This Client Advisory addresses some frequently asked questions for SARS-CoV-2 diagnostic test developers and provides an overview of recent updates relating to Emergency Use Authorizations (EUAs) published by the U.S. Food and Drug Administration (FDA).

What is an EUA?

Since the start of the federally-declared COVID-19 public health emergency, the FDA has been working with numerous SARS-CoV-2 test developers to help accelerate testing efforts in the country. Under the EUA authority, the FDA may allow unapproved medical products or unapproved uses of approved medical products to be used in times of a public health emergency.

Unlike traditional FDA approvals or clearances, in issuing an EUA, certain regulatory requirements are waived, and data requirements have been lowered to expedite marketing and availability of products covered by EUAs. That said, EUA is a temporary authorization and is effective until the government declares that circumstances justifying the emergency use is terminated or until the EUA is revoked by the FDA or the Secretary of Health and Human Services, whichever occurs first.

Importantly, an EUA prescribes the indication (or the specific use) that the FDA has authorized for a particular test and, if applicable, the specific laboratories or types of laboratories that are authorized to use or perform the test. The EUA also prescribes the type of biological sample (e.g., blood, saliva), and the method of sample collection (e.g., home collection or collection by a healthcare professional). EUAs also set forth various conditions applicable to the EUA applicant and the product, including, but not limited to, conditions related to printed materials, advertising and promotions, required disclosures, product labeling, distribution conditions, and documentation or records requirements in the event of an FDA inspection.

What are the different types of SARS-CoV-2 or COVID-19-related tests for which an EUA is available?

There are three general categories of SARS-CoV-2 or COVID-19-related tests that are subject to EUA by the FDA.

• Diagnostic Tests—these detect parts of the SARS-CoV-2 virus and can be used to diagnose an active infection with the SARS-CoV-2 virus, and include:
  • Molecular Diagnostic Tests—typically using polymerase chain reaction (PCR) technology to detect nucleic acid sequences of the virus; the majority of the currently available diagnostic tests authorized by the FDA are molecular diagnostic tests; and
  • Antigen Tests—using various methods to detect viral antigens; to date, the FDA has granted individual EUAs for only two antigen diagnostic tests, both of which use an immunoassay to detect the presence of the SARS-CoV-2 nucleocapsid protein antigen.
• Serology or Antibody Tests—these detect the presence of antibodies (e.g., IgM, IgG) generated by the body after an initial exposure to the SARS-CoV-2 virus and cannot be used to diagnose an active infection.
• Tests for Management of COVID-19 Patients—these include additional tests used to inform patient management decisions after they have been diagnosed with COVID-19, e.g., tests that detect biomarkers related to inflammation; to date, the FDA has granted one individual EUA for the measurement of interleukin 6 in human serum and plasma to assist in identifying inflammatory response in patients with confirmed COVID-19 illness to aid in determining the risk of intubation with mechanical ventilation, in conjunction with clinical findings and the results of other laboratory testing.

The FDA can issue individual EUAs covering specific tests developed by individual manufacturers or an umbrella EUA for tests developed and performed by laboratories certified under Clinical Laboratory Improvement Amendments of 1988 (CLIA). The FDA maintains a listing of high complexity CLIA certified laboratories that are authorized to perform molecular-based laboratory developed tests for the detection of SARS-CoV-2.

How can a test developer get the EUA process started with the FDA?

Before engaging with the FDA, we recommend reviewing the Policy for Coronavirus Disease-2019 Tests During the Public Health Emergency (Revised), which describes the FDA's current thinking on test validation and recommendations based on technological principles of tests, FDA notification, EUA request, and clinical testing. This Policy also sets forth different EUA requirements depending on the type of test and the type of entity developing the test—clinical laboratories and commercial manufacturers.

Test developers should also review the applicable template(s) published by the FDA for EUA submissions. These templates set forth the FDA's current thinking on the data and information expected in an EUA submission. The templates are subject to change by the FDA. To date, the FDA has published the following templates for SARS-CoV-2 tests, which are also available on FDA's In Vitro Diagnostics EUAs webpage:

Test developers interested in pursuing an EUA may submit a pre-EUA to begin discussions with the FDA or may submit an EUA request to CDRH-EUA-Templates@fda.hhs.gov.

Is an EUA by the FDA the only way to make a SARS-CoV-2 test available?

No, a state or territory in the United States can also authorize laboratories certified under CLIA that meet CLIA regulatory requirements to perform high-complexity testing. Pursuant to the current Policy, "FDA does not intend to object to the use of such tests for specimen testing where the notification of SARS-CoV-2 test validation is not submitted to FDA and the laboratory does not submit an EUA request to FDA, and where instead the State or territory takes responsibility for COVID-19 testing by laboratories in its State during the COVID-19 outbreak."

Do commercial manufacturers have to wait until FDA issuance of an EUA before they can distribute the test or start testing?

No, but commercial manufacturers should exercise caution and think through the potential risks and exposure to liability when considering distribution of a test before the FDA issues the EUA. Should a significant problem arise and cannot be addressed in a timely manner after the manufacturer has already distributed the test prior to FDA authorization, the manufacturer would need to suspend distribution and conduct a recall of the test.

That said, for diagnostic tests intended for use by clinical laboratories or healthcare workers for point-of-care testing, i.e., not for at-home testing or at-home sample collection kits, the current Policy allows commercial manufacturers to distribute SARS-CoV-2 test kits for specimen testing by CLIA certified high-complexity laboratories for a reasonable period of time (or 15 business days) before submitting an EUA application, provided that the diagnostic test has been validated, the manufacturer gives notification of validation to the FDA, and the manufacturer provides instructions for use of the test and posts data about the test's performance characteristics on the manufacturer's website.

For serology tests, which are not used for diagnostic purposes, the current Policy allows a commercial manufacturer to distribute serology tests for a reasonable period of time (10 business days from the date of FDA notification), provided that the test has been validated, the manufacturer gives notification of validation to the FDA, and includes FDA's required disclosures regarding the limitations of serology tests in the instructions for use, including the following:

• This test has not been reviewed by the FDA.
• Negative results do not preclude acute SARS-CoV-2 infection. If acute infection is suspected, direct testing for SARS-CoV-2 is necessary.
• Results from antibody testing should not be used to diagnose or exclude acute SARS-CoV-2 infection.
• 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.

Does the recently published EUA template for diagnostic tests for non-laboratory use apply to surface tests? What kind of tests are covered by this template?

On July 29, 2020, the FDA published a new EUA template for manufacturers of diagnostic COVID-19 tests for non-laboratory use. This EUA template applies to human diagnostic tests and does not apply to tests intended for testing the presence of the SARS-CoV-2 virus on environmental or industrial surfaces, such as restaurant counters and public seating surfaces, as such surface tests are not intended for any diagnostic purposes. Also, this template does not apply to home collection kits (which are different from at-home testing) that are used by clinical laboratories to collect samples from individuals and where the clinical laboratories perform the analysis on the returned samples.

This new EUA template applies to molecular and antigen diagnostic COVID-19 tests intended for prescription use or for over-the-counter use by lay users at home and/or at other non-laboratory settings, such as offices, sporting events, airports, and schools, for the detection of SARS-CoV-2 in respiratory or saliva samples. Developers of such non-laboratory tests that use non-respiratory specimens, such as blood or stool, should contact the FDA to discuss their validation strategy.

This template sets forth the data and information expected by the FDA for an EUA. Additionally, this template provides that all test results should be reported to healthcare providers and relevant public health authorities and that test developers need to describe how they will ensure all users of the test can report all test results to the applicable authorities in accordance with local, state, and federal requirements. The FDA proposes a couple options for reporting test results, including automatic reporting through a mobile application/software and instructions directing users to a website for facilitating reporting. For mobile or web applications and software used with such tests, the template provides a guideline for information relating to software verification and validation.

What are some general considerations for commercial manufacturers interested in developing a diagnostic test that includes an at-home collection kit?

The FDA has published a separate EUA template for the collection of anterior nasal swab or saliva specimens that are intended to be returned to a clinical laboratory for testing with a SARS-CoV-2 molecular diagnostic test authorized by the FDA for use with the specific home collection kit. Manufacturers or test developers that wish to use other types of respiratory specimens (e.g., sputum, throat/tongue swabs, or nasal aspirates) or non-respiratory specimens should contact the FDA regarding the applicable validation strategy for the collection kit and the diagnostic test.

The home collection EUA template makes it clear that an authorization for a home collection kit must be accompanied by authorization of one or more molecular diagnostic tests that have been validated with the specimens collected and transported using the said home collection kit. The FDA provides three options for obtaining an EUA for a molecular diagnostic test with a home collection kit:

• Combine the EUA requests for the diagnostic test and the home specimen collection kit in one EUA application (e.g., when the same developer makes the home collection kit and the molecular diagnostic test and seeks authorization for both components at the same time);
• Request separate EUAs for the home specimen collection and the molecular diagnostic test (e.g., when the developer of the home collection kit is different from the developer(s) of the diagnostic test(s)); or
• Request an EUA for the specific home collection kit as an amendment to an EUA of a previously authorized diagnostic test to add the collection kit to the diagnostic test.

The validation and performance evaluation requirements, including human usability testing, described in the home collection EUA template reflects some of the issues previously raised by the FDA regarding home collection by lay users and the transport of samples back to clinical laboratories, including whether lay users can safely and properly collect the specimen, whether the components of the specimen transport media are safe for use in the home environment (as some reagents may be toxic), proper shipment, and adequate stability of the specimen given the time lapse between sample collection and testing and the potential impact of shipping conditions (e.g., degradation of the specimen when transported in a hot truck).

Further, the FDA recommends distributors of home collection kits to contact the Pipeline and Hazardous Materials Safety Administration (PHMSA) within the Department of Transportation to confirm the packaging and shipping instructions needed to ensure users comply with the hazardous materials regulations for shipping medical material.