ISO 20916 2024 IVDR harmonization IVD studies

April 2, 2024

IVDR Performance Studies and the ISO 20916:2024 Revision

ISO 20916:2024—Clinical performance studies using specimens from human subjects: Good study practice—was first introduced in 2019. In March 2024, it was published as EN ISO 20916:2024, marking a major step in ISO 20916 2024 IVDR harmonization IVD studiesacross Europe. This update aligns clinical performance study requirements directly with the IVDR.

In today’s rapidly evolving IVD landscape, safety and performance remain top priorities. ISO 20916 provides a solid framework to ensure clinical performance studies are planned, executed, recorded, and reported with scientific rigor. Its goal is simple: ensure IVD studies are ethical, reliable, and aligned with regulatory expectations.

This standard supports robust study design, promotes high‑quality data generation, and strengthens compliance for IVD manufacturers navigating the IVDR.

MDx hosted a live webinar on “Preparing for IVDR Clinical Performance Studies under ISO20916 and the new annex ZA” on the 30th April 2024.

Contact us to watch the replay

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

The March 2024 revision introduced a key milestone: Annex ZA, which formally harmonizes ISO 20916 with the IVDR. While the IVDR already referenced ISO 20916, the addition of Annex ZA creates a unified regulatory pathway for clinical performance studies.

Annex ZA bridges the remaining gaps between the standard and the regulation. As a result, manufacturers benefit from clearer expectations and a more predictable approval process.

EN ISO 20916:2024 was approved by CEN without modification, reinforcing its relevance for EU regulatory compliance. However, at the time of writing, official recognition of ISO 20916:2024 as an IVDR harmonized standard in the EU Official Journal is still pending.

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 theEuropean 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

1. Presumption of Conformity

Compliance with the ISO 20916 clauses listed in Table ZA.1 gives manufacturers a presumption of conformity with IVDR GSPRs. This presumption simplifies regulatory alignment across IVD clinical performance studies.

2. Definition Alignment

When definitions differ between ISO 20916 and the IVDR, Annex ZA prioritizes IVDR terminology. This ensures consistency across regulatory submissions.

3. Risk‑Management Updates

Annex ZA strengthens risk‑management expectations. It requires alignment with IVDR principles such as “reducing risks as far as possible.” It also notes that ISO 20916 does not include foreseeable misuse, while the IVDR does—requiring sponsors to bridge this gap.

4. Acceptable Risk Policies

Manufacturers must align acceptable risk decisions with specific GSPRs. Annex ZA also clarifies that while ISO 20916 excludes training as a risk‑reduction measure, the IVDR allows it.

Synergies between ISO 20916 and IVDR:

Despite some differences, the ISO and IVDR frameworks remain closely aligned in key areas:
Clinical performance parameters: Nearly identical, except ISO 20916 omits expected values for normal and affected populations.
Ethical considerations: ISO 20916 provides more detail, defining responsibilities for sponsors and investigators.
Bias mitigation: ISO 20916 offers explicit direction on preventing population, protocol, and reference‑method bias.
Site qualification: More detailed under ISO 20916, specifying resources, equipment validation, and QMS expectations.
CPSR content: ISO 20916 includes additional requirements, especially for interventional studies.
Comparator devices: The standard requires clear listing with commercial name, manufacturer, and catalog number.
Investigator’s Brochure: Both the IVDR and ISO 20916 are aligned, though ISO adds more detail on risk‑benefit documentation.

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

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

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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MDx: Your Dedicated CRO for IVD Clinical Studies in the EU

August 24, 2023

Introduction

In the rapidly evolving world of in vitro diagnostics (IVD), manufacturers are increasingly understanding the need for rigorous clinical performance studies. Such studies form the backbone for ensuring the safety, efficiency, and overall market readiness of IVD devices. With the European Union’s (EU) stringent regulatory environment, conducting these studies requires expertise and precision. That’s where MDx CRO, a trusted name in IVD Contract Research and regulatory consulting, stands out.

Why are IVD Clinical Studies Imperative?

Evidence-based Decision Making: Clinical performance studies furnish the data that can prove the diagnostic accuracy, precision, and utility of IVD devices. They help manufacturers refine their offerings and justify their product claims.
Regulatory Adherence: Ensuring compliance with the EU’s In Vitro Diagnostic Regulation (IVDR) and standards like ISO 20916 is non-negotiable. Clinical studies often form the bedrock in gaining these credentials and opening up the European market.

Navigating the Challenges with MDx CRO

Whether you’re a fledgling startup or an established IVD giant, challenges like site selection, study design, effective monitoring, and regulatory adherence can be daunting. This is where MDx CRO can be your guiding light:

Proven Expertise: With its legacy in the IVD realm and former Notified Body experts on board, MDx CRO offers unparalleled insights into effective study design, ensuring manufacturers derive actionable insights every time.
Network of Clinical Sites: Owing to its years in the industry, MDx CRO has built strong affiliations with leading clinical sites, guaranteeing timely and efficient study conduct.
Regulatory Insight: Navigating the IVDR and ISO 20916 maze becomes simpler with MDx CRO’s regulatory consulting wing, which ensures manufacturers always stay on the right side of the law.
End-to-End Monitoring: With a keen focus on detail, MDx CRO ensures every study stays on track, protocols are maintained, and data integrity remains uncompromised.

Why MDx CRO?

Simply put, MDx CRO isn’t just a service provider – it’s a partner in your IVD journey. Our seasoned team understands the unique challenges IVD manufacturers face, making them an indispensable asset in your product’s journey from concept to the European market.

Conclusion

IVD clinical studies, while challenging, present a golden opportunity to IVD manufacturers to rigorously validate their product’s claims. In the intricate web of EU regulations, manufacturers need more than just expertise; they need a partner. And who better than MDx CRO, which has consistently demonstrated excellence in study design, monitoring, and ensuring complete regulatory compliance? Choose MDx CRO, and let’s work together to bring transformative and reliable IVD devices to the EU market.

FAQs about IVD Clinical Studies and MDx CRO:

What are IVD Clinical Studies?
- IVD clinical studies refer to rigorous research and evaluations conducted to determine the safety, efficiency, and overall performance of in vitro diagnostic (IVD) devices.
Why are IVD Clinical Studies important in the EU?
- The EU has stringent regulatory requirements. IVD clinical studies provide the necessary evidence to support product claims, ensuring compliance with the EU’s In Vitro Diagnostic Regulation (IVDR) and international standards like ISO 20916.
What challenges can manufacturers expect while conducting IVD studies in the EU?
- Manufacturers may face challenges like site selection, creating an effective study design, regular study monitoring, and ensuring compliance with EU regulations and standards.
How does MDx CRO help with these challenges?
- MDx CRO offers expertise in study design, has affiliations with top clinical sites, provides regulatory consulting for EU standards, and ensures end-to-end study monitoring to maintain the quality and integrity of data.
Is MDx CRO suitable for both startups and established manufacturers?
- Absolutely! Whether you’re a startup entering the IVD market or a seasoned manufacturer, MDx CRO’s tailored solutions cater to the unique needs of every client.
How does MDx CRO ensure compliance with the IVDR and ISO 20916?
- MDx CRO boasts a regulatory consulting wing with deep knowledge of IVDR and ISO 20916, ensuring manufacturers receive accurate guidance and assistance throughout their IVD device’s journey to the market. Our team of former Notified Body experts on board help design studies that meet CE mark expectations
What advantages does MDx CRO offer in terms of site selection for IVD studies?
- With its extensive experience and industry connections, MDx CRO has built relationships with leading clinical sites for a variety of technologies and clinical applications, ensuring timely and efficient study initiation and execution.
How does partnering with MDx CRO impact the success rate of IVD devices in the EU market?
- With MDx CRO’s comprehensive services, from design to monitoring and regulatory guidance, manufacturers enhance their chances of a successful and compliant IVD product launch in the EU.
Where can I learn more about MDx CRO’s success stories or case studies?
- It’s best to reach out to MDx CRO directly or visit our website for detailed testimonials, case studies, and more insights into our work.

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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