Agency Tells EUA SARS-CoV-2 Test Makers to Account for Viral Mutations

On Sept. 23, FDA issued a letter requiring producers of SARS-CoV-2 tests with Emergency Use Authorization (EUA) to take additional steps to account for viral variants. The new Conditions of Authorization apply to certain molecular, antigen and serology tests that have already received EUA for SARS-CoV-2 diagnosis and detection. They don’t cover EUAs for authorized IL-6 assays, standalone specimen collection devices, or standalone home collection kits. Nor do they cover EUAs that include substantially equivalent viral mutation Conditions of Authorization.

The New EUA Requirements

The revisions require test makers to take three steps to account for genetic variants:

1. Updated Labeling

FDA wants test makers to update their authorized labeling and submit it to the agency as a supplement to the EUA within three months. The letter includes a pair of Appendices setting forth detailed instructions. Appendix A requires test makers to add the following specific limitation language to their IFU/Laboratory SOP and/or EUA Summary:

 

The performance of this test was established based on the evaluation of a limited number of clinical specimens. Clinical performance has not been established with all circulating variants but is anticipated to be reflective of the prevalent variants in circulation at the time and location of the clinical evaluation. Performance at the time of testing may vary depending on the variants circulating, including newly emerging strains of SARS-CoV-2 and their prevalence, which change over time.

Appendix B of the letter sets out limitation language that must be added to the Fact Sheet for Healthcare Providers, depending on the type of test:

Molecular and Antigen Tests: The following language must be added at the end of the section of the Fact Sheet titled “What does it mean if the specimen tests negative for the virus that causes COVID-19?”:

The performance of this test was established based on the evaluation of a limited number

of clinical specimens. The clinical performance has not been established in all

circulating variants but is anticipated to be reflective of the prevalent variants in

circulation at the time and location of the clinical evaluation. Performance at the time of

testing may vary depending on the variants circulating, including newly emerging strains

of SARS-CoV-2 and their prevalence, which change over time.

Serology Tests: The following paragraph must be added to the end of the Fact Sheet section called “What does it mean if the specimen tests negative for antibodies against virus that causes COVID-19?”:

The performance of this test was established based on the evaluation of a limited number

of clinical specimens. The clinical performance has not been established in all

circulating variants but is anticipated to be reflective of the prevalent variants in

circulation at the time and location of the clinical evaluation. Performance at the time of

testing may vary depending on the variants circulating, including newly emerging strains

of SARS-CoV-2 and their prevalence, which change over time.

2. Performance Evaluation

FDA is also requiring test makers to perform ongoing evaluation of SARS-CoV-2 viral mutations impact on test performance. Multianalyte test evaluation must address how mutations impact all analytes. Viral mutations that affect the expected performance of the test must be relayed to the agency by email, CDRH-EUA-Reporting@fda.hhs.gov).

3. Additional Labeling Updating

If requested by FDA, labeling must be updated within seven calendar days to include

any additional labeling risk mitigations that the agency identifies regarding the impact of

viral mutations on test performance.

Molecular Tests Cited by FDA as Being Potentially Affected by Viral Mutations

In addition to the letter, FDA published a list of molecular tests whose performance could be impacted by viral mutations:

 

Test Maker	Test
Mesa Biotech	Accula SARS-CoV-2 Test
Cepheid	Xpert Xpress SARS-CoV-2 test + Xpert Xpress SARS-CoV-2 DoD test + Xpert Omni SARS-CoV-2 test
Thermo Fisher Scientific	TaqPath COVID-19 Combo Kit
Applied DNA Sciences	Linea COVID-19 Assay Kit

 

FDA suggested that mutation impact on these tests “does not appear to be significant” for overall sensitivity and that it is providing the information “out of an abundance of caution.”

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Here are some of the key new FDA EUAs and clearances announced in September 2021:

 

New FDA Emergency Use Authorizations (EUAs) & Approvals (NEW)

 

Manufacturer(s)	Product
ANP Technologies	EUA for NIDS COVID-19 Antigen Rapid Test Kit
Northeastern University Life Sciences Testing Center	EUA for RT-PCR-based SARS-CoV-2 test
MolecuLight	510(k) clearance for MolecuLight i:X imaging device detecting wounds containing elevated levels of Pseudomonas aeruginosa
Paige	de novo marketing authorization for Paige Prostate
MeMed	510(k) clearance for MeMed BV test on MeMed Key platform
Takeda Pharmaceutical	Accelerated approval for mobocertinib (Exkivity) for previously treated, metastatic non-small cell lung cancers harboring EGFR exon20 insertion mutations
Quanterix	EUA for Simoa SARS-CoV-2 N protein antigen test expanded to include testing with saliva samples and for asymptomatic serial testing with nasal swab samples
Cairn Diagnostics	Expanded clearance for 13C-Spirulina Gastric Emptying Breath Test, or GEBT, to include at-home under virtual supervision
Cepheid	EUA for Xpert Xpress COV-2/Flu/RSV plus, a new version of its multiplex SARS-CoV-2, influenza, and respiratory syncytial virus test
Yale School of Public Health	EUA for SalivaDirect DTC Saliva Collection Kit and SalivaDirect test
Swiss Precision Diagnostics	Clearance for home-use Clearblue Early Digital Pregnancy Test
Atlas Link Technology	510(k) clearance for 3 over-the-counter pregnancy tests *Atlas One Step hCG Urine Pregnancy Test (Strip) *Atlas One Step hCG Urine Pregnancy Test (Cassette) *Atlas One Step hCG Urine Pregnancy Test (Midstream)
Abbott Laboratories	Clearance for use of i-Stat Chem8+ cartridge with i-Stat 1 System
Inova Diagnostics	510(k) clearance for Aptiva Celiac Disease IgG Reagents
Diazyme	Clearance for use of PLAC Test for Lp-PLA2 Activity on automated clinical chemistry analyzers
Ark Diagnostics	Clearance for Ark Lacosamide Assay
Ortho Clinical Diagnostics	Clearance for Vitros Chemistry Products PHBR Slides
Assure Tech	Clearance for AssureTech DOA Dipstick Screen Panel Tests
CD Diagnostics	Clearance for Synovasure Alpha Defensin Lateral Flow Test Kit
Manufacturer(s)	Product
Paige	de novo marketing authorization for Paige Prostate
MeMed	510(k) clearance for MeMed BV test on MeMed Key platform
Takeda Pharmaceutical	Accelerated approval for mobocertinib (Exkivity) for previously treated, metastatic non-small cell lung cancers harboring EGFR exon20 insertion mutations
Quanterix	EUA for Simoa SARS-CoV-2 N protein antigen test expanded to include testing with saliva samples and for asymptomatic serial testing with nasal swab samples
Cairn Diagnostics	Expanded clearance for 13C-Spirulina Gastric Emptying Breath Test, or GEBT, to include at-home under virtual supervision
Cepheid	EUA for Xpert Xpress COV-2/Flu/RSV plus, a new version of its multiplex SARS-CoV-2, influenza, and respiratory syncytial virus test

 

New CE Marks & Global Certifications

 

Notable European CE certifications announced during the period:

 

NEW CE MARKINGS IN EUROPE

Manufacturer(s)	Product(s)
Zymo Research	EZ DNA Methylation-Lightning Kit
Zymo Research	SafeCollect line of sample collection kits
LGC SeraCare	AccuPlex SARS-CoV-2, Flu A/B, and RSV Reference Material Kit
Roche	PCR-based influenza A/B and respiratory syncytial virus test
Roche	PCR-based adenovirus, human metapneumovirus, and enterovirus/rhinovirus test
Roche	PCR-based parainfluenza 1, 2, 3, and 4 test
Microbio	InfectID-COVID-19 tests
DiaSorin Molecular	Simplexa COVID-19 & Flu A/B Direct test
Thermo Fisher Scientific	TaqPath COVID-19 RNase P 2.0 kit
Seegene	Use of its Combo Swab self-collection device with four of firm’s SARS-CoV-2 molecular diagnostic assays

 

Other international clearances announced during the period:

 

Manufacturer(s)	Country(ies)	Product(s)
Thermo Fisher Scientific	Japan	Oncomine Dx Target Test as companion diagnostic to identify patients with RET-fusion positive non-small cell lung cancer (NSCLC) who may be candidates for treatment with Eli Lilly’s selpercatinib
Co-Diagnostics said this week that CoSara Diagnostics (joint venture of Co-Diagnostics in India)	India	Saragene RT-PCR tests for dengue and chikungunya viruses