Harmonization of Clinical Laboratory Test Results: The Role of the IVD Industry

Abstract

At the start of the 21st century, a dramatic change occurred in the clinical laboratory community. Concepts from Metrology, the science of measurement, began to be more carefully applied to the in vitro diagnostic (IVD) community, that is, manufacturers. A new appreciation of calibrator traceability evolved. Although metrological traceability always existed, it was less detailed and formal. The In Vitro Diagnostics Directive (IVDD) of 2003 required manufacturers to provide traceability information, proving assays were anchored to internationally accepted reference materials and/or reference methods. The intent is to ensure comparability of patient test results, regardless of the analytical system used to generate them. Results of equivalent quality allows for the practical use of electronic health records (EHRs) capture a patient's complete laboratory test history and allow healthcare providers to diagnose and treat patients, confident the test results are suitable for correct interpretation, i.e., are "fit for purpose" and reflect a real change in a patient's condition and not just "analytical noise." The healthcare benefits are obvious but harmonization of test systems poses significant challenges to the IVD Industry. Manufacturers must learn the theory of metrological traceability and apply it in a practical manner to assay calibration schemes. It's difficult to effect such a practical application because clinical laboratories do not test purified analytes using reference measurement procedures but instead deal with complex patient samples, e.g., whole blood, serum, plasma, urine, etc., using "field methods." Harmonization in the clinical laboratory is worth the effort to achieve optimal patient care.

Keywords: harmonization; metrology; standardization; traceability.

Figure 1

General metrological traceability diagram from ISO 17511, in vitro diagnostic medical devices — Measurement of quantities in biological samples — Metrological traceability of samples assigned to calibrators and control materials, 2003 Abbreviations: ARML - Accredited reference measurement laboratory (such a laboratory may be an independent or manufacturer’s laboratory); BIMP - International Bureau of Weights and Measures; CGMP - General Conference on Weights and Measures; ML - Manufacturer’s laboratory; NMI - National Metrology Institute. The symbol u_c(y) stands for combined standard uncertainty of measurement.

Figure 2

Commutability is demonstrated if fresh patient samples and reference materials, e.g., calibrators, demonstrate an equivalent analytical response when tested by two methods Commutable: same relationship for clinical samples and reference materials.

Figure 3

Manufacturers may prepare calibrators starting with traceability to the same reference material and/or reference method, but the calibrator manufacturing process may diverge at some point, resulting in significantly different results for the same measurand in the same patient sample if tested by the two field methods, despite metrologically acceptable traceability for each assay’s calibrators