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Medicare Contractor Outlines Criteria for Analytical Validity of Circulating Tumor DNA Tests

NEW YORK (GenomeWeb) – Medicare contractor Palmetto has outlined the coverage criteria by which it will assess the analytical performance of circulating tumor DNA (ctDNA) tests used to detect somatic variants.

Among the pre-analytical, analytical, and post-analytical requirements that a ctDNA test will have to meet, Palmetto wrote that "laboratories are encouraged to submit reported somatic variants, their interpretations of clinical significance, and associated clinical phenotypes to ClinVar," a freely available archive of genotype and phenotype relationships the National Institutes of Health launched three years ago. To date, more than 500 submitters have contributed data to the repository.

This is the first time a Medicare contractor has encouraged such data sharing, although support for this kind of activity has been growing. GenomeWeb recently reported that at least one national insurer, Aetna, is requiring that all newly contracted labs submit their variant interpretations to ClinVar as a condition of participation in its network for BRCA1 and BRCA2 genetic testing. Meanwhile, the US Food and Drug Administration is supportive of sharing in public data repositories, and many peer-reviewed journals now encourage, if not require, such activity as a condition for publication.

The analytical validation criteria outlined by Palmetto apply to qualitative assessment of ctDNA performed by any methodology, including next-generation sequencing. The contractor noted, though, that the specifications are not intended for the analysis of circulating tumor cells or CTC-derived tumor DNA, matched tumor-normal testing with ctDNA, or quantitative ctDNA analysis for drug response, disease monitoring, or minimal residual disease. 

"CtDNA-based somatic variant detection may be considered a form of surrogate testing," the contractor explained. "A ctDNA 'analyte' is the surrogate for the tumor tissue 'analyte.'" As such, the lab must establish the performance metrics for the surrogate analyte and demonstrate the degree to which the surrogate agrees with the primary reference analyte.

Palmetto said it will first look to see if the test is being performed in a CLIA-certified lab, whether it has New York State Department of Health approval, and if it is part of an external proficiency testing program.

Then, for the pre-analytical assessment, the contractor will consider whether the test has been validated in all sample types that the lab accepts for testing. Moreover, the lab must specify its minimum requirements in terms of, for example, cell-free DNA, library concentration, and coverage.

As for the analytical requirements, labs have to meet the requirements for the molecular alterations they report, Palmetto said. The contractor laid out detailed criteria for how labs should establish a test's positive percent agreement, analytical positive predictive value, as well as negative percent agreement and reproducibility, if applicable.

Among the post-analytical requirements, while Palmetto only encouraged variant data submissions to ClinVar, the contractor required a number of other things. For example, a physician board certified in molecular genetic pathology must identify variants detected through ctDNA testing, interpret them clinically, and make therapeutic recommendations. "A PhD is not a recognized Medicare provider," Palmetto said.