Needs

According to the in vitro diagnostic regulation (IVDR) EU/2017/746, the metrological traceability of values assigned to calibrators and/or control materials shall be assured through suitable reference measurement procedures (RMPs) and/or suitable Certified Reference Materials (CRMs) of a higher metrological order. Due to a lack of biological CRMs and RMPs (spanning from small molecules to protein to nucleic acids), IVD manufacturers are often unable to comply with regulation.

The lack of higher order RMPs to assign target values to calibrators or quality control materials is due to i) the time needed to validate high accuracy methods with fit for purpose measurement uncertainties, ii) the cost to operate such labour-intensive methods and iii) the lack of primary calibrators of well-characterised purity. There is a need for more efficient purity assessment techniques to assign target values to primary calibrators, e.g., quantitative Nuclear Magnetic Resonance (qNMR) and for high-throughput RMPs, e.g., automated LC/MS/MS methods that can be used to provide cost-effective calibration services and value assign CRMs and quality control materials.

In addition to the lack of RMPs, the lack of secondary CRMs largely originates from the difficulty and cost to properly assess materials’ commutability, which is a property describing their ability to properly mimic the behaviour of patient samples. The paramount importance of commutability has only been recognised recently and to date, however, causes for materials non-commutability remain largely unknown. As properly assessing commutability represents prohibitive costs for Reference materials (RM) producers, there is a need for more efficient and cost-effective ways of conducting commutability studies to identify suitable manufacturing processes.

To support manufacturers in post-market surveillance, there is a need to improve availability of External Quality Assessment (EQA) schemes using control materials of proven commutability and reference method target values.

Addressing these needs requires a coordinated metrological response involving all stakeholders: IVD manufacturers, EQA providers, RM producers, international organisations promoting standardisation.

Objectives

The overall aim of this project is to establish the necessary metrological infrastructure to provide calibration services to External Quality Assessment (EQA) providers and IVD manufacturers to evaluate and improve accuracy and harmonisation of medical test results. This will help the in vitro diagnostic industry meet the requirements of the In Vitro Diagnostic Medical Devices Regulation (IVDR) regarding calibration and performance verification of IVD tests. The specific objectives are:

1. To improve the availability of fit for purpose calibrators and quality control materials that can be used by in vitro diagnostic (IVD) manufacturers and External Quality Assessment (EQA) providers for establishing and verifying metrological traceability of clinical measurements for various measurands including bilirubin, cyclosporine, Parathyroid Hormone (PTH), Human Cytomegalovirus (hCMV), estradiol, Point of Care Test (POCT) for glucose and a panel of clinically relevant biomarkers. To develop or optimise purity assessment techniques necessary to value assign primary calibrators which can be used to calibrate RMPs with fit for purpose uncertainties and limits of quantification (U < 4 % and LOQ < 1 pg/mL for estradiol, U < 2.3-7.6 % for therapeutic drugs, U < 5.2 % and LOQ < 5 pg/mL for PTH). To assign SI-traceable target values to existing or new secondary CRMs and EQA materials of well-characterised commutability.
2. To identify manufacturing processes for the production of calibration and quality control materials of high commutability levels. To evaluate and compare the commutability of various secondary CRMs and EQA materials so as to improve the understanding of key common causes of limiting materials commutability (WP3). To establish commutability acceptance criteria, measurement uncertainty will be considered at each level of the calibration hierarchy, as well as its impact on the quality of laboratory tests.
3. To develop more efficient and cost-effective ways of conducting commutability studies by e.g., mutualising the resources and capabilities of reference measurement service providers supporting a European Metrology Network infrastructure TraceLabMed (EMN TLM). To develop alternative strategies, such as abbreviated commutability studies, multiparameter commutability studies, the use of commutability panels, the use of high throughput RMPs and automated data analysis in order to make commutability assessment more straightforward.
4. To support post-market surveillance of IVD tests by working in close cooperation with EQA providers and IVD manufacturers. To assign reference method target values to existing EQA materials as well as to evaluate their commutability. Additionally, to organise at least one accuracy-based program relying on commutable EQA materials with reference method target values. To combine EQA data obtained and to develop novel approaches for EQA data aggregation in order to evaluate harmonisation of measurement results on an international basis. (WP4)
5. To facilitate the take up of the technology and measurement infrastructure developed in the project by the measurement supply chain (accredited laboratories, instrumentation manufacturers, EMN TLM), standards developing organisations (e.g., ISO, CEN, CLSI), and end users (e.g., international organisations (e.g., IFCC, ICHCLR), assay manufacturers, material producers, EQA providers and medical associations).

 

Project overview

 

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