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FDA Issues Alert About Potential False Negative Test Results From SARS-CoV-2 Mutations

NEW YORK – The US Food and Drug Administration issued a letter to clinical laboratory staff and healthcare providers Friday, alerting them to the potential for false negative SARS-CoV-2 test results due to mutations in the virus genome.

Through its ongoing analyses of viral sequences and proprietary Emergency Use Authorized test information, the agency has identified three molecular assays whose performance could be impacted by SARS-CoV-2 genetic variants.

In the letter, FDA identified the Mesa Biotech Accula SARS-Cov-2 Test, the Thermo Fisher Scientific TaqPath COVID-19 Combo Kit, and the Applied DNA Sciences Linea COVID-19 Assay Kit as tests with potential issues.

The Thermo Fisher Scientific and Applied DNA Sciences tests target the viral spike protein, or S gene. Thermo's test also targets the N gene and a gene called Orf1b, while Applied DNA's test targets two regions in the S gene.

Since both tests are designed to detect multiple genetic targets, the overall test sensitivity should not be impacted, FDA wrote.

Furthermore, "The pattern of detection when certain mutations are present may help with early identification of new variants in patients to reduce further spread of infection." 

For these tests, the agency guided that users be aware of the pattern of detection associated with certain mutations, including the B.1.1.7, or UK variant. Specifically, the variant would be manifest as a pattern of two out of three positive targets showing the S-gene dropout or reduced sensitivity with the S-gene target when using the TaqPath COVID-19 Combo Kit, and a pattern of one out of two positive targets showing the S-gene drop out when using the Linea COVID-19 Assay Kit, FDA said.

"If local or state clinical laboratories have access to quick-turnaround whole-genome sequencing services, such as those using the EUA-authorized Illumina COVIDSeq Test, these labs should consider further characterizing the specimen with genetic sequencing when this pattern is identified," FDA also said.

The Mesa Biotech test detects a single target in the viral nucleoplasmid, or N gene. It may be impacted when patient samples having a genetic variant at position 28881 (GGG to AAC) are tested, the agency said.

"While the impact does not appear to be significant, the FDA is providing this alert to health care providers out of an abundance of caution while we continue to gather additional data and work with the manufacturer," the agency said.

Overall, the agency guided providers to be alert to the potential for false negative results, as "genetic variants of SARS-CoV-2 arise regularly," and to "Be aware that tests that use multiple genetic targets to determine a final result are less likely to be impacted by increased prevalence of genetic variants."

Negative results should be considered along with clinical observations, patient history, and epidemiological information, and providers and labs should consider repeat testing with a different test — with different genetic targets — if COVID-19 is still suspected after receiving a negative test result, the agency said.

The FDA will continue to monitor the effects of different variants on EUA SARS-CoV-2 molecular tests and "will update clinical laboratory staff and healthcare providers accordingly," the letter states.

For an in-depth look at the challenges and opportunities diagnostic developers are facing in light of emerging mutations, click here.