While the FDA said the risk that SARS-CoV-2 virus mutations will only have a minor impact on testing accuracy is low, the agency singled out three tests are they had a higher concern.
January 8, 2021 — The U.S. Food and Drug Administration (FDA) is alerting healthcare providers that it is monitoring the potential impact of COVID (SARS-CoV-2) viral mutations, including the emerging variant from the United Kingdom and its potential to produce false negative results on FDA authorized SARS-CoV-2 molecular tests.
Despite the alert issued today, the FDA believes the risk that these mutations will impact overall testing accuracy is low.
The new, more virulent strain of the SARS-CoV-2 virus from the U.K., known as the B.1.1.7 variant, is a mutation. Of the virus originally used in developing the 309 COVID tests cleared under FDA emergency use authorizations (EUAs) in the past year. These include 235 molecular tests and sample collection devices, 63 antibody tests, and 11 antigen tests. There are now 32 molecular authorizations that can be used with home-collected samples. There is one molecular prescription at-home test, one antigen prescription at-home test, and one over-the-counter (OTC) at-home antigen test.
The FDA said false negative results can occur with any molecular test for the detection of SARS-CoV-2 if a mutation occurs in the part of the virus’s genome assessed by that test. The SARS-CoV-2 virus can mutate over time, like all viruses, resulting in genetic variation in the population of circulating viral strains, as seen with the B.1.1.7 variant. The FDA said it is taking additional actions to ensure authorized tests remain accurate by working with test developers and conducting ongoing data analysis to evaluate all currently authorized molecular tests.
“The FDA will continue to monitor SARS-CoV-2 genetic viral variants to ensure authorized tests continue to provide accurate results for patients,” said FDA Commissioner Stephen M. Hahn, M.D. “While these efforts continue, we are working with authorized test developers and reviewing incoming data to ensure that healthcare providers and clinical staff can quickly and accurately diagnose patients infected with SARS-CoV-2, including those with emerging genetic variants. At this time, we believe the data suggests that the currently authorized COVID-19 vaccines may still be effective against this strain. The FDA will continue to keep healthcare providers and the public informed of any new information as it becomes available.”
The FDA has been monitoring SARS-CoV-2 viral mutations, and potential impact on testing, throughout the pandemic. The presence of SARS-CoV-2 genetic variants in a patient sample can potentially change the performance of a SARS-CoV-2 test. Tests that rely on the detection of multiple regions of the genome may be less impacted by genetic variation in the SARS-CoV-2 genome than tests that rely on detection of only a single region.
New U.K. Strain of COVID May Impact 3 Molecular Tests
The FDA singled out three currently authorized molecular tests, MesaBiotech Accula, TaqPath COVID-19 Combo Kit, and Linea COVID-19 Assay Kit, may be impacted by genetic variants of SARS-CoV-2. However, the agency said the impact does not appear to be significant.
Importantly, the detection pattern that appears with the TaqPath and Linea diagnostic tests when certain genetic variants are present may help with early identification of new variants in patients to reduce further spread of infection. The recently identified B.1.1.7 variant has been associated with an increased risk of transmission, therefore early identification of this variant in patients may help reduce further spread of infection.
• Accula SARS-Cov-2 Test: The FDA’s analysis, including additional information provided by the manufacturer, Mesa Biotech Inc., indicates that the Accula SARS-Cov-2 Test performance may be impacted when a SARS-CoV-2 virus patient sample having a genetic variant at position 28881 (GGG to AAC) is tested. While the impact does not appear to be significant, the FDA is providing this alert out of an abundance of caution while we continue to gather additional data and work with the manufacturer.
• TaqPath COVID-19 Combo Kit: The FDA’s analysis, including additional information provided by the manufacturer, Thermo Fisher Scientific, and multiple reports from clinical laboratories, indicates that one of three targets of the TaqPath COVID-19 Combo Kit has significantly reduced sensitivity due to certain mutations, including one of the mutations in the recently identified B.1.1.7 variant (UK VOC-202012/01). Since this test is designed to detect multiple genetic targets, the overall test sensitivity should not be impacted. 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.
• Linea COVID-19 Assay Kit: The FDA’s analysis, including additional information provided by the manufacturer, Applied DNA Sciences, Inc., indicates that one of the two targets of the Linea COVID-19 Assay Kit has significantly reduced sensitivity due to certain mutations, including one of the mutations in the recently identified B.1.1.7 variant. Since this test is designed to detect multiple genetic targets, the overall test sensitivity should not be impacted. 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.
All COVID Tests Have Some Level of False Negative Results
In the alert, the FDA reminds clinical laboratory staff and healthcare providers that there is a risk of false negative results with all laboratory tests, including molecular tests. Laboratories should expect some false results to occur even when very accurate SARS-CoV-2 tests are used. Issues with false negatives have been known since the start of the pandemic
A study of COVID tests published last year from Johns Hopkins researchers found that testing people for SARS-CoV-2 too early in the course of infection is likely to result in a false negative test, even though they may eventually test positive for the virus. This is important to understand since many hospitals are using these COVID tests to screen patients before imaging exams, diagnostic testing or procedures. Tests are also use to confirm staff members are not infected.
The report found even a week after infection, there was a false negative rate of 20 percent, meaning one in five people who had the virus had a negative test result. The researchers estimated that those tested with SARS-CoV-2 in the four days after infection were 67 percent more likely to test negative, even if they had the virus.
“A negative test, whether or not a person has symptoms, doesn’t guarantee that they aren’t infected by the virus,” said Lauren Kucirka, M.D., Ph.D., M.Sc., obstetrics and gynecology resident at Johns Hopkins Medicine. “How we respond to, and interpret, a negative test is very important because we place others at risk when we assume the test is perfect. However, those infected with the virus are still able to potentially spread the virus.”
In July 2020, the FDA issued a letter to providers alerting them of an increased risk of a false positive result with BD SARS-CoV-2 Reagents for the BD Max System test. In one study, the manufacturer found about 3% of results were false positive results.
Read the related article COVID-19 Genetic PCR Tests Give False Negative Results if Used Too Early.
FDA Recommendations on Testing With New COVID Mutation
Today’s announcement also provides important information and recommendations for clinical laboratory staff and healthcare providers who use molecular tests for the detection of SARS-CoV-2:
1. Be aware that genetic variants of SARS-CoV-2 arise regularly and false negative test results can occur.
2. 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.
3. Consider negative results in combination with clinical observations, patient history, and epidemiological information.
4. Consider repeat testing with a different test (with different genetic targets) if COVID-19 is still suspected after receiving a negative test result.
The FDA will continue to communicate with the public as we have additional information to share. The FDA encourages stakeholders to report any adverse events or suspected adverse events experienced with molecular tests for detection of SARS-CoV-2. Voluntary reports can be submitted through MedWatch, the FDA Safety Information and Adverse Event Reporting program. Health care personnel and clinical laboratory staff employed by facilities that are performing COVID-19 testing should follow the reporting requirements for authorized laboratories as specified in the test’s Emergency Use Authorization. Prompt reporting of adverse events can help the FDA identify and better understand the risks associated with medical devices.
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1. Lauren M. Kucirka, Stephen A. Lauer, Oliver Laeyendecker, et al. Variation in False-Negative Rate of Reverse Transcriptase Polymerase Chain Reaction–Based SARS-CoV-2 Tests by Time Since Exposure. Annuals of Internal Medicine. May 13, 2020. doi.org/10.7326/M20-1495.