Lab Test Harmonization Gets a $2 Million Boost

Lab Test Harmonization Gets a $2 Million Boost

In late March, the American Association for Clinical Chemistry (AACC) released an announcement applauding the $2 million in funding that the Centers for Disease Control and Prevention (CDC) has received from the recent 2018 omnibus spending package, for lab test result harmonization—a cause that AACC had been working to advance for nearly twenty years. Harmonization, according to AACC as well as the National Institute of Standards and Technology (NIST), will lead to more accurate diagnoses and thus to improved medical treatment. Without standardization, numerical resultsfor the same tested samplecan vary from lab to lab, which could potentially botch clinical, financial, regulatory, and technical decisions.1 Such tests include those for thyroid-stimulating hormone, human chorionic gonadotropin, and prostate-specific antigen, among a whole host of others.

The AACC published a position statement last April2reiterating the need to harmonize test results and outlining some steps they deem necessary to be taken by a number of groups to continue improving the matter:

  • Laboratory organizations need to educate the public about variability in test results, thus emphasizing the importance of standardizing them; they should also provide the leadership necessary in organizing stakeholders to do so and to ensure that healthcare providers are sufficiently implementing the changes
  • Clinical societies should identify measurement procedures in the lab that are used in developing guidelines, as well as their limitations
  • The government will need to emphasize and promote harmonized procedures as regulatory requirements evolve, and to streamline regulatory processes to ensure harmonization is implemented quickly, though care should be made not to compromise patient safety
  • IVD manufacturers should calibrate their test procedures to be traceable to a reference method where applicable, and if not, test results should be harmonized among different measurement procedures based on a consensus approach so that uniform results are achievable
  • Reference material providers—as well as external quality assessment and proficiency testing providers—must work with IVD manufacturers to ensure that materials to be used as common calibrators for clinical laboratory measurement procedures are interchangeable with representative clinical patient samples
  • Payers should encourage harmonization, as doing so will mitigate or even eliminate error, reducing the cost of patient care

The AACC also suggested that all stakeholders should support the Association’s International Consortium for Harmonization of Clinical Laboratory Results3and the activities carried out thereby, and that funding should be made available from public and private sources to further accomplish these goals.

The earliest global involvement by AACC was through an international forum hosted jointly with NIST in Gaithersburg, MD in October 2010. There, the goals of the conference were to reach a consensus on procedures for how to accomplish harmonization of results for which there are no higher-order reference measure procedures (RMPs), to form working groups charged with tasks to enforce the recommendations, and to identify organizations willing to accept responsibility of enforcement. The conference’s findings were published in AACC’s research journal,Clinical Chemistryin July 2011;1[1]participants to the conference agreed that they would need to develop an infrastructure to systematically identify and prioritize, based on clinical significance and technical practicability, the harmonization of clinical test targets to be measured (measurands, in conference parlance), and to determine how best to approach it. However, the participants also recognized that there are challenges in calibration traceability for certain analytes, that is may not be possible for test results for some analytes to be standardized until technical advances have been made that can better enable more specific measurement procedures.

Harmonization is a concept that has been pursued for decades, by numerous pathology groups. The globally active Pathology Harmony initiative was launched in 2007, which aims not only to standardize reference intervals (the acceptable ranges of healthy physiological parameters, e.g. cortisol in blood, glucose in urine), test names, and reporting units, but also to develop guidelines in pathology testing. The initiative has centered on these improvements in three particular clinical areas—clinical biochemistry, hematology, and immunology. Jonathan Berg, Director of Pathology at Sandwell and West Birmingham Hospitals in the United Kingdom, outlined in a few articles,4,5the techniques that the group had developed to determine the suitability of a clinical test target to be harmonized:

  • Quantify the degree, through lab surveys, to which an analyte varies in its results
  • Determine if there is a scientific basis for this variation—if not, harmonization can proceed
  • Develop recommendations by consensus, then communicate said recommendations to key stakeholders, such as the pathology community, relevant clinical groups, IT providers, Departments of Health
  • Implement the recommendations with the distribution of appropriate support documentation to consumers

An editorial6published in the August 2012 issue ofClinical Biochemistry Reviews(later reviewed in 20167) suggested that harmonization in pathology should encompass more than just the standardization of terminology and analyte reporting units and so on, but should also cover topics that extend beyond the analytical phase of clinical pathology.

  • “Pre-pre-analytical”: “Right test at the Right Time for the Right Patient”
  • Pre-analytical: standardize pre-analytical processes, establish standard operating procedures to reduce error and ensure patient safety, recommend evidence-based guidelines for appropriate test selection
  • Analytical: standardize pathology test names and their units, as well as their requesting and reporting procedures for the electronic health record (EHR), harmonize report formats where there are patient safety concerns, harmonize patient results through a standardization process
  • Post-analytical: harmonize reference intervals so that between-method bias is within allowable limits of performance, which requires that bias to be monitored for the long term
  • “Post-post-analytical”: this phase focuses more on pathology lab working relationships and the public, in which consumers are educated on what functions laboratory tests serve, and labs and clinical providers continue efforts to harmonize

In 2016, the authors of the aforementioned article published an edition of theJournal of the International Federation of Clinical Chemistry and Laboratory Medicine(eJIFCC) dedicated entirely to updating interested parties on the current state of harmonization efforts. One article8focused on the challenges that the IVD industry will have to face regarding traceability in their assay calibration. Part of the problem lies in manufacturers test their equipment using purified analytes, while clinical laboratories do not have that luxury, using complex samples like whole blood. This is akin to a laboratory carrying out an experiment in perfect, controlled settings and expecting similar outcomes in an unpredictable real-world environment.

Manufacturers have recently begun to restandardize assays, provide calibrator traceability/uncertainty information, and test commutability with patient samples; however, they have yet to choose atotal allowable error(TEa) goal from a number of options put forth by, for example, CLIA or CAP.  There are some formulæ that can be used to define TEa based on biological variability targets, but current assays are too imprecise to meet them, and due to cost and limited resources, IVD manufacturers have to use an internally stored calibrator material rather than to follow full traceability steps for every new calibrator lot. While this is likely still valid, variability between calibrator lots is a common—and very legitimate—complaint. A working group within the IFCC has pointed out that calibrators for the same analytes produced by different manufacturers can be derived from valid, but separate traceability chains, but will produce results with variability; to mitigate this, a correction factor can be determined through correlation studies, and be used to produce equivalent results.

The $2 million granted to the CDC will allow the agency to advance harmonization for free testosterone, thyroid-stimulating hormone, and estrogen, and to provide materials and monitoring for labs and manufacturers to improve calibrating their tests. This will lead to improved diagnosis and treatment for illnesses such as chronic kidney disease, hypothyroidism, osteoporosis, and polycystic ovary syndrome.

For further background reading, see:

References

1 Miller WG, Myers GL, Gantzer ML, Kahn SE, Schönbrunner ER, Thienpont LM, Bunk DM, Christenson RH, Eckfeldt JH, Lo SF, Nübling CM, and Sturgeon CM. (2011) Roadmap for Harmonization of Clinical Laboratory Measurement Procedures.Clinical Chemistry; 57(8), 1108-17. DOI: 10.1373/clinchem.2011.164012

2 American Association for Clinical Chemistry (AACC). Harmonization of Clinical Laboratory Test Results.https://www.aacc.org/health-and-science-policy/advocacy/position-statements/2017/harmonization-of-clinical-laboratory-test-resultsPublished 20 April 2017. Accessed 01 May 2018.

3 AACC. Harmonization.https://www.aacc.org/global-health-outreach/harmonizationAccessed 01 May 2018.

4 Berg J and Lane V. (2011) Pathology Harmony; a pragmatic and scientific approach to unfounded variation in the clinical laboratory.Annals of Clinical Biochemistry; 48, 195-7. DOI: 10.1258/acb.2011.011078

5 Berg J. (2014) The UK Patholpogy Harmony initiative; The foundation of a global model. Clinica Chimica Acta; 432, 22-6. DOI: 10.1016/j.cca.2013.10.019

6 Tate JR, Johnson R, and Legg M. (2012) Harmonisation of Laboratory Testing.Clinical Biochemistry Reviews; 33(3), 81-4. PMCID: PMC3428255

7 Tate JR and Myers GL. (2016) Harmonization of Clinical Laboratory Test Results.The Electronic Journal of the International Federation of Clinical Chemistry and Laboratory Medicine(eJIFCC); 27(1), 5-14.

8 Armbruster D and Donnelly J. (2016) Harmonization of clinical laboratory test results: the role of the IVD industry.eJIFCC; 27(1), 37-47.