Performance evaluation (PE) is an important part of design validation and technical documentation required to place an in vitro diagnostic device (IVD) on the EU market. Article 56 of the EU 2017/746 In Vitro Diagnostics Regulation (IVDR) requires manufacturers to prepare a performance evaluation report to demonstrate the safety and performance according to the manufacturer’s intended purpose.

IVDR Performance evaluation requirements are described within Chapter VI of EU 2017/746 and supported by Annexes I, II, III and XIII. To prepare an effective performance evaluation plan , you should understand some basic concepts.

Performance Evaluation and Clinical Evidence

Performance Evaluation is “an assessment and analysis of data to establish or verify the scientific validity, the analytical and, where applicable, the clinical performance of a device”. (Source Article 2 (44) of EU 2017/746 IVDR)

Annex XIII (1) – “Performance evaluation of a device is 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.”

These definitions refer to clinical evidence that is extremely important for an in vitro diagnostic medical device which reads as;

Clinical evidence is necessary to demonstrate conformity with the relevant general safety and performance requirements and to prove that the device complies with the intended performance characteristics and purpose. The level of clinical evidence shall be specified and justified by the manufacturer.

 “clinical data and performance evaluation results, pertaining to a device of a sufficient amount and quality to allow a qualified assessment of whether the device is safe and achieves the intended clinical benefit(s), when used as intended by the manufacturer.” (Source: Article 2 (36) of EU 2017/746 IVDR)

Performance Evaluation Process

Performance Evaluation is a continuous process which is required to generate and maintain the clinical evidence needed to support an IVDs intended purpose. It shall be a part of the quality management system and carried out throughout the life cycle of an IVD. According to MDCG 2022 -2 Performance evaluation processes consists of 6 main phases and can be summarised as follows:

1.Planning

The performance evaluation process begins with the establishment of the Performance Evaluation Plan (PEP) which is one of the key requirements according to IVDR 2017/746. Therefore, manufacturers shall establish and maintain a Performance Evaluation Plan, in order to prove device performance and to generate the necessary clinical evidence based on the characteristics of the device and intended purpose.

When designing the PEP, manufacturers shall take into account the following topics considering the safety and performance requirements for the device:

• the intended purpose,
• the novelty and degree of innovation,
• the scientific validity of the analyte,
• the specification of methods,
• the assay technology,
• the state-of-the-art,
• the risk to the patient,
•  the intended user(s),
• the disease state(s),
• the device classification,
• the degree of variability of the study subject population,
• prevalence of the clinical state,
• the availability of certified reference materials or certified reference methods,
• the target population,
• the stability of specimens, reagents, etc.
• availability of CS.

The requirements for the Performance Evaluation Plan are described within Annex XIII of EU IVDR 2017/746.

2. Data Establishment

Clinical evidence for IVDs is established through the collection of data as a result of a performance evaluation. Performance evaluation covers the assessment and analysis of data to establish and verify the scientific validity, analytical performance and clinical performance of an IVD. The definition of the three key elements of performance evaluation is as follows:

• Scientific validity: The extent to which the analyte, or marker to be determined by the IVD is associated with the targeted physiological state or clinical condition,
• Analytical performance: Demonstration of the IVD’s ability to correctly detect or measure a particular analyte,
• Clinical performance: Demonstration of IVD’s ability to deliver results relevant to a particular clinical condition or physiological/pathological process, or to the target population and intended user.

For each element an individual plan should be prepared and referenced in the PEP.

3. Analysis, conclusions, and documentation

After planning and data establishment processes, analysis, conclusion and documentation of data is one of the most important aspects of performance evaluation process. It covers the followings:

• Analysis and documentation of the scientific validity, analytical performance data and clinical performance data,
• Evaluations and conclusions in the performance evaluation report (PER),
• Preparation of the summary of safety and performance (for Class C and D devices).

4. Performance Evaluation Report

The Scientific Validity Report, Analytical Performance Report, and Clinical Performance Report are used to generate the Performance Evaluation Report. The Performance Evaluation Report shall include:

• Justification for the approach taken to gather clinical evidence,
• The literature search methodology, protocol, and report,
• The technology behind the device, its intended purpose, and any claims about its performance or safety,
• The nature and extent of the scientific validity and the analytical and clinical performance data evaluated by the manufacturer,
• A comparison of the clinical evidence with the State of the Art,
• Any updates from PMPF Evaluation Reports.

5.Post Market Performance Follow-up

The following activities should be identified to provide a review of the PMPF.

• Monitoring and analysis of data from post-market use,
• Assessment of published experience gained by routine diagnostic testing,
• Involvement in external quality control schemes,
• identification of new mutations, strains or variants which may impact the performance of the IVD,
• Inputs from post-market surveillance, including information on serious incident,
• reports and field safety corrective actions,
• Post-market performance studies.

6. Continuous monitoring and updates

As we mentioned above, performance evaluation is a continuous process conducted over the lifecycle of the IVD. Manufacturers shall continuously monitor and collect the data which maintains the safety, effectiveness, and performance of the IVD. Such data may include:

• Changes in the state-of-the-art,
• Post market information such as complaints, PMPF data, direct end-user feedback,
• Newly published literature, guidelines, harmonised standards,
• Design changes.

The clinical evidence of the IVD shall be updated or re-established before such changes are implemented. In addition to these, IVDR requires that the following documents be kept up to date.

• Post Market Surveillance Plan
  •  As necessary. (Article 79) (For all device classes)
• Post Market Performance Follow-up (PMPF) report
  • Continuously through product’s lifetime (Annex XIII Part B)(For all device classes)
• The performance evaluation report
  • As necessary and at least annually. (Article 56(6)) (For Class C and D)
  • Continuously through product’s lifetime (Article 56 (6)) (For Class A and B)
• Post Market Surveillance Report
  • When necessary and made available to the notified body and the competent authority upon request (Article 80) (For Class A and B)
• Periodic Safety Update Report (PSUR)
  • At least annually (Article 29, Article 56(6)) (For Class C and D)
• The summary of safety and performance (SSP)
  • As soon as possible, where necessary (Article 81 (1)) (For Class C and D)

Of course, risk management is continuously applied in the performance of evaluation process of the IVD, considering the clinical risks to be addressed as part of the performance evaluation, performance studies, and post market performance follow-up.

For further information you can check MDCG 2022-2, MDCG 2020-1 and Medtech  Clinical Evidence Requirements under the EU In Vitro Diagnostics Regulation (IVDR) Rev 03 guidances.