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FDA Fleshes Out Emergency Guidance for Coronavirus Test Developers


NEW YORK – The US Food and Drug Administration has been updating its guidance for COVID-19 diagnostic tests in a piecemeal fashion as the outbreak expands. On Wednesday, the agency held a webinar to flesh out its evolving policies, providing key insights on regulatory paths for molecular and serological diagnostic testing in commercial and state labs, and for commercial test products and devices.

The agency had previously issued Emergency Use Authorization guidance for COVID-19, the disease caused by SARS-CoV-2 virus, on Feb. 28. It then expanded the guidance on March 16.

In Wednesday's webinar, Elizabeth Hillebrenner, associate director for scientific and regulatory programs at FDA's Center for Devices and Radiological Health, summarized and organized four pathways for COVID-19 tests, and offered some information on the numbers of tests the agency is currently aware of.

A pathway dubbed "Policy A" has been set out for high-complexity CLIA labs that wish to launch validated SARS-CoV-2 laboratory-developed tests, including molecular tests, or antigen or antibody tests. Labs are permitted to begin using tests on patient samples as soon as they are validated internally, provided they have notified FDA and subsequently file an EUA application within 15 days. Hillebrenner said that the agency had received 98 notifications from labs running LDTs to date.

A policy created in the March 16 guidance expansion, called "Policy B" by Hillebrenner, enables US States to authorize tests within their jurisdictions that will be run in high-complexity CLIA labs.

The tests covered by Policy B can be used on patients as soon as they are validated and the FDA is notified, and a subsequent EUA is not required. Policy B applies to any molecular, antigen, or antibody technology, and to date four states — Washington, Nevada, New York, and Maryland — have notified FDA of their intent to pursue this pathway.

For commercial manufacturers of COVID-19 tests, a pathway called "Policy C" will apply. In this pathway, a manufacturer can launch its test and platform as soon as it is validated, provided it has notified FDA and will submit an EUA application within 15 business days.

Policy C applies to molecular, antigen, and antibody tests that can be used in clinical labs and at the point-of-care, and Hillebrenner emphasized that the policy does not apply for tests intended to be used at home.

She said that four manufacturers have notified FDA that they are distributing kits under the Policy C path since the March 16 guidance. On the agency's website, on its Frequently Asked Questions page, it lists the four developers; Becton Dickinson, Qiagen, BGI, and Co-Diagnostics.

The fourth pathway, "Policy D," applies only to antibody-based serology tests. These tests, whether they come from a commercial manufacturer or are developed by a high-complexity lab, do not need to submit an EUA application at all, and makers can begin selling them and using them on patients as soon as they are validated.

Hillebrenner said there have been 12 developers to date that have notified FDA they are pursuing the Policy D path. A list on the FDA's website, which may have been updated since the webinar, now includes 19 developers of antibody tests. "The FDA has not reviewed the validation of tests offered by these developers, who will not be pursuing EUAs, and is including this list … to provide transparency regarding the notifications submitted to FDA," the website says.

The agency has also granted 16 Emergency Use Authorizations to date, including for commercial tests and labs, and state labs.

Color and clarification

Hillebrenner and her colleague Tim Stenzel, director of FDA's office of in vitro diagnostics and radiological health, also added color to these four pathways and offered additional direction and clarification.

Specifically, the agency offered insights on test validation, and the role it intends to play in regulating tests that involve slight modifications of existing tests or protocols, including modified commercial tests. It also provided information on non-CLIA labs doing testing in the emergency, and the types of samples that can be used.

The validation requirements in the guidance pertain to determining clinical agreement and cross reactivity for all tests. Molecular tests require an inclusivity study and limit of detection determination. The latter applies to antigen tests as well, which must also be validated with a microbial interference study. Antibody tests must be validated with class specificity testing.

Molecular tests run in highly complex CLIA labs are supposed to have an additional validation, comparing the first five positive and negative patient samples to a previously validated test, for example one performed at the local state public health labs. Labs that wish to modify an EUA test or protocol to suit their equipment availability need to run a bridging study. "Since you are validating something new, it wouldn't hurt to go ahead and just confirm the first five positives and negatives with someone else who is already set up and using an EUA authorized assay, as a check," Stenzel commented. "But I wouldn't say right here and now that it is required," he added, unless the lab were developing its own LDT from scratch.

Hillebrenner also said that, as noted in the March 16th guidance, "We do not intend to object to the use of a test without a new or amended EUA where the test is validated using a bridging study to an EUA-authorized test. A lab can take an authorized test, whether it is CDC's or somebody else's, make some changes to it — whether it is a new platform, a new component — and if they do the appropriate bridging study, or rely on somebody else who has done a bridging study for that change, then they don't need to come in with an EUA or a notification," she said.

The agency "would like to see the validation data of that bridging study informally through an email," she said.

The FDA would also like to aggregate this bridging study data, provided that developers will offer it up, so that other test makers and users don't have to "reinvent the wheel for every test modification," Stenzel added.

Hillebrenner said the FDA would review the bridging study data. If the data supports the modification, and "if the lab or other entity who own that data agrees to FDA sharing that information on our website, we would intend to update [FAQ's] so other labs can refer to that validation for their testing without having to conduct their own their own bridging study" for the same modification.

"We are essentially looking to serve as a clearing house, where if one entity is able to validate a particular tweak to an authorized test, and they are willing to share that — they don't have to share the raw data with the public, but if they're willing to allow others to leverage their findings — we can serve as that clearing house, check that the data are good, and put it up on our website so that others can benefit," Hillebrenner said.

For example, Hillebrenner referred webinar attendees to the agency's FAQ page for a list of alternate sources for swabs and viral transport media, as well as to alternates for the reagents, and extraction and PCR kits and instruments that had been in short supply.

"We urge you to share whatever data you have with us so we can keep adding to our [FAQs] and help everybody out," she said.

If a manufacturer wishes to modify its own EUA products, it is permitted to send FDA an amendment for the change and implement the change immediately, while the FDA reviews it.

For Policy C — the commercial tests seeking EUA that can now launch a test as soon as it is validated — Stenzel emphasized that developers can simply notify FDA that they are following that pathway. "Then, you have 15 business days to submit your EUA package, all the while you can stay on the market," provided the developers post the package insert and performance data on their websites.

For serology tests, Hillebrenner said there is not yet a template available for manufacturers to file for EUA. "The idea with [Policy D] is that most people would likely choose this policy and not actually come in with an EUA," she said.

Stenzel added that IgG and IgM serology tests that are not for sole diagnosis do not require an EUA submission. The agency does however require that these tests, or test reports, be labeled with specific language that is provided in the guidance.

Specifically, the test reports should indicate that the serology test has not been not been reviewed by the FDA, that negative results do not rule out SARS-CoV-2 infection, and that follow-up testing with a molecular diagnostic should be considered. Reports should also indicate that results from antibody testing should not be used as the sole basis to diagnose or exclude SARS-CoV-2 infection or to inform infection status, and that "positive results may be due to past or present infection with non-SARS-CoV-2 coronavirus strains, such as coronavirus HKU1, NL63, OC43, or 229E."

The validation of serology tests performed in other countries can be applied in the US in this case. "It doesn't matter where the validation is done," Stenzel said, "Just that a proper validation is done and that you notify the FDA, and that you follow the other information in the guidance as far as labeling and the proper claims."

Serology kits and devices can be distributed to labs or healthcare providers. Hillbrenner clarified that this means tests could be sold to physician offices, although the developer would need to ascertain what the CLIA certification requirements would be.

Stenzel offered clarification on serology tests, saying there are two different pathways. "One is, just notify and don't submit an EUA, and that is for a test where you are just reporting the presence of IgG or IgM antibody. If you wish to make a claim as a sole diagnostic, then we would want you to come in through the EUA process," he said. The latter applies to the test developers, so labs that purchase and run such tests are not required to do an EUA, he also said.

The agency also addressed a few queries about states and labs wishing to extend CLIA waivers to enable non-clinical labs to run COVID-19 testing in the emergency. Stenzel said that is not under FDA's authority, but rather would require working through the Centers for Medicare and Medicaid Services. That said, Stenzel noted that labs could request additional space or personnel be covered under an existing CLIA certification. "If you are a facility that would like to become a CLIA lab, you can make an application for that, and ask if that can be expedited," he added.

FDA is also working on issues with getting products from registered foreign manufacturers that either have an EUA, or are developing an EUA product, through the US import process, Stenzel said. "If you encounter any problems, do send us an email … and we will endeavor to assist you," he said.

For serology products being imported under Policy D, once the importer, distributor, or the foreign test manufacturer notifies FDA of the intent to market the test in the US, the test is permitted to be distributed in the US. If there are any issues with customs and border control, "We'll work with you to work through all the import issues," Stenzel said.

He also said that CLIA-waivable serology tests can be distributed to CLIA-waived labs, even though the guidance specifies that manufacturers are not allowed to make claims about CLIA waived status. In terms of what guidance companies can give physicians who want to run these tests, Stenzel said that he will begin a discussion with the office of in vitro diagnostics and post a response on the FAQ page as soon as possible.

For additional sample types, Stenzel said that the agency is trying to be very precise, "and where there is insufficient data to recommend something, we make that clear." He also said that late Monday night the agency updated its guidance on the FAQ page to say that while nasopharyngeal swabs are still the preferred sample type, mid-turbinate and lower nasal samples from symptomatic patients are now acceptable. "Looking at study data which is not public yet, but which the United Health Group will hopefully publish very soon, [these samples] look equivalent to performance for nasopharyngeal swabs," Stenzel said.

Finally, regarding the FAQ page, Hillbrenner also commented, "I would really encourage folks to check that out — we are updating it almost daily with new information, so please continue to monitor that."