COVID test developers get variant-related FDA guidance

Regulatory NewsRegulatory News | 22 February 2021 |  By 

A new guidance from the US Food and Drug Administration (FDA) provides considerations for developers of molecular, antigen and serology COVID-19 tests as they evaluate how viral mutations may affect test performance.
As variants in the SARS-CoV-2 virus emerge and spread, FDA has been monitoring mutations tracked in global databases and checking to see whether mutations are occurring in regions of the virus genome that various molecular tests target, explained the agency in the document issued Monday. FDA had issued a safety alert on 8 January warning stakeholders that these variants might impact test performance.
In the new guidance, FDA notes that developers should consider how their test performs against variants when submitting new emergency use authorization (EUA) submissions for COVID-19 tests: “During FDA’s review of an EUA request for a COVID-19 test, FDA intends to consider the performance of the test across all known variants, as well as the developer’s plans for postauthorization monitoring.”
The EUA request, said FDA, should address whether test labeling will include statements limiting the geographic region or temporal period of specimen collection for which the tests were evaluated. Additionally, developers should note “that the clinical performance has not been established in all circulating variants, and that performance may vary depending on the variants, and their prevalence, circulating at the time of patient testing.” (RELATED: First OTC, at-home COVID-19 test garners EUA, Regulatory Focus 15 December 2020)
For developers of molecular diagnostic tests, FDA lays out design considerations that may minimize the impact of mutations on test performance. When tests are designed with multiple targets, this redundancy may forestall obsolescence of a particular test. Additionally, FDA pointed to whole genome sequencing as the test “that may be best suited for genotyping claims” because of the tests’ ability to pick up on currently known and emerging viral mutations. “FDA recommends that developers of sequencing tests pursuing an EUA with a genotyping claim engage in early discussions with FDA,” added the agency.
The EUA request should include a thorough description of how test performance has been evaluated across all known variants with mutations that involve the test’s targeted region, as well as a discussion of how the developer’s test design strategy mitigates against the risk of reduced performance against future mutations.
In particular, FDA recommends that developers consider the strategy of including “a highly conserved pan-SARS-CoV target” not specific to SARS-CoV-2 in a multiple-target test. However, such a strategy should also plan for the need for interpretation of mixed and complex results, as when the pan-SARS-CoV target is positive but the SARS-CoV-2 ones are not.
Test developers should also include a plan for routine monitoring of viral mutations, including periodic sequence alignment of primer/probe sequences with publicly available genomes. When mutations are identified, developers should assess the impact on a particular test with an eye to seeing whether performance drops by 5% or more, or falls below the threshold identified in the applicable template for the EUA.
Hybridization of test reagents can also be affected by mutations, so FDA lays out a three-step process for investigation of the impact of mutations on hybridization. First, sponsors can conduct an in silico calculation; next, they can perform a wet test of genomic material, followed by wet testing of a virus isolate that has a mutation. When clinical samples are not available, synthetic RNA agents with and without the mutation can be substituted.
Testing, analysis, and a benefit-risk assessment should accompany the EUA request or supplemental request. The guidance also walks developers through specific steps recommended depending on the magnitude of difference in level of detection (LoD).
FDA plans to work with test developers as the impact of mutations on test performance is assessed. “For instance, FDA may request to establish the LoD using limiting dilutions of quantified synthetic RNA or quantified in vitro transcripts of both the target sequence from the reference genome (i.e., perfect match target) and the sequence harboring the mutation of interest,” according to the guidance.
"Monitoring the impact of genetic variants on antigen tests and serology tests is not as straightforward as for molecular tests,” said FDA. The agency is still considering the best strategy to assess how new variants may affect these tests; options include using samples of variant virus to assess impact on analytical performance, using various modeling approaches, and using clinical specimens to evaluate clinical performance.
For developers of antigen and serology tests, the best approach is early and frequent engagement with FDA to stay abreast of the agency’s approach in addressing how variants may affect test performance.
The guidance document includes a list of additional resources for test developers, listing intra-FDA resources as well as those from the Centers for Disease Control and Prevention and global health partners.



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Tags: CDRH, coronavirus, FDA, US

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