CAP TODAY Pathology/Laboratory Medicine/Laboratory Management
“It’s also up to the laboratory community to inform the physician groups about the need for standardization on a much larger scale. That would help raise the profile of this problem and increase the pressure on Congress or other funding agencies to make harmonization a greater priority.”
Dr. Myers
Most IVD companies, although they may be U.S. or European based, serve laboratory medicine worldwide and have the responsibility to meet whatever regulatory requirements exist where they market their tests. In response to the European IVD directive, the JCTLM was formed in 2002 by the International Bureau of Weights and Measures in France, the International Federation of Clinical Chemistry and Laboratory Medicine, and the International Laboratory Accreditation Cooperation. The goal of the JCTLM, says Dr. Myers, is to provide a worldwide platform to promote and give guidance on internationally recognized and accepted equivalence of measurements in laboratory medicine and traceability to appropriate measurement standards.
To support IVD manufacturers in meeting the IVD directive essential requirement for traceability to higher order standards, the JCTLM provides an online database (www.bipm.org/jctlm) of reference methods and materials as well as labs that provide reference measurement services. “These are all evaluated in accordance with ISO standards,” Dr. Myers says, “and the ones found acceptable are made part of this database” that IVD companies can consult to find reference methods and materials to use to trace their methods, as many countries now require. ISO 17511, currently under revision, describes principles for metrological traceability of values assigned to calibrators and controls, which form the basis for approaches establishing traceability to higher order reference systems.
The ICHCLR’s full list of priority tests was compiled from a number of different sources of lab tests ordered by physicians, says Dr. Myers, who also serves as chair of the ICHCLR council. “Our harmonization oversight group, made up of experts in laboratory medicine, has been systematically looking at the clinical data, performance data, and need for use in managing and diagnosing patients’ conditions to prioritize which ones need to be harmonized.” The organization’s website (www.harmonization.net) shows which tests have been designated high, low, and medium priority.
Although industry perspectives are represented, “we’re not looking necessarily at harmonization from an industry standpoint but from a medical need standpoint—how the tests are used to diagnose patient conditions and which are higher priority.” Historically, manufacturers have lacked the resources to do all of their harmonization internally, so industry has played a key role in selecting the analytes targeted for harmonization by looking at the competition for resources internally and the external forces pushing harmonization.
“For example, when the National Cholesterol Education Program came along and said, ‘Know your number,’ the laboratory industry said, ‘We can’t measure cholesterol reliably enough for “know your number” to make sense,’” Dr. Myers says. “So manufacturers lined up with the lab community to improve the methods and develop and use standards in the calibration process.” For other methods, the usual approach is to establish a working group or committee to work on developing the reference system components for a particular analyte.
Currently 26 analytes have complete reference systems (a reference method, material, and certified laboratory that can provide measurement services) in the JCTLM database. A total of 293 reference materials, including a combination of pure material and matrix-based materials, are listed in the JCTLM database as well as 184 reference methods; 161 reference measurement services are listed as being delivered by 17 certified reference laboratories.
Harmonization of all lab tests will be no small task, Dr. Myers says. “There’s a group in the Netherlands that estimates there are several thousand lab tests commonly measured in the lab, maybe not routinely. But if you look at it from that standpoint, there’s still a lot of work to do. The 80 or so analytes that have been harmonized or standardized are the tip of the iceberg. The majority of tests that haven’t been touched, because of technical difficulty or another reason, is the mass of the iceberg below the surface of the water.”
In contrast with the EU, the FDA does not require traceability of an in vitro device to a reference system as part of its approval process. And that is a concern, Dr. Myers says. Since long before the EU adopted its standard, “the FDA has required that a method be equivalent to what’s considered a predicate device that has already been through the approval process. They can’t require, as the EU IVD regulations do now, that IVD companies provide documentation indicating their method is standardized or traceable to a higher order standard.”
However, the FDA does consult the JCTLM database for a more limited purpose. “If an IVD company says in its product literature that it has established traceability to a reference method and reference material, the FDA will look to make sure that what the company is stating it has established traceability to is the appropriate standard of a reference material and reference method.”
Dr. Myers would like to see the EU requirement of calibration traceability to a higher order reference system become adopted worldwide by regulators, including the United States. “If we’re going to have standardization and have IVD companies work for more equivalency across different platforms that measure the same analyte, it’s going to have to be done either through traceability to a standard that’s out there or a harmonization process that may use patient samples to do the same thing.”
“But there has to be a process. It doesn’t seem reasonable that a technology to measure something that’s developed in 2017 may be okay as long as it’s traceable to something that was developed in the 1960s or 1970s, especially where there may have been no standards available back when that initial technology was evaluated by the FDA.”
Under the EC directive, an estimated 80 percent of devices will have to go through certification. Only 20 percent, those that fall into a category A in terms of low risk, will be able to be self-declared by the IVD manufacturers themselves, Dr. Myers notes. Self-declaration is practiced in the U.S. now when an IVD company intends to seek a CE mark allowing its products to be sold in Europe.
What manufacturers are doing with harmonization and standardization is changing their calibration, which is going to change the numeric value of results. “But they’re not making a change in the method itself,” Dr. Myers notes. “You’re not changing the precision or reaction conditions or anything like that, so there should be a more streamlined process to allow these IVD companies to submit their work and get approval based on how they changed their calibration to be consistent with particular standards.”
“If an IVD company has to make modifications to a method—for example, to make it more selective for the particular test they are trying to measure—obviously they will need to follow the FDA guidelines that are in place for a major change in the method.”
“So we’re saying that if they recalibrate and just move the curve up, say, five percent, and nothing else changes other than the numeric value—the methods still measure cholesterol, for example, the same way we measured it before—they’re just recalibrating to a new standard that should not require major submissions and new studies that are very costly.”
The laboratory medicine community does recognize and has been working on standardization schemes for quite a while, Dr. Miller of VCU notes. “But it’s very slow going, and it hasn’t been until the last 20 years that its importance has been appreciated. Physicians who are community and family practitioners probably make the assumption that the lab tests are pretty equivalent.”“That’s an educational challenge for pathology,” he says, adding that the CAP’s resource committees are well aware of these problems. When he asked the audience during his own AACC presentation on harmonization whether they have received a call from a physician asking why one result was different from another when the answer was because it was from a different method, nearly 100 percent answered yes.
One of the key things identified as missing in the 2010 conference that led to the creation of the ICHCLR, Dr. Miller says, was a process to harmonize analytes when no reference method or certified reference material exists. “The classical way to approach harmonization and standardization is to develop a reference method and reference material, and the IFCC is the main sponsor of such projects. But for many analytes, those are not available and are not likely to become available due to technical constraints.”
Dr. Miller
He estimates that of the roughly 1,500 analytes in a typical clinical laboratory test catalog, only about 100 have had reference systems developed to support standardization. “That leaves a very large number of tests, and there needs to be something developed to help them meet the needs of standardization.” Among those 100 analytes, not all calibration hierarchies use reference materials that are commutable with patient samples, which means they are not suitable for use as calibrators. “Before 2010 there was not general recognition and agreement that commutability with patient samples should be required for reference materials,” Dr. Miller says.
To fill the gap, a new process built around a harmonization protocol has been evolving. The IFCC committee working on standardization of thyroid tests has developed a harmonization protocol for TSH, based on using a panel of patient samples as calibrator materials, Dr. Miller says. The ISO Technical Committee 212 for laboratory medicine is currently developing an international standard for harmonization protocols, expected to be published in 2019 or 2020.
He agrees that the laboratory medicine community has moved beyond striving for perfection where perfection is not necessary, and that has opened the door to more progress in harmonization. As a sign: “We now agree that the new harmonization protocol is an acceptable approach. Ten years ago people would have said, ‘You can’t use that—it violates scientific principles.’”
Now it’s better understood that the assays do not need to be perfect but “fit for purpose,” Dr. Miller says. “They just have to be good enough to be able to get reliable results that physicians can use to make medical decisions about patient care.” He commends the educational efforts of the AACC and the CAP’s strong support of harmonization through articles and expansion of its accuracy-based Surveys. “That is essential to understanding what needs to be harmonized and how well harmonized or not harmonized results are.”
Still more outreach is needed to bring harmonization into the spotlight, however. “There are many people who haven’t thought about it yet and don’t really understand that harmonization is critically important and there are now tools to achieve it,” Dr. Miller says. “More education will help our profession understand that harmonization is important and can be achieved with the new tools being developed.”n
Anne Paxton is a writer and attorney in Seattle.