Evolution of an Assay

Thursday, June 06, 2013

On May 23, FDA announced, for the first time, they will allow marketing of a Hemoglobin A1c assay for diagnosis of diabetes (Roche COBAS INTEGRA Tina-quant HbA1c). This comes a little over two years after the American Diabetes Association (ADA) joined the International Diabetes Federation (IDF) and the European Association for the Study of Diabetes (EASD) in the endorsement of the use of HbA1c to diagnose diabetes.

The ADA report proposed a diagnosis of diabetes for HbA1c levels ≥6.5%, when testing is performed by a laboratory method certified by the National Glycohemoglobin Standardization Program (NGSP) and standardized to the Diabetes Control and Complications Trial assay (DCCT). Other criteria for diagnosis include a fasting plasma glucose level of ≥126 mg/dL, a 2-hour plasma glucose level ≥200 mg/dL during an oral glucose tolerance test, and a random plasma glucose level of ≥200 mg/dL in patients with symptoms of hyperglycemia or a hyperglycemic crisis.

Glycosylated hemoglobin tests for diabetes monitoring have been cleared by FDA as Class II devices since 1978. Since 1991, FDA guidance Review Criteria for Assessment of Glycohemoglobin (Glycated or Glycosylated) Hemoglobin in Vitro Diagnostic Devices has defined requirements for FDA clearance of these hemoglobin assays for monitoring. In addition FDA has required that tests for monitoring HbA1c participate in ongoing certification by the National Glycohemoglobin Standardization Program (NGSP). The purpose of the NGSP is to standardize Hemoglobin A1c test results to those of the Diabetes Control and Complications Trial (DCCT) and United Kingdom Prospective Diabetes Study (UKPDS), which established the direct relationships between HbA1c levels and outcome risks in patients with diabetes. Since assays marketed for HbA1c monitoring were required by FDA to maintain NGSP certification, industry initially hoped that the certification would be sufficient to justify the expansion of the intended use to include diagnosis since that criterion had been stated in the ADA endorsement. Early discussion with FDA indicated that FDA was not ready to define the criteria without further consideration to the complex assay and understandably so. 

HbA1c assesses the A1c portion as a percent of total hemoglobin in a blood specimen. Studies have shown that HbA1c provides a weighted index of the average glucose over the preceding weeks and months making it an effective tool for monitoring long term glucose control in individuals with diabetes mellitus. Maintenance of HbA1c levels below 7% was generally considered to be evidence of control. In reviewing these assays for the broadened intended use, FDA would have to determine what additional evidence would be needed to establish the performance for the specified cut off.  

Although guidance for this expanded intended use has yet to be released, FDA has shared in their news release, that the cleared test was found to have less than 6% difference in the accuracy of test results versus the standard reference for hemoglobin analysis (n=141).  

Compared to other cleared diabetes diagnostics the HbA1c test offers the advantage of no pretest fasting requirements, and no administration of glucose to evaluate timed response. If the test achieves broad acceptance it may be more revolution than evolution in diabetes testing. Perhaps HbA1c may be nominated for next year’s IVD Hall of Fame...

Tags: CDRH, IVD

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