In order to be compliant with the EU In Vitro Diagnostic Regulation (IVDR), Annex XIII 1.2.3, the greater majority of in vitro diagnostic (IVD) devices require clinical performance evidence which must be based on at least one or a combination of the following sources: scientific peer-reviewed literature, published experience gained in routine diagnostic testing or clinical performance studies (CPS). As a result, how to demonstrate clinical performance, using which source(s) of evidence available, and if applicable, how best to do so via a CPS, have become an essential piece of the puzzle in demonstrating an IVD device’s overall performance. This puzzle is as challenging for manufacturers of legacy devices as those of novel devices. Legacy device manufacturers are faced with the conundrum of determining how to package the clinical data they may have previously collected to provide evidence of clinical performance in line with IVDR. Even if said legacy evidence is sufficient, these legacy device manufacturers will eventually have to perform CPS for new devices and therefore come to terms with the IVDR requirement.
A CPS is required to establish aspects of device performance that cannot be established by other methods such as analytical performance studies, literature review, and/or previous experience gained by routine diagnostic testing. To be considered a clinical performance study under the IVDR, the study must be carried out according to Annex XIII which outlines the requirements for planning and documenting a CPS. IVDR also stipulates that the study should comply with ISO20916 In vitro diagnostic medical devices — clinical performance studies using specimens from human subjects — good study practice). IVDR Chapter VI and Annex XIII Part A Section 2 provide high-level requirements for all CPS, with specific articles within Chapter VI addressing additional requirements for studies involving more risks to subjects and or users.
This article will walk through the IVDR requirements for conducting a CPS, as defined in Chapter 6, and Annexes XIII and XIV of the EU In Vitro Diagnostic Regulation (2017/746). The first step in this process is to design a clinical performance study, which should ensure all elements of the clinical claim(s) within the device’s intended use are evaluated. The individual or organization taking responsibility and liability for the conduct and performance of the CPS is termed the CPS Sponsor. While sponsors may outsource activities, ultimate liability for the clinical performance study and the welfare of any participating subjects lies with the Sponsor. It is then necessary to select and qualify the organizations that will perform the study (i.e., investigate and establish the clinical performance of the device (the study investigating sites)) and define a qualified individual at each investigating test site that will be responsible for the CPS at that investigating site (i.e., principal investigator (PI)). The status of the device used in the study (CE marked, device for performance study) and the risk posed to subjects in the study (direct/indirect harms) determine what aspects of the IVDR clinical performance study regulation may be applicable.
All clinical performance studies must adhere to basic requirements including:
- First and foremost, the study must be designed to protect rights, safety, dignity, and well-being of subjects, and must meet ethical and scientific principles. The manufacturer must ensure that the CPS device complies with the applicable general safety and performance requirements (GSPRs) set out in IVDR Annex I, apart from those addressed by the CPS which will include evidence of analytical performance. This requires the device to be developed under an appropriate quality management system (QMS). The study must adhere to all applicable laws on data protection (Directive 95/46/EC (Data Protection Directive)).
- When appropriate, the study should be performed in circumstances similar to normal conditions of use.
- The study must be documented with a clinical performance study plan and report with the content outlined in Annex XIII.
Some studies may present direct harm to subjects – such as requiring them to undergo invasive sample collection procedures. Other studies may present indirect harms to subjects – such as when the results of a device for performance study are provided to clinicians for medical management (also known as an interventional clinical study). In such cases, the risk of an incorrect result may lead to mismanagement of patient care. These studies are subject to additional requirements per IVDR, as described below. Studies that are conducted on samples from patients who cannot consent such as children or the elderly also have to follow these additional ethical requirements.
Interventional CPS using surgically invasive sample-taking, or invasive procedures that pose a risk to subjects, or studies using companion diagnostics are subject to the following requirements stated in Article 58 and Annex XIV, in addition to the general requirements listed above: - The study sponsor or their legal representative must be established in the European Union.
- The performance study must be reviewed by an ethical committee and cannot receive a negative opinion from the EC.
- The study must be authorized by the member state in the country where the study is to be performed, using EUDAMED per Annex XIV.
- Subjects, or their legal representatives, must provide informed consent, and all vulnerable populations must be appropriately protected. If subjects require medical care as part of the study, it must be provided by appropriately qualified medical personnel.
- The sponsor demonstrates that the investigator and study staff are qualified for their roles by training, and prior experience in the relevant field of study.
- The facilities are suitable for conducting the performance study.
When using left-over specimens, study sponsors must still consider whether principles of informed consent were used for sample collection, and whether it covers the use of the samples in the CPS. In such cases, the study sponsor must meet the IVDR requirements for a CPS, however, they are only required to notify applicable EU competent authorities (CAs), rather than submit a CPS application for authorization.
Study sponsors should also consider the status of their device. Where the performance of a CE-marked device is being evaluated within a CPS to modify its intended purpose, or where the CPS study sponsor is not using a CE-marked device in accordance with its intended purpose, the CPS must follow the requirements set out in IVDR and described above.
Sponsors may demonstrate evidence of meeting these requirements with the clinical performance study plan and report, clinical performance study conduct documentation, and ethical and EU Member State Competent Authority (CA) authorization. IVDR stipulates that CPS authorization applications and notifications are to be submitted through the European Database on Medical Devices (EUDAMED). However, the EUDAMED clinical performance module is not estimated to be functional until Q4 2024. In the interim, CPS authorization applications and notifications must be submitted to each EU CA within which the study will be conducted.
The MDCG published guidance MDCG 2022-19 (“Performance study application/notification documents under Regulation (EU) 2017/746”) provides templates for CPS application, a list of documentation required for CPS application and a GSPR checklist. Please note, some EU CAs may not accept the templates provided within MDCG 2022-19, instead requiring completion of EU CA specific templates which they have created and established systems for in lieu of EUDAMED functionality. Therefore, timely engagement of relevant EU CAs by the CPS sponsor to determine EU CPS application requirements (inclusive of translation requirements) is advised.
What’s the takeaway?
In summary, clinical performance studies are one component of demonstrating clinical performance and IVDR conformity of an IVD. CPS are subject to basic requirements as outlined in IVDR Chapter VI and Annex XIII including being documented with a clinical performance study plan and report. If the CPS requires invasive specimen collection, is interventional in nature and/or poses additional risks to study subjects, it must meet additional requirements including an authorization application to applicable EU CAs. In lieu of a functional EUDAMED, sponsors must submit an application and/or notification to each EU CA where the study will be performed. Whilst the requirement for ethical and, where applicable, EU CA authorization can seem burdensome, the principle of authorization is to ensure the safety, as well as protect the rights and welfare, of the CPS subjects. However, the EUDAMED vacuum is currently causing a lot of confusion for IVD CPS sponsors, unsure of the required documentation and timelines for CPS authorization application.
Given the potential complexities and challenges associated with meeting CPS IVDR requirements, including CPS authorization applications, let Qserve’s experienced IVD team assist you in preparing for your clinical performance study.
Want to learn more? Join us on June 27th for a free webinar and Q&A, “Recommendations for clinical performance studies under IVDR” This webinar will cover:
- Using clinical performance studies to support clinical performance evidence –demonstrating clinical performance when devices do not have a formal clinical performance study
- The realities of conducting clinical performance studies in Europe in the absence of EUDAMED –recommendations and tips for managing CPS applications, including recommendations for submitting CPS applications for clinical trial assays to support pharmaceutical therapeutic clinical trials
- Quality management system considerations – what processes study sponsors should have in place prior to initiating a clinical performance study
- Q&A
For further information on clinical performance studies see below: