The EU Regulation 2017/746, commonly referred to as In Vitro Diagnostic Medical Device Regulation (IVDR), imposes manufacturers to prepare and submit a performance evaluation of In Vitro Diagnostic Medical Devices (IVD) to demonstrate their safety and performance according to the manufacturers’ intended use. Compared with the previous directive (Directive 98/79/EC), the IVDR explicitly states that the technical documentation for IVDs must contain a performance evaluation report. Thus, this article will describe the main performance evaluation requirements under the IVDR to support manufacturers introducing their IVDs in the European Market. The IVDR defines the performance evaluation of an IVD as “a continuous process by which data are assessed and analysed to demonstrate the scientific validity, analytical performance and clinical performance of that device for its intended purpose as stated by the manufacturer” (Annex XIII, Part A, section 1). Qualified evaluators should assess the data provided by these three elements to ensure the amount of clinical evidence is sufficient to guarantee the safety and performance of the IVD under evaluation.
Consider visiting the following link to get more information about the IVDR: https://akrnconsulting.com/what-is-the-ivdr/
“How do I start?”
The best way to start addressing the performance evaluation of an IVD is by creating a plan, also referred to as the Performance Evaluation Plan (PEP). This plan should contain the information detailed in IVDR Annex XIII, section 1.1 and constitute the Performance Evaluation Report (PER)’s base. The PER is a critical document that will contain the results of the methods laid out in the PEP and the reports from the scientific validity, analytical performance and clinical performance. Before starting with the PEP, manufacturers should also ensure a performance evaluation procedure is available as part of the Quality Management System.
Scientific validity, analytical performance and clinical performance
A performance evaluation shall follow a defined and methodologically sound procedure for the demonstration of compliance with the applicable general safety and performance requirements (Annex 1, sections 1 to 9). The performance evaluation shall contain evidence of the following IVD aspects:
- Scientific validity is “the association of an analyte with a clinical condition or a physiological state”. The methodology to demonstrate the scientific validity general includes a systematic review of the existing (peer-reviewed) literature relevant to the IVD under evaluation. If gaps in scientific validity are identified, IVD manufacturers need to generate additional data by performing proof of concept studies, pre-clinical studies or clinical performance studies. Scientific validity should be planned in a Scientific Validity plan and it demonstrated and documented in a Scientific Validity report, which is included within the PER.
- Analytical performance is “the ability of a device to correctly detect or measure a particular analyte”. Analytical performance is commonly defined by parameters such as specificity, sensitivity, reproducibility, among others. Section 9.1 of Annex I of the IVDR describes all the parameters that need to be assessed. Analytical performance should be planned in the Analytical performance plan. To prepare the plan, IVD manufacturers can use internationally recognised guidelines such as the CLSI and WHO. Analytical performance is demonstrated and documented in the analytical performance report, which is included within the PER.
- Clinical performance is “the ability of a device to yield results that are correlated with a particular clinical condition or a physiological or pathological process or state following the target population and intended user”. In other words, clinical performance provides demonstrates how good the IVD is for delivering a result or diagnosis. Manufacturers commonly conduct systematic scientific literature searches. If gaps in clinical performance data are identified, clinical performance studies can be designed to obtain additional data. Clinical performance shall be planned (Clinical performance plan) and documented in the clinical performance report, which is included within the PER.
IVD Clinical Performance Studies are further explained in the following article: https://akrnconsulting.com/ivd-clinical-performance-studies/
Here comes the PER
Following the PEP and the assessment of the scientific validity, analytical performance and clinical performance, the PER needs to be prepared. The PER shall include the individual scientific validity, analytical and clinical performance reports and their assessment, ensuring that the data obtained demonstrate sufficient clinical evidence.
Moreover, the PER shall include additional information such as a justification of the approach used to generate clinical evidence, the literature search methodology, the technology and the intended purpose of the IVD, among others. Annex XIII, part A, section 1.3.2 of the IVDR lists the PER’s requirements.
Performance evaluation is not static, but a continuous process
A pivotal requirement introduced by the IVDR is the obligation for manufacturers to continuously evaluate the performance of their IVDs throughout their entire life cycle. This way, CE-marked IVDs are monitored to confirm their safety and performance once placed in the European market. To this aim, the PER shall be periodically updated with the information obtained via Post-Market Performance Follow-up (PMPF). Similar to the performance evaluation, the PMPF is defined following a pre-established plan termed the PMPF plan. Following this plan, manufacturers should periodically generate PMPF evaluation reports, which are used to update the PER (Annex XIII, part B of the IVDR state the requirements for PMPF plans and reports). In addition, manufacturers should notice that the frequency for PER updates depends on the risk class of the IVD. Thus, Class A and B devices can be updated as needed, but Class C and D IVDs must be updated at least yearly.
IVD classification under the IVDR is further explained in the following article: https://akrnconsulting.com/classification-ivd-under-ivdr/
Do you need help?
Within the PER, the manufacturer must demonstrate sufficient clinical evidence that supports the intended use for the device in medical practice, and this needs to be updated throughout the device’s life. For successful IVDR compliance, IVD manufacturers are required to be vigilant all through the performance evaluation process, which spans planning, collecting and assessing the clinical evidence data and preparing and submitting the PER as part of the IVDR Technical Documentation (TD).
To ensure that manufacturers of IVDs align with IVDR TD requirements, AKRN Scientific Consulting performs a systematic review of the scientific literature and develops a performance evaluation plan along with a compliant PER.
Subject Matter Experts
Albert Negrete, Ph.D.
Regulatory Affairs Scientist LinkedIn
José Velazquez, M.Sc.
Quality Assurance Manager LinkedIn