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Idea to ease PT standard for HbA1c stirs alarm

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Anne Paxton

July 2019—Excellence is considered the hallmark of progress throughout health care. We don’t expect to hear that, for a particular diagnostic test, standards may already be too high. Yet a proposed rule by the Centers for Medicare and Medicaid Services, announced Feb. 4, does convey that message in its recommendation to add HbA1c to the list of analytes regulated under CLIA’s proficiency testing regulations related to analytes and acceptable performance.

If the rule is adopted, the CMS would CLIA-regulate HbA1c proficiency testing for the first time. But in an atypical turn to lower standards, for HbA1c—for which the CAP sets an acceptance limit of ±six percent around the target value—the CMS is proposing a looser CLIA PT accuracy standard of ±10 percent.

The almost universal reaction of the diabetes and laboratory medicine community to this proposal to weaken the HbA1c accuracy standard has been alarm—and puzzlement. “I was shocked” when the proposed rule was issued, says David B. Sacks, MB, ChB, FRCPath, senior investigator and chief of the clinical chemistry service in the Department of Laboratory Medicine at the National Institutes of Health. He had no inkling that a proposal to weaken the standard was being prepared. David C. Klonoff, MD, medical director of the Diabetes Research Institute at Mills-Peninsula Medical Center, part of Sutter Health, in San Mateo, Calif., also was taken aback. “It’s one of the strangest situations I have seen in medicine.”

The CMS’ invitation to submit public comment about the proposed rule produced 108 responses between February and the extended deadline of June 4, when comments closed. Along with others, the CAP voiced support for the CMS’ effort to update the list of regulated analytes by proposing the addition of 29 and the deletion of six current analytes, but objected to loosening the HbA1c accuracy standard.

Comments on the rule submitted to the CMS by individuals and organizations expressed more than strong reservations: “Would totally erase the progress in quality improvement in measuring HbA1c that has served the diabetes community so well in the past few years” (International Society for Pediatric and Adolescent Diabetes). “The diagnostic utility of the test will be lost” (Paul Yip, Institute for Quality Management in Healthcare, University of Toronto). “Flies in the face of successful efforts to tighten the assays and harmonize them across the country” (David Nathan, Massachusetts General Hospital). “An unexplainably retrograde step” (Simon O’Neill, Diabetes UK).

Dr. Klonoff

In fact, it appears that no commenters support the ±10 percent standard for HbA1c. “I have heard no one publicly support this—not one doctor, not one organization, not one company,” Dr. Klonoff says. So how did the idea garner enough consensus to appear in a proposed rule? On that question, he says, “I am just baffled. Why they came up with ±10 percent, I don’t know.”(Dr. Klonoff notes that the opinions he expresses are his own and he is not speaking on behalf of Sutter Health.)

Dr. Klonoff and Dr. Sacks are among eight leading endocrinologists and clinical chemists—all caught by surprise by the proposed rule—who penned a joint editorial for Journal of Diabetes Science and Technology (2019;13[3]:424–427), explaining why they believe the CMS proposal is a step backward. The authors’ core message: “We believe that CLIA’s proposed rule loosening the acceptance limits for proficiency testing from the current level of ±6% to a proposed level of ±10% would significantly harm the effectiveness of HbA1c testing and threaten patient safety.”

The recent history of HbA1c is one of progressive improvement. Criteria for passing the CAP Survey tightened from ±15 percent in 2007 to ±six percent by 2013, and in 2018 the CAP began to offer educational grading at ±five percent. There may be further improvement in the future. By contrast, the authors believe, the accuracy standard offered in the proposed CLIA rule is regressive.

“It is very unusual for a regulatory agency to say, ‘We want to have less stringent standards,’” Dr. Klonoff says. “There would have to be some really unusual problem—maybe a shortage of a product, or somebody did something wrong. But in normal practice, as technology improves, the capability of making an accurate measurement improves. That’s why the CAP standards have been mandating a lower and lower variability. For any regulatory body to permit higher variability for any analyte is strange. There has been no shortage of HbA1c instruments and no unusual events that would support changing standards, except for the gradual tightening of standards.”

Some companies with devices on the market are rightly upset about the proposed rule, he adds. “They say, ‘We go to a lot of trouble to build an accurate product; now you—CMS and CLIA—want to allow lower quality products to compete with us.’ So this is an instance where industry and academia are in agreement.”

The CMS had not proposed a standard for HbA1c before now because HbA1c was not a high-profile test the last time the CMS established CLIA rules, Dr. Klonoff says. “They’ve specified proficiency testing limits since the mid-1990s for a group of analytes they thought were important, but they previously decided not to include HbA1c.”

In the absence of professional testing rules, “the CAP has had proficiency testing policies that all labs have been following, and the NGSP has similar requirements.” The NGSP (originally known as the National Glycohemoglobin Standardization Program) sets strict international standards that manufacturers must adhere to, and sometimes laboratories don’t do as well as the method does in the hands of the manufacturer, he notes.

As Dr. Klonoff explains, the CAP is the de facto organization that sets the performance of clinical chemistry devices to make sure they are sufficiently accurate. “The NGSP also wants to make devices that measure HbA1c accurate, but for an additional purpose.” The NGSP seeks to ensure all the instruments in the country are standardized to the Diabetes Control and Complications Trial by calibrating a network of reference labs to the DCCT reference values; those reference labs work with manufacturers to standardize their methods.

“This year, NGSP has reset the standard for manufacturers at ±five percent for HbA1c. Manufacturers have been preparing for the shift to ±five percent,” Dr. Klonoff says. Since their methods will still have to be NGSP-certified, he believes manufacturers won’t be able to ignore the tighter NGSP accuracy standard, even if the CMS adopts its proposed rule.

The leadership of NGSP is also opposed to a lower standard, Dr. Klonoff says. “This proposed rule would apply only in the U.S., so it would probably not affect the international body. But you never know. If the U.S. were to mandate a looser requirement, then possibly the international body would follow. Although they probably would want to know why these looser standards are acceptable, and I haven’t read anything showing that.”

A ±10 percent accuracy margin is difficult to compare across analytes, Dr. Klonoff says. “I don’t think it’s meaningful to say that because a test for one analyte has a proficiency test margin of ±10 percent, then another test should also be specified to have the same range. The permitted range depends on biological variability among people and how easily the analyte can be measured. If you have an analyte that is difficult to measure, then you’re going to allow greater differences, and if people’s results can change from one day to the next, then as a general rule you’d also allow greater differences.”

However, Dr. Klonoff adds, there has been clear progress toward less variability in the HbA1c standard. “It has taken a long time to get these instruments down to a proficiency target of ±six percent. Ironically, almost every device on the market right now is ±six percent. So why go back to ±10 percent?”

The CAP does support part of the proposed rule. As it said in its comments to the CMS, it agrees with the agency’s effort to update the list of regulated analytes by proposing the addition of the 29 new analytes and the deletion of six current analytes. It also agrees with the effort to allow PT programs more autonomy to establish peer groups and parameters for PT offerings, and to protect the integrity of the program by ensuring nonprofit status for administrative activities.

But the CAP does not support a change to acceptable performance criteria of target value ±10 percent for HbA1c. The CAP offered for consideration two sets of criteria for HbA1c: “one for commutable (matrix effect free) whole blood material, where the criterion should be ±6%, and the second criterion for other matrix, where the acceptable performance could be a target value of ±10%.” The CAP said it “can accept use of ±10% for non-commutable material so long as the accuracy-based criterion of 6% is simultaneously implemented.”

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