On November 15, 2021, the U.S. Food and Drug Administration (“FDA” or the “Agency”) issued the fifth edition of the Agency’s guidance entitled “Policy for Coronavirus Disease-2019 Tests During the Public Health Emergency.” The issuance of the updated guidance shortly followed a statement from the U.S. Department of Health and Human Services (“HHS”) announcing the withdrawal of a policy established by the previous administration that directed FDA not to require premarket review of laboratory developed tests (“LDTs”). The prior policy was previously announced by HHS on August 19, 2020.
The revised guidance contains significant updates of interest for both developers of SARS-CoV-2 laboratory developed tests (“COVID-19 LDTs”) and manufacturers of SARS-CoV-2 test kits.
KEY TAKEAWAYS FOR DEVELOPERS OF COVID-19 LDTS
At the outset, developers of COVID-19 LDTs should be aware that the fifth iteration of the guidance represents FDA’s return to its traditional approach towards regulation of tests utilized in the context of a public health emergencies. Specifically, FDA has revised its enforcement policy to now require, with limited exceptions, emergency use authorizations (“EUAs”) or traditional marketing authorizations (e.g., a granted De Novo or cleared 510(k)) for COVID-19 LDTs.
While FDA expects to ultimately review and require marketing authorization for most COVID-19 LDTs, the manner in which a particular COVID-19 LDT is being handled by FDA varies. Below we summarize the key takeaways for developers of COVID-19 LDTs from FDA’s updated enforcement policy:
- COVID-19 LDTs offered after November 15, 2021 generally require an EUA or traditional marketing authorization prior to clinical use: Significantly, with the fifth iteration of FDA’s COVID-19 test policy, FDA is ending the Agency’s policy that previously allowed developers to offer their COVID-19 tests prior to or without an EUA after the test was validated and notification was provided to FDA of completion of test validation (hereafter, “FDA Notification”). After November 15, 2021, FDA generally expects newly offered COVID-19 tests, including LDTs, to have an EUA or traditional marketing authorization prior to the tests being distributed or offered. Further, whether FDA will accept for review and process an EUA request depends on whether FDA determines such test to fall within the Agency’s priorities with respect to review of EUA requests for COVID-19 tests. As described in additional detail in the revised guidance, FDA generally intends to focus its review on the following types of tests:
- At-home and point-of-care (POC) diagnostic tests for use with or without a prescription and that can be manufactured in high volumes, e.g., a manufacturing capacity of ≥ 500,000 tests per week within 3 months of authorization;
- Certain high-volume, lab-based molecular diagnostic tests (and home collection kits for use with such tests) with high throughput that expand testing capacity or accessibility such as through pooling of specimens, testing specimens collected at home and shipped to the lab, screening asymptomatic individuals, or detecting multiple different respiratory viruses at once, and are from experienced developers who can scale up to high volumes;
- Certain lab-based and POC high volume antibody tests that can measure the amount of antibodies (fully quantitative antibody tests) or the amount of neutralizing antibodies; and
- Tests for which the request is from, or supported by, a U.S. government stakeholder, such as the Biomedical Advanced Research and Development Authority or the National Institutes of Health’s Rapid Acceleration of Diagnostics.
Developers of COVID-19 LDTs falling outside FDA’s current priorities may consider pursuing traditional marketing authorization, such as 510(k) clearance or De Novo classification.
- COVID-19 LDTs offered prior to November 15, 2021 require submission of an EUA request, but generally may continue to be offered while FDA reviews the EUA request. Given the various prior iterations of FDA’s enforcement policy for COVID-19 tests, developers of COVID-19 LDTs may or may not have previously submitted FDA Notifications and/or EUA requests to FDA. The types of action needed to continue to offer a COVID-19 LDT under FDA’s revised enforcement policy vary depending on whether FDA Notification and/or an EUA request have been previously submitted to FDA:
- For serology tests developed by laboratories offered without the submission of an EUA request after FDA Notification and LDTs being offered without submission of an EUA request following the August 2020 HHS announcement, FDA expects developers to either submit an EUA request to FDA or to cease marketing and offering their tests within 60 calendar days of issuance of the revised guidance (i.e., by January 14, 2021);
- For diagnostic and serology tests for which an EUA request was submitted after February 1, 2021 and before November 15, 2021 following FDA Notification (and which do not appear on the removal list on FDA’s website), FDA will review or will continue to review the submitted EUA request and such tests may generally continue to be offered for the period of time while FDA reviews the EUA request; and
- For diagnostic and serology tests for which an EUA request was submitted prior to February 1, 2021 following FDA Notification (and which do not appear on the removal list on FDA’s website), FDA expects the developer to, within 45 calendar days of issuance of the revised guidance (i.e., by December 30, 2021), submit a confirmation to FDA that (1) the developer wants FDA to continue reviewing its EUA request, (2) the EUA request is for the current version of the test, and (3) the developer has no additional data to add, or if there is data to add, to submit the updated information within the 45 calendar-day timeframe. Should FDA not receive such confirmation, FDA intends to decline to review or to decline to further review the EUA request.
For the tests described above, FDA intends to notify test developers by email if FDA declines to review, declines to issue an EUA, or otherwise decides not to authorize the test for any reason. Should such notification be received, FDA expects developers to cease distribution, marketing, and offering their tests within 15 calendar days. Further, FDA may request developers to conduct a recall of the test and/or notify customers concerning potential performance issues should FDA identify a significant problem or concern with a test.
- Certain types of COVID-19 LDTs can continue to be offered without notification of test validation or submission of an EUA request to FDA. Specifically, a test that is designed, developed, and used within a single, high-complexity CLIA-certified laboratory can be offered without such notification or submission to FDA where the laboratory has been authorized by a State or territory that has chosen to authorize laboratories within that State or territory to develop COVID-19 tests and perform specimen testing. FDA has indicated that the Agency does not intend to extend this policy to additional States or territories as of November 16, 2021. The States and territories that have chosen to authorize laboratories are as follows:
- New Jersey;
- New York;
- Washington; and
- Puerto Rico.
In tandem with FDA’s issuance of its updated COVID-19 test policy, FDA issued an umbrella EUA for certain RT-PCR based COVID-19 tests developed by laboratories for detection of nucleic acid from SARS-CoV-2 from anterior nasal respiratory specimens for use as part of a serial testing program, such as those established at schools, workplaces, or community groups. For tests to qualify for the umbrella EUA, they must meet certain eligibility criteria specified in the umbrella EUA, and tests authorized by the umbrella EUA are limited to use by the single high-complexity CLIA-certified laboratory that developed the test. Tests will be added to Exhibit 1 of the umbrella EUA following submission of a complete notification to FDA with the information required by the umbrella EUA and confirmation by the FDA that the required documentation has been submitted. Inclusion on Exhibit 1 means only that complete documentation has been submitted and confirmed by FDA, but it does not necessarily mean that FDA has reviewed the underlying validation data submitted.
KEY TAKEAWAYS FOR MANUFACTURERS OF COVID-19 TEST KITS
For developers of SARS-CoV-2 test kits, the fifth iteration of the guidance is significant in two ways. First, FDA has shifted away from the Agency’s previous enforcement policy that allowed for certain test kit manufacturers to notify FDA upon completion of test validation and immediately offer the test kit following notification, subject to certain conditions, including submission of an EUA request. Second, the revised guidance updates the Agency’s current priorities for assessment of EUA requests for COVID-19 tests. Significantly, the revised guidance contains a number of illustrative examples and definitions that elucidate FDA’s review priorities (e.g., illustrative examples of what FDA considers to be “high throughput”). Developers of test kits falling outside FDA’s current EUA review priorities may consider pursuing traditional marketing authorization, such as 510(k) clearance or De Novo classification.
IMPACT OF VIRAL MUTATIONS
Additionally, COVID-19 LDT developers and COVID-19 test kit manufacturers alike should continue to be aware of FDA’s expectations regarding evaluation of the impact of viral mutations on COVID-19 tests. In February 2021, FDA issued the Agency’s “Policy for Evaluating Impact of Viral Mutations on COVID-19 Tests” and subsequently, FDA revised a number of EUAs for certain authorized molecular, antigen, and serological tests to establish conditions of authorization in response to the continued emergence of new variants of SARS-CoV-2, including continued evaluation of the impact of SARS-CoV-2 viral mutations on test performance.
Notably, with respect to the SARS-CoV-2 omicron variant, on preliminary review, FDA believes high-volume polymerase chain reaction (PCR) and antigen tests to have a low likelihood to being impacted by the new variant. Information on tests whose performance has been identified by FDA to potentially be impacted by SARS-CoV-2 viral mutations, including the omicron variant, can be found on FDA’s website entitled “SARS-CoV-2 Viral Mutations: Impact on COVID-19 Tests.”
 The limited enforcement policies described herein do not apply to at-home tests, tests with home specimen collection, or any testing outside a high-complexity CLIA-certified laboratory. FDA expects such tests to have an EUA or traditional marketing authorization prior to being distributed for clinical use.