturers should factor this in as they plan for their CDx submissions. There is the possibility to request a pre-submission meeting which will include representatives from Notified Bodies, EMA and could also include the drug manufacturer – this is used strictly to align on procedural and timing considerations (it is not used to provide feedback on study design or the content of the technical documentation).

One of the key documents used in the consultation and submitted by the notified body to the EMA is the SSP (Summary of Safety and Performance). The EMA expects manufacturers to use the SSP template provided in MDCG 2022-9. A lot more detail is expected in the SSP when compared to the information provided in the IFU. For example, detail on concordance studies is needed, particularly for co-developed CDx when different versions of a diagnostic have been used throughout the clinical development program.

MDx CRO: Your Partner in Companion Diagnostics Consultancy

Our companion diagnostics consultancy services encompass every stage of development, approval, and post-market surveillance:

Guidance on IVDR Requirements: In-depth support in understanding and meeting the specific demands of IVDR as they relate to CDx. MDx CRO can help a diagnostics company identify the specific requirements that apply to its CDx. For example, the requirements for a CDx that is intended to assess a patient’s suitability for treatment may be different from the requirements for a CDx that is intended to be used to monitor a patient’s response to treatment.
Preparation for Notified Body Assessment: Tailored strategies for successful assessment of a CDx under the IVDR: Assistance with compiling and submitting the necessary technical documentation and quality related documents.
Providing training to the manufacturer’s staff: MDx CRO can provide training to the manufacturer’s staff on the EMA’s requirements for CDx, as well as the notified body’s assessment process and expectations. This training will help to ensure that the manufacturer’s staff are prepared to answer any notified body questions and increase chances of success.
Stakeholder Communication: Facilitating communication with all relevant parties.
Global Perspective: Navigating international considerations for CDx in multi-country studies.
Post-Market Support: Focused on maintaining the highest standards through ongoing compliance monitoring with IVDR and other regulatory requirements. This includes implementing strong post-market surveillance processes and Post-Market Performance Follow-up (PMPF) evaluations, monitoring the CDx’s performance in real-world clinical settings, tracking and analyzing adverse events related to CDx usage, and conducting ongoing studies to evaluate the long-term impact and effectiveness of the CDx.

Why MDx CRO for Companion Diagnostics IVD Consultancy?

Expertise: Our in-depth knowledge of CDx, IVDR, and EU regulations offers unparalleled support.
Collaboration: Working closely with clients, we tailor our approach to meet specific needs.
Efficiency: Our insights and guidance save valuable time and resources, simplifying complex regulatory pathways.
Commitment: Our dedication to excellence, patient safety, and innovation sets us apart.

Navigating the multifaceted world of companion diagnostics in the EU, with the added complexity of IVDR, requires a dedicated and skilled partner. MDx CRO stands ready to be your guide in this critical journey, ensuring alignment with all regulatory standards. Reach out to explore how our companion diagnostics consultancy can be the key to unlocking your CDx potential in the EU’s dynamic regulatory environment.

FAQs

Q: What is a co-developed Companion Diagnostics in the context of EMA consultation?

A: A co-developed CDx is a device developed alongside a medicinal product for either initial authorization or a change of indication. This can include development during a pivotal clinical trial or a bridging study, with sufficient documentation to ensure performance alignment.

Q: How does a follow-on CDx differ from a co-developed CDx?

A: A follow-on CDx seeks the same indication as the original CDx but is not developed in parallel with the medicinal product. The follow-on CDx targets the same biomarker but may not be based on the same technology. It should be highly comparable to the original in performance, safety, and effectiveness.

Q: What documentation is required for a follow-on CDx?

A: Sufficient documentation must be provided for a follow-on CDx to prove that its analytical performance is comparable to the original CDx and that there’s no impact on clinical performance incompatible with the safe and effective use of the medicinal product.

Q: How are devices transitioning from IVDD to IVDR handled?

A: Devices initially marketed under Directive 98/79/EC (IVDD) that transition to IVDR fall under the co-developed or follow-on scenarios, depending on how they were initially developed.

Q: Is it possible to proceed with a single CDx consultation procedure for multiple authorized medicinal products and indications?

A: Yes, if a device’s intended purpose includes several authorized medicinal products and indications, it’s recommended to proceed with one single CDx consultation procedure. All concerned medicinal products should be listed in the intention to submit a letter by the Notified Body and in the application form.

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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