Clinical Performance Definition IVDR

Performance evaluation has changed drastically under the IVDR (2017/746) and has become far more stringent and demanding. Annex XIII part A describes performance evaluation as a three step process comprising of Scientific Validity, Analytical Performance, and Clinical Performance, which are all to be completed in the premarket evaluation of the device.

In the IVDR 2017/746, Article 2, Clinical Performance is defined as: “the ability of a device to yield results that are correlated with a particular clinical condition, a physiological or pathological process, or in accordance with the target population and intended user.” After demonstrating analytical performance, the manufacturer must now plan Clinical performance studies. The purpose of a clinical performance study is to establish and confirm aspects of the IVD medical device that cannot be addressed with the analytical performance data, literature, and/or experience gained by routine diagnostic testing.

Annex XIII states that demonstration of the clinical performance of a device should be based on one, or a combination of the following sources:

• Clinical performance studies
• Scientific peer-reviewed literature
• Published experience gained by routine diagnostic testing (as stated in Annex XIII).

The IVDR requires that clinical performance studies be performed unless the manufacturer can give valid justifications as to why they are not needed. Only in the case of established tests where the equivalence can be demonstrated, manufacturers may rely on other sources of clinical performance data. It should be kept in mind that planning, conducting, and executing clinical performance studies takes a lot of time and manufacturers must start the process well in advance.

As a first step, it is the manufacturer or sponsor’s* responsibility to design the clinical study protocol and obtain the necessary regulatory approvals and ethics committee approvals, without this the study cannot proceed. These are formal written approvals. The manufacturer also must find an appropriate site with the right capabilities and then engage with them for conducting the studies. A Principal Investigator is usually appointed to manage the entire program. Another important activity is designing consent forms and obtaining informed consents from the participants who enroll into this clinical study. The studies are to be performed in circumstances similar to the normal conditions of use of the device.

(* Article 2 of IVDR defines the term Sponsor: Any individual, company, institution or organization which takes responsibility for the initiation, for the management and setting up of the financing of the performance study).

The study design should be such that the data generated is relevant with bias being minimized during the study. Manufacturers can choose what type of study design suits the intended purpose of the IVD:

1. Observational study – a study in which test results obtained during the study are not used for patient management and do not impact treatment decisions. The observational study design includes cross-sectional, longitudinal, retrospective, prospective design, and prospective-retrospective design.
2. Interventional study – a study in which test results obtained during the study may influence patient management decisions and may be used to guide treatments. Such a study is used only if an observational study cannot be conducted.

For a clinical performance study, many aspects should be kept in mind. These can include factors such as; the purpose and objectives of the study, what is the intended use of the devices, what are the storage conditions of the device, the risk classification, who are the target population, what kind of  specimens should be used (e.g. Serum, plasma), handling of these specimens (storage included), and also who the intended user is and his/her setting.

Most IVD products undergo clinical performance studies using the observational design. This is because clinical performance studies are done parallel along with routine testing, and so do not determine patient management decisions. The specimens used in these studies are mostly:

• Previously-collected specimens, such as archived specimens or leftover specimens that would otherwise have been discarded (also called surplus specimens); and/or
• Additional specimens collected specifically for the study purposes (Ref. More details in GHTF SG5/N8)

For instance, a clinical performance study for an HIV or HBV kit can be planned using serum samples collected for routine testing and also certain certified panels. There are a lot considerations related to the use of archived samples.

An interventional design is to be used when an observational study cannot be planned. Consider a situation where there is no established test available. Here an interventional design may be required.

Secondly, another situation would be that the manufacturer intends to determine the impact on clinical outcomes by using the IVD product. Or thirdly, the IVD product is co-developed along with a therapeutic product and the information provided by the IVD will influence the patient treatment in a therapeutic clinical trial.

In both these cases  an interventional design may be required for determining patient outcome by monitoring the analyte in question. This is determining what is referred to as treatment efficacy.

The CPSP must define the rationale, objectives, design and proposed analysis, methodology, monitoring, conduct, decision algorithms, and record-keeping of the clinical performance study. It should also include a description of the expected risks and benefits of the device and of the clinical performance study in the context of the state of the art in clinical practice. Parameters of clinical performance and the expected clinical outcomes should be clear and predetermined. The quality of data is crucial. The CPSP could be based on the ISO 20916:2019 which is a stand-alone standard specific for IVDs and therefore very appropriate. It provides guidance for conducting clinical studies for IVDs. By following the ISO standard, the study would be undertaken under GCP and a robust quality management system.

After creating a CPSP, the study can be initiated. For the study, products representative of the final manufactured IVD which is ready for commercialization should be used.

Annex XIII provides complete details regarding the contents of the CPSP. Also refer to the GHTF guidelines (Ref. GHTF SG5/N8).

A clinical performance study report should have complete details about the clinical performance study protocol plan, results, and conclusions of the clinical performance study, including negative findings. The results and conclusions should be transparent, free of bias, and clinically relevant. The report should also include any protocol amendments or deviations, and data exclusions with the appropriate rationale.

Clinical performance provides performance characteristics such as diagnostic sensitivity, diagnostic specificity, positive predictive value, negative predictive value, likelihood ratio, and expected values in normal and affected populations.

The Clinical performance report is to be included as a part of the Performance Evaluation report (PER) which provides the Clinical Evidence of the IVD. They are a part of the Technical Documentation of the device.

The level of detail of the CPSR depends on the class of the IVD:

• ISO 14155:2020: Clinical investigation of medical devices for human subjects — Good clinical practice. It is meant  for the design, conduct, recording, and reporting of medical device clinical studies.
• ISO 20916: 2019:In vitro diagnostic medical devices — Clinical performance studies using specimens from human subjects — Good study practice. This standard is specific for IVDs.
• GHTF/SG5/N8:2012: Clinical Evidence for IVD Medical Devices – Clinical Performance Studies for In Vitro Diagnostic Medical Devices.

It is important to note that all clinical performance studies need to comply with the EU GDPR regulations which define the protection of data belonging to patients and generated from the studies. Secondly, all clinical studies have to follow the recent version of the Declaration of Helsinki on Ethical Principles for Medical Research Involving Human Subjects. This protects the rights, safety, dignity, and well-being of the subjects providing specimens for use in clinical performance studies and applicable national laws.