Harmonization: Its Time Has Come.

The importance of standardization of laboratory test results has a long history traceable to the first proficiency testing results in 1947 that demonstrated large discrepancies among results from 59 hospital laboratories (1 ). The AACC published a series of monographs in 1953– 1972 titled Standard Methods of Clinical Chemistry that promoted a single measurement procedure (MP) for a measurand. This effort ultimately failed because technology and commercial interests produced different MPs for the same measurand. A conference organized in 1977 by the Centers for Disease Control [now the Centers for Disease Control and Prevention (CDC)], the Food and Drug Administration (FDA), and the National Bureau of Standards (now NIST) spawned the National Reference System for the Clinical Laboratory that established the hierarchy of Certified Reference Materials (CRMs) and reference measurement procedures (RMPs) that are now accepted as higher-order references for standardization of measurand results (2 ). The IFCC and professional organizations in various countries began to publish RMPs for different measurands in the mid-1970s. About this time, professional organizations and metrology institutes introduced matrix-based CRMs as the basis for calibration traceability of medical laboratory MPs for measurands for which there were no RMPs. In 1998, the European Union (EU) passed a regulation known as the EU Directive that for the first time required calibration traceability to higher-order references, when available, for medical laboratory MPs (3 ). This landmark legislation with an effective date of 2003, although only applicable to products sold in the EU, had a global influence to improve standardization of results for medical laboratory MPs. The International Organization for Standardization (ISO) responded to the EU Directive by publishing, in 2003, standard 17511 that specified requirements for calibration traceability to higher-order references that included several levels of traceability depending on how complete a reference system existed for a measurand (4 ). ISO also published standards for CRMs, RMPs and reference laboratories that performed RMPs (5–7 ). Cooperation among the International Bureau of Weights and Measures, the IFCC, and the International Laboratory Accreditation Cooperation established the Joint Committee for Traceability in Laboratory Medicine (JCTLM) in 2002. The JCTLM maintains a database of CRMs, RMPs, and reference laboratories that conform to the ISO requirements (8 ). Manufacturers of MPs use the JCTLM listed resources to ensure the calibration traceability hierarchies they use will be compliant with the EU Directive. An important attribute of a RMP and a CRM is that they can be reproduced at any time or location with the expectation of being suitable for use in a calibration traceability hierarchy. The term standardization has traditionally been used when equivalent results, within medically meaningful limits, were achieved among different MPs by having calibration traceable to a RMP or CRM. However, the standardization principles described in ISO 17511 have 2 key limitations. One is that pure-substance CRMs and RMPs do not exist and are not likely to be developed because of technical limitations for hundreds of important but complex measurands in laboratory medicine. In the preceding situation, calibration can be traceable to a matrix-based CRM but these too are only available for a relatively small number of measurands. The second limitation is that many matrix-based CRMs have not been validated to be commutable with patient samples and in many cases are not commutable and thus are not suitable for use in an ISO 17511 compliant calibration traceability hierarchy (9 ). In fact, tracing calibration to a noncommutable CRM will cause differences in results for clinical samples among different MPs. For example, 5 commercially available MPs for parathyroid hormone had 1.4–4.2-fold differences in results for patient samples that caused errors in medical treatment decisions (10 ). Harmonization is a generalization of the concept of standardization that means achieving equivalent results, within medically meaningful limits, among different MPs using a scientifically sound approach. Standardization as described above is a special case of achieving harmonization when a suitable CRM and/or RMP is avail1 Department of Pathology, Virginia Commonwealth University, Richmond, VA. * Address correspondence to the author at: PO Box 980286, Richmond, VA 23298-0286, USA; Fax 1-804-828-0353; e-mail [email protected]. Received April 18, 2017; accepted April 25, 2017. Previously published online at DOI: 10.1373/clinchem.2017.274860 © 2017 American Association for Clinical Chemistry 2 Nonstandard abbreviations: MP, measurement procedure; FDA, Food and Drug Administration; CRM, Certified Reference Material; RMP; reference measurement procedure; EU, European Union; ISO, International Organization for Standardization; JCTLM, Joint Committee for Traceability in Laboratory Medicine. Clinical Chemistry 63:7 1184–1186 (2017) Editorials