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FDA Requiring Real Patient Samples for Emergency Use Authorization of COVID-19 MDx Tests

NEW YORK – The US Food and Drug Administration has updated its requirements for molecular diagnostic developers seeking Emergency Use Authorization for COVID-19 tests to include the use of actual positive specimens.

In the eighth of its weekly virtual town hall meetings on Wednesday, Timothy Stenzel, director of the agency's office if in vitro diagnostics and radiological health, said going forward FDA will require developers to use such specimens as part of the validation process.

Previously, assay manufacturers had been permitted to use contrived patient samples for their EUA submissions.

The updated requirements were issued on Monday and incorporated in the molecular diagnostic template for developers. Although the EUA templates had been part of the agency's guidance document when it was updated on May 4, these templates are now available as downloads from the FDA's EUA webpage.

"Now that there are positive patient samples, we are shifting from use of contrived samples to supplement applications to the recommendation that actual patient samples are used for the clinical performance testing," Stenzel said.

"As a result, for molecular tests the recommendation is to make comparisons to previously authorized molecular tests in order to assess whether or not accurate performance has been established," he said.

The template specifies that a minimum of 30 positive prospective, retrospective, or leftover patient samples be evaluated, and frozen samples are acceptable. Results should be compared to a high-sensitivity EUA RT-PCR assay, which uses a chemical lysis step, followed by solid phase extraction of nucleic acid, according to the template.

Sara Brenner, associate director of medical affairs at FDA, noted during the town hall that the new requirements may or may not apply to developers who have already begun the EUA submission process.

With respect to pending applications, the agency encourages manufacturers to discuss the new requirements with their assigned reviewers. "The plan is to be reasonable, but make the transition as expediently as possible," Brenner said. The agency might ask that manufacturers do additional post-market analysis if the submission has already been prepared with contrived specimens, for example.

A commenter noted that a strict standard is unlikely to be uniformly applied in cases where patient samples are extremely difficult for a developer to obtain.

Brenner said the submission's lead reviewer can indicate "how reasonable it would be" to incorporate, change course, or add some post-market data.

"The intention is certainly not to slow things down, but to improve the quality of tests over time as the situation is evolving — one size fits all generally isn't an appropriate way to go, so we try to work with each developer individually," she said.

The agency announced last week that it has published an EUA template for viral antigen tests as well as updated its guidance for serology tests.

For direct antigen tests, the agency has outlined validation requirements in the template, Stenzel said. "We authorized our first one last week, on Friday," he said, referring to the Quidel Sofia 2 SARS Antigen FIA.

Stenzel said the agency has a minimum performance expectation of 80 percent sensitivity relative to a high-sensitivity molecular assay for antigen tests. "We also are recommending that the specificity be very high, so that a positive result can be relied upon," Stenzel said.

A lower sensitivity test raises the concern of false negative results, he said.

"We do have language in the [Quidel assay] authorization dealing with what to do with a negative result, and that is that reflex from a direct antigen-negative result to a molecular result should be considered, depending on the situation."

Stenzel said the next EUA template to be made available will be for home sample collection. "We'll update as soon as we can for that. We do see a lot of continued and growing interest in home collection, and so, we think this will be helpful as well," he said.

In addition to the new guidance, the agency also commented on a panel of control samples for serology test validation that is being developed by the National Cancer Institute and the interagency serology test assessment group.

This panel will soon be made available to serology test developers. "We are working on the availability of the interagency panel, or a subset of the panel, to developers," Stenzel said, noting this is being spearheaded by Health and Human Services' Biomedical Advanced Research and Development Authority.

"There are a growing number of other entities that are [developing serology control panels] as well, and to the extent that we can help connect people, we're happy to do that," Stenzel added.