Jonathan R. Genzen, MD, PhD, MBA
David B. Sacks, MBChB
November 2024—Hemoglobin A1c (HbA1c) is a glycated form of hemoglobin that is increased in individuals with diabetes mellitus. HbA1c concentrations generally reflect plasma glucose levels (and therefore glycemic control) over the past eight to 12 weeks. The association between type one diabetes and HbA1c elevation was discovered in the late 1960s, and clinical HbA1c assays first came to market in 1978. As these early assays were not in widespread use when federal regulations under the Clinical Laboratory Improvement Amendments of 1988 were being developed, HbA1c was not included as an initial CLIA-regulated analyte.
The Diabetes Control and Complications Trial showed an association between HbA1c and the chronic complications of diabetes in people with type one diabetes. This trial, published in 1993, led to a rapid increase in the use of HbA1c for the management of diabetes. Most clinical diabetes organizations recommended routine (at least six-monthly) HbA1c measurement in all people with diabetes, resulting in increased assay availability and use. Improvements in HbA1c assay performance led to the American Diabetes Association recommendation in 2010 that HbA1c could be used for screening for and diagnosis of diabetes (American Diabetes Association Professional Practice Committee. Diabetes Care. 2024;47[suppl 1]:S20–S42). The following year, the International Diabetes Federation and other clinical organizations in many countries endorsed HbA1c for diabetes diagnosis.
Given the widespread use of HbA1c assays in routine clinical care, in the July 2022 final rule on CLIA proficiency testing (PT) regulations published by the Centers for Medicare and Medicaid Services, HbA1c has now been added as a CLIA-regulated analyte, with a criterion for acceptable performance in PT being the target value ± eight percent. These changes will go into effect for laboratories on Jan. 1, 2025.
While the addition of HbA1c as a regulated analyte was met with strong support from the clinical laboratory community and medical professional organizations, the established acceptance limit for PT grading was more controversial. In the original proposed rule published in February 2019, the CMS proposed an HbA1c acceptance limit of ± 10 percent. Public comments submitted by numerous professional organizations at the time—including the American Association of Diabetes Educators, American Diabetes Association, American Heart Association, Juvenile Diabetes Research Foundation, and American College of Physicians—expressed concern with the proposed HbA1c acceptance limit of ± 10 percent, given that most HbA1c assays in the CAP’s accuracy-based hemoglobin A1c programs (GH5/GH2) can already achieve successful performance using a much stricter acceptance limit of ± six percent. Initially, the CAP used peer group grading for HbA1c and switched to accuracy-based grading in 2007 with a ± 15 percent acceptance limit. Acceptability limits were reduced, going to 12 percent in 2008 and 10 percent in 2009 and reaching ± six percent in 2014. More than 95 percent of participants pass at ± six percent. In the eyes of many, a ± 10 percent acceptance limit felt like a step backward from what the clinical laboratory community had already achieved.
In its response to public comments published in the 2022 final rule, the CMS noted that poorer laboratory performance with PT was observed in simulation studies when noncommutable specimens were used. Thus, to establish a single acceptance limit (regardless of whether a PT program uses commutable or noncommutable specimens), the CMS finalized its HbA1c acceptance limit at ± eight percent, essentially a compromise between the original proposed and community-recommended thresholds.
While CLIA-defined grading criteria must be used in CMS reporting of PT results for regulated analytes, having CLIA acceptance limits that are wider than what PT programs can achieve (and what clinical professional organizations would like PT programs to use) creates a unique challenge.
To continue its focus on supporting high-quality HbA1c testing, the CAP Clinical Chemistry Committee worked with the CAP Council on Scientific Affairs and Council on Accreditation to update the GH5/GH2 PT evaluation reports to provide results using both the new required CLIA grading of ± eight percent, as well as the ± six percent evaluation criterion that the committee has used for years. A participant laboratory’s evaluation at ± six percent will not be reported to accreditation agencies. However, a laboratory’s review of the ± six percent evaluation will meet the requirements of a newly introduced Laboratory Accreditation Program checklist item (CHM.12925, POC.03325, and LSV.40010), applicable to all CAP-accredited laboratories that use accuracy-based proficiency testing for HbA1c. In this manner, CAP-accredited laboratories will continue to lead the way in ensuring high-quality HbA1c testing for patients, while also meeting the new CLIA requirements and grading criteria for HbA1c as a regulated analyte.
Looking back, the ability of current HbA1c assays to meet accuracy-based PT challenges using the ± six percent evaluation criterion has been the result of a multi-decade effort between diagnostic manufacturers and clinical laboratorians to improve the accuracy and precision of HbA1c assays. The National Glycohemoglobin Standardization Program (NGSP) was established in 1996 to standardize HbA1c assays so that clinical laboratory results are comparable to those reported in the landmark Diabetes Control and Complications Trial. Furthermore, the American Diabetes Association recommends that HbA1c assays be certified by the NGSP to promote ongoing standardization.
Because the CAP GH5 and GH2 programs are accuracy-based (i.e. specimens are whole blood with a defined reference method target value), results from these programs can provide valuable feedback to manufacturers, and this feedback has been used to further improve the standardization of HbA1c assays worldwide. For PT participants, the CAP also provides valuable graphs in the participant summary reports that visually demonstrate differences of methods from the reference method target. Starting in 2025, these graphs will include evaluation limits at both ± eight percent and ± six percent for easy interpretation and comparison of results. The preceding efforts demonstrate how collaboration can lead to remarkable improvements in assay performance and standardization.
As certification by the NGSP requires assay manufacturers to annually meet even stricter grading criteria of ± five percent of expected results for 36 out of 40 specimens, it is reasonable to assume that accuracy-based PT programs should also one day be able to achieve this more stringent acceptance limit. That remains a future goal of the Clinical Chemistry Committee. The history of accuracy-based PT helping to inform global improvements in HbA1c assay quality remains a truly remarkable example of the clinical laboratory and in vitro diagnostic communities working together to improve clinical care and patient outcomes.
Dr. Genzen is chair of the CAP Clinical Chemistry Committee and chief medical officer, ARUP Laboratories, and professor (clinical), University of Utah School of Medicine, Salt Lake City. Dr. Sacks is a member of the Clinical Chemistry Committee and senior investigator and chief of the clinical chemistry service, National Institutes of Health Clinical Center, Bethesda, Md.