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FDA Will Consider EUA Submissions for SARS-CoV-2 Variant Genotyping Assays

NEW YORK – The US Food and Drug Administration said on Wednesday that it will consider Emergency Use Authorization submissions for SARS-CoV-2 variant genotyping assays.

In a virtual town hall with developers, Tim Stenzel, director of the Office of In Vitro Diagnostics and Radiological Health, said that while sequencing remains the gold standard, "the turnaround times and the throughput that sequencing assays have remains challenging when you want to determine genotypes for a large number of samples."

Stenzel said that the agency has previously provided validation recommendations for select developers of high-volume variant PCR genotyping assays.

Now, "test developers that are interested in developing new assays or have assays already developed that do genotype ... can approach the FDA and receive the validation recommendations that have been given to others previously by sending an email to [email protected]," Stenzel said.

The choice of markers for variant genotyping tests is a challenge for assay developers, Stenzel noted, as is the choice of which variants to detect and distinguish. And, even if a test can distinguish all the known variants, new variants will also present a challenge.

"Because these variants and mutations seem to come and go, the panel of genetic markers could be shifting a lot more quickly than we would like, making it a challenge to keep these assays up to date," he said.

Technologies that can be updated quickly may be more ideal for this task, Stenzel said, while ones that can't swap out primers and probes without affecting other components of the assay may be more challenging to revalidate.

For this reason, the FDA will welcome submissions that include a request for pre-authorized change modification procedures, Stenzel said.

"Simply put, if you know you have a technology that you may want to update when the next variant comes along ... [modification procedures can specify] how do you alter your assay for that, what are the validation recommendations, and what are the results of those validations that would allow the FDA to quickly perform a review because it meets the pre-specified change outcomes," he added.

"We will entertain those requests because of the necessity when you are developing genotyping assays for this virus," he also said.

Finally, if and when genotyping becomes clinically important in light of the new Omicron variant, "the need will be for high volumes, fast turnaround times, and accurate tests," Stenzel said, because a true clinical need will essentially mean all positive patients in the US would need to be tested.

"That is a challenge," he added.

Target failure updates

On Wednesday, the FDA also updated its list of Emergency Use Authorized molecular diagnostic assays it believes will fail to detect the Omicron variant.

The list now includes three tests — the Meridian Bioscience Revogene SARS-CoV-2 test, the Tide Laboratories DTPM COVID-19 RT-PCR test, and the Applied DNA Sciences Linea COVID-19 Assay Kit. The latter is also unique in that it is the first test that fails two viral targets.

"We think these are relatively low-abundance tests and services, so the impact on the overall national response we hope is muted," Stenzel said on the call.

The FDA website also includes 26 tests demonstrating S-gene target failure as well as two assays demonstrating N-gene target failure. These assays can still be used to detect SARS-CoV-2 infection because their other targets should not be impacted.

"Just like the S-gene dropout, the N-gene dropout may be helpful in identifying samples where Omicron may be present so that sequencing can be considered to characterize the variant," Stenzel said.

He further noted, however, that there are now two sublineages of Omicron, namely BA1 and BA2.

"Only BA1 has S-gene dropout, BA2 does not; however, both sublineages do have the N-gene dropout," Stenzel said, but added, "the challenge here is S-gene dropout is not present in all BA1s, nor is N-gene dropout present in all BA1s or all BA2s."

The S-gene dropout in particular can happen with non-Omicron variants as well, including some sublineages of the Delta variant, Stenzel said.

"If you see N-gene dropout, that would be a positive ID for Omicron to our understanding at the moment, but again the problem is that it is not present in all Omicron samples," Stenzel added, so not having SGTF or NGTF does not rule out Omicron.

Therefore, these markers are "not ideal" to distinguish the Omicron variant, he added.