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.
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The importance of ISO 20916 Annex ZA 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
Annex ZA bridges the gap between ISO 20916 and the IVDR, providing a clear and actionable framework for CROs and sponsors to achieve compliance.
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.
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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.
Author: Carlos Galamba, Founder and Head of IVD
Carlos has spent the past 18 years in the IVD sector, primarily at the renowned Notified Body, BSI. There, he not only built an extensive global network with leading EU Notified Bodies but also pioneered as the first in-house clinician for IVDs. Carlos spearheaded the BSI clinical oversight process, paving the way for hundreds of CE markings for IVDs. Prior to his regulatory roles, Carlos honed his expertise as a senior scientist in prestigious UK diagnostic institutions, working with various IVD technologies giving him a thorough understanding of the field’s unique demands. Beyond BSI, Carlos served as Vice President for Diagnostics at a large medtech consultancy and was also an inspector with the MHRA. Currently, he serves as an independent advisor to the EU Commission, sharing his vast knowledge and experience with a variety of stakeholders.
