FDA Watch

FDA Watch: Molecular Tests May Miss New SARS-CoV-2 Strains, Agency Warns

Like many viruses, the SARS-CoV-2 is a shape-shifter. And that may make it harder to detect. With this in mind, the U.S. Food and Drug Administration (FDA) is warning clinical laboratories and health care providers of the risk that genetic mutations to the virus may lead to false negative test results.

The Diagnostic Challenge

The first and vast majority of tests with FDA emergency use authorization (EUA) for SARS-CoV-2 are molecular assay designed to detect specific RNA sequences found in the viral genome. However, the SARS-CoV-2 virus mutates regularly, resulting in several genetically unique variants, each with different RNA sequences. The presence of SARS-CoV-2 genetic variants in a patient sample can potentially change the performance of the SARS-CoV-2 test. If a molecular test is not engineered to detect the particular sequences associated with these variants, it may miss the variant leading to the false conclusion that the test subject does not have the virus. The resulting false negative may prevent the subject from receiving necessary treatment and enhance the risk of infection by keeping him/her out of self-isolation.


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Molecular tests designed to detect multiple SARS-CoV-2 genetic targets are less susceptible to the effects of genetic variation than tests designed to detect a single genetic target. The clinical impact of genetic variants on test sensitivity is influenced by the sequence of the variant, the design of test and the prevalence of the variant in the patient population. Tests that rely on the detection of multiple regions of the genome may be less impacted by genetic variation in the SARS-CoV2 genome than tests that rely on detection of only a single region.

The FDA Response

The FDA has been monitoring the potential effects of genetic variation in molecular tests that have received EUA on an ongoing basis throughout the pandemic. On Jan.8, it sounded the alarm in a letter. “The FDA reminds clinical laboratory staff and health care providers about the risk of false negative results with all laboratory tests,” FDA wrote, including molecular tests. The FDA letter also identifies specific molecular tests that have received EUAs whose performance could be impacted by SARS-CoV-2 genetic variants. “No test is perfect,” according to the letter. “Laboratories should expect some false results to occur even when very accurate SARS-CoV-2 tests are used.” The letter lists three tests with EUA that could be impacted by mutations:

  • The Mesa Biotech Accula SARS-Cov-2 Test, which received EUA on March 24;
  • The Thermo Fisher Scientific TaqPath COVID-19 Combo Kit, which received initial EUA on March 15 and received subsequent expansions allowing for home collection and use with additional instruments and reagents; and
  • The Applied DNA Sciences’ Linea COVID-19 Assay Kit, first cleared on May 13 and subsequently cleared for use with robotic RNA extraction.

FDA Recommendations

The FDA recommends that clinical laboratory staff and providers who use molecular tests for the detection of the SARS-CoV-2 virus:

  • Recognize that genetic variants of SARS-CoV-2 arise regularly and may result in false negative test results;
  • 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;
  • Analyze negative results in combination with clinical observations, patient history and epidemiological information; and
  • Consider ordering repeat testing with a different test with different genetic targets for patients who test negative after molecular testing if COVID-19 is still suspected.

Meanwhile, here are the key new FDA EUAs and clearances announced in January:

New FDA Emergency Use Authorizations (EUAs) & Approvals

Manufacturer(s) Product
Bio-Rad Laboratories EUA for Bio-Rad Reliance SARS-CoV-2 RT-PCR Assay
United Biomedical EUA for UBI SARS-CoV-2 ELISA antibodies test
SML Genetree EUA for Ezplex SARS-CoV-2 G Kit
Ortho Clinical Diagnostics Vitros SARS-CoV-2 Antigen test, first high-volume COVID-19 antigen test to get EUA
Phadia (Thermo Fisher Scientific subsidiary) EUA for EliA SARS-CoV-2-Sp1 IgG Test fluoro-enzyme immunoassay
Abbott 510(k) clearance for rapid handheld blood test for traumatic brain injury
Helix de novo clearance for Helix Laboratory Platform, first whole-exome sequencing platform to get FDA clearance
Helix 510(k) clearance for Helix Genetic Health Risk App (HRA) DTC genetic test for late-onset Alzheimer’s
Siemens Healthineers EUA for Dimension Vista SARS CoV 2 IgG (COV2G) antibodies immunoassay
Siemens Healthineers EUA for lab-based IL-6 assay to measure presence of interleukin-6 in human serum or plasma
Advaite EUA for RapCov Rapid COVID-19 Test point of care serology test
Quanterix EUA for Simoa SARS-CoV-2 N Protein Antigen Test
Nirmidas Biotech EUA for MidaSpot COVID-19 Antibody Combo Detection Kit point of care test
Roche EUA for Elecsys Anti-SARS-CoV-2 S electrochemiluminescence immunoassay run on firm’s Cobas E analyzers
Lucira Health EUA for Lucira COVID-19 All-in-One Test Kit, first fully at-home test authorized for COVID-19
GenScript Biotech EUA for cPass SARS-CoV-2 Neutralization Antibody Detection Kit, first SARS-CoV-2 neutralizing antibody test to receive EUA

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