Performance Evaluation Requirements

Performance Evaluation Requirements – Lessons learnt

For the last 18 months, LFH Regulatory have supported many IVD manufacturers for their IVDR transition preparation and submission in relation to performance evaluation. Here, we will provide a brief overview of what performance evaluation (PE) is and share some cases of our submission experiences with various Notified Body (NB) feedback.

Since the implementation of the in vitro diagnostic medical devices Regulation EU 2017/746 (IVDR) on 26th May 2022, the PE process is now required by the manufacturers when placing an in vitro diagnostic device (IVD) on the EU market.

Performance evaluation is defined in Article 2 – “Definitions” of IVDR as:

‘an assessment and analysis of data to establish or verify the scientific validity, the analytical and, where applicable, the clinical performance of a device’.

The requirements for performance evaluation are described within Chapter VI of IVDR, and supported by Annexes I, II, III and XIII.

Chapter VI – Clinical evidence, performance evaluation and performance studies

Annex I – General Safety and Performance Requirements

Annex II – Technical Documentation

Annex III – Technical Documentation on Post-Market Surveillance

Annex XIII – Performance Evaluation, Performance Studies and Post-Market Performance Follow-Up

In practice, the Performance Evaluation Plan (PEP) and Performance Evaluation Report (PER) are the output of the PE process. The PER consists of three pillars: scientific validity, analytical performance, and clinical performance, which should be well-defined and documented in PE documentation.

Scientific validity is the demonstration of an association of an analyte with a clinical condition or a physiological state. This is normally demonstrated through one or more of the following routes;

  • Relevant information on the scientific validity of devices measuring the same analyte or marker
  • Scientific (peer-reviewed) literature; consensus expert opinions/positions from relevant professional associations;
  • Results from proof of concept studies;
  • Results from clinical performance studies. The data obtained shall be used in the performance evaluation process and be part of the clinical evidence for the device.


The analytical performance
demonstrates the ability of your device to correctly detect or measure a particular analyte. This can include such testing as analytical sensitivity and specificity; trueness (bias); precision (repeatability and reproducibility); accuracy (resulting from trueness and precision); limits of detection and quantitation; measuring range; linearity; cut-off, including determination of appropriate criteria for specimen collection and handling and control of known relevant endogenous and exogenous interference.

Clinical performance is to establish or confirm aspects of your device performance which cannot be determined by analytical performance studies, literature and/or previous experience gained by routine diagnostics. A clinical performance study aims to demonstrate your IVD’s ability to yield results that correlate with a particular clinical condition or a physiological/pathological process or state in accordance with the target population and intended user. Clinical performance is established through testing such as diagnostic sensitivity, diagnostic specificity; positive predictive value; negative predictive value; likelihood ratio; expected values in normal and affected populations. The data obtained shall be used in the performance evaluation process and be part of the clinical evidence for the device.

The Performance evaluation is not a one-off process that is carried out during the development of the device; it should be maintained throughout the device(s) lifetime and updated where necessary. The PER for class C and D devices shall be updated at least annually but shall be updated beforehand should the need arise. It is highly recommended that manufacturers implement suitable, standardised processes to make updating performance evaluation documentation as easy as possible and nonburdensome.

Case 1: Non-compliant Intended Use Statement

The IVDR defines the performance of a device as the ability of a device to achieve its intended purpose as claimed by the manufacturer, and the Regulation, clearly states the requirements for the “Intended purpose” statement. The terms “intended use” and “intended purpose” are interchangeable under IVDR.

The most frequent feedback that we have seen being provided by the NB, is that the IUS is not compliant under the requirements of IVDR.  Annex II – Technical Documentation clearly states what information should be considered when populating the intended use statement under section 1.1(c).  The intended purpose must also meet the applicable requirements under Annex I – General Safety and Performance Requirements, requirements 20.4.1(c).  The table below can be used as a checklist aid, and it would be recommended to review your intended use statement prior to any submission to your NB.

Performance Evaluation Requirements – Lessons learnt

Case 2: PE Documentation Planning and Timeline

Although certain aspects of performance evaluation have been a requirement under the In Vitro Diagnostic Directive 98/79EC, such as scientific validity and analytical performance, the actual compiling of PE documentation has only become a requirement under EU IVDR.

To plan accordingly, the PE process should be defined and implemented into your Quality Management system from an early stage in the design process of your device (where possible), or for devices already on the market as soon as possible to align with your transitional timeline.  NB’s will assess procedures and documents associated with the PE documentation, so a robust process will minimise the risk of non-conformity during an audit situation.

In addition, it is vital that consideration is taken for NB reviewing time when planning PE documentation in the process.  A standard conformity assessment can take up to approx. 12 months from application to certification and approx. 18 – 20 months for a companion diagnostic IVD (CDx).  It must be noted that these timeframes are approximately based on LFH Regulatory’s current experience and could vary depending on the NB you are working with.

Case 3: Taking into consideration General Safety and Performance Requirements

Feedback from NB’s has seen requests that the specification for conforming with the relevant GSPR’s to be provided, which should be clearly outlined in the PEP. It has been specifically requested that Annex I, Chapter II, GSPR 10 onwards would need to be “taken into account” within the performance evaluation, and their results should be reflected in the PER as documented in MDCG 2022-2 “guidance on general principles of clinical evidence for in vitro diagnostic medical devices (IVDs)”.

Therefore, GSPR 1 – 9.4 has been tabulated to provide detail on how this will be met through performance evaluation activities in the PEP. In addition, for GSPR 10-20, the manufacturer could not provide a similar level of detail on how they will conform in the PEP (as detail as done for GSPR’s 1-9.4) but rather state if the GSPR 10 onwards is applicable or not and justify non-applicability in alignment with the Annex 1 checklist. The verification activities carried out and supporting data generated were then described in the PER to demonstrate how it conformed with the additional GSPR’s, not specific to analytical or clinical performance.

LFH Regulatory have expert medical writers to assist you with the creation of performance evaluation documentation and navigate through the approval process.  Contact us today to see how we can help.

References:

  1. Regulation EU 2017/ 746 of the European Parliament and of the Council of April 5, 2017 on in vitro diagnostic medical devices
  2. MDCG 2022-2 – Guidance on general principles of clinical evidence for In Vitro Diagnostic medical devices (IVDs) – January 2022

 

Written by Dr Yupei Xiao, Clinical and Regulatory Consultant at LFH Regulatory Ltd.

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