By: Jeff Shuren, M.D., J.D., Director, Center for Devices and Radiological Health

The U. S. Food and Drug Administration has been proactive and supportive of test development by all comers including laboratories, and large and small commercial manufacturers to speed development and to quickly authorize tests that the science supports. The agency engaged with the lab and commercial manufacturer communities even before any cases of COVID-19 were diagnosed in the U.S., working with over 500 developers since January, and has been working around the clock to authorize over 180 Emergency Use Authorizations (EUAs) for tests, including molecular, serology, antigen, and tests with at-home specimen collection indications.

This pandemic has created a demand for new tests that is unprecedented in both volume and urgency. The FDAs important roles in testing include determining whether the tests developed for use in the U.S. provide sufficiently accurate and reliable results and helping to provide timely access to such tests.

In a public health emergency, getting an accurate test is important not only for the individual patient, but for the public at large. False positive or false negative results can contribute to the spread of COVID-19, so all tests used for COVID-19 should be validated before use. Similarly, timely access to diagnostic tests is also critically important. To best address these dual, and sometimes competing, needs, the FDA has used its EUA authorities. EUAs permit the emergency use of a product, in this case a test, when the FDA determines that certain criteria are met based on the totality of the scientific evidence available. The EUA process made it possible for molecular diagnostic tests to be developed, validated, and offered for clinical use within weeks rather than months or longer.

The FDAs EUA authorities allow the FDA to authorize the emergency use of tests more quickly than full FDA approval or clearance because the evidentiary standard is different. For full approval or clearance, we typically require validation testing using patient samples; however, due to the immediate need and the small number of patient samples available, we utilized our emergency authorities to authorize tests based on data from contrived clinical samples or smaller sets of patient samples. For example, early-on in the emergency, instead of using specimens from individuals infected with SARS-CoV-2, developers could add different amounts of inactivated SARS-CoV-2 RNA to human specimens, such as sputum, to assess how well their test could detect the virus. As a result, validation could be completed rapidly, in some cases in only a few days once inactivated RNA became available. This approach was less likely to accurately characterize test performance so the FDA has taken several actions now that clinical specimens have become more readily available.

Once multiple sources of positive patient samples were available, we asked developers of new tests to validate with these clinical samples. In addition, as part of each EUA for a COVID-19 test, the FDA requires that each test developer and its authorized distributors collect test performance information, including any suspected occurrence of false results, and report to the FDA as a condition of authorization. An additional condition of authorization requires test developers to track adverse events and report them to the agency. These actions have helped generate more robust evidence of test performance to help providers, patients, laboratories, and the government make better informed decisions.

Additionally, these conditions enable the FDA to detect trends and take swift action to prevent harm to patients, especially when device malfunctions may affect many tests across the nation (e.g., in sample collection swabs, or shared test reagents). For example, we were able to quickly alert the public about potential inaccuracies with the Abbott ID Now point-of-care test to diagnose COVID-19 when we began to see a trend in the adverse event reports we received. In some cases, such as tests that used contrived clinical samples for validation, we required developers to conduct post-authorization studies as a condition of their authorization to further evaluate the clinical performance of the test using clinical specimens. This approach gives patients timely access to potentially beneficial and high-volume tests while assuring a more robust understanding of test performance in a real-world setting. The agency monitors all of this information so that we are able to take action when a tests benefits no longer outweigh its risks. Finally, the FDA requires that manufacturers of certain tests provide evidence that their manufacturing processes will deliver consistent results, helping to ensure that accurate tests are produced in every manufacturing lot.

Another step the FDA took to support independent validation for SARS-CoV-2 diagnostic tests was providing developers with a reference panel. Starting with live SARS-CoV-2 virus we obtained, FDA personnel in the Center for Devices and Radiological Health and the Center for Biologics Evaluation and Research worked collaboratively to create a reference panel from a validated inactivated viral stock, and made it available to developers of molecular diagnostic tests. The FDA-supplied reference panels include well-characterized samples of the SARS-CoV-2 virus genetic material (RNA). The FDA panel is available as an independent performance validation step for commercial and laboratory developers of SARS-CoV-2 nucleic acid diagnostic tests who previously validated their authorized tests with contrived samples, or who are currently having difficulty validating their new test. Data from use of the reference panel will provide the FDA with more accurate information on the comparative performance of different tests so that we will have a better understanding of which tests are more sensitive than others. The FDA will make this information available on our website.

We recently announced our participation in the COVID-19 Diagnostics Evidence Accelerator, a multi-stakeholder collaborative project to advance the development of diagnostics through the generation of real-world evidence. It is organized by the Reagan-Udall Foundation for the FDA in collaboration with Friends of Cancer Research to allow the community to analyze both diagnostic and clinical data in real time, which has the potential to contribute to the scientific evaluation of diagnostic tools and medical interventions for COVID-19. The Accelerator project will leverage FDA's SHIELD initiative, a multi-stakeholder collaboration to improve the quality, interoperability and portability of laboratory data within and between institutions so that diagnostic information can be drawn from different sources or shared between institutions. SHIELD harmonizes COVID-19 test data referenced in the HHS COVID-19 laboratory data reporting requirements, which can be used to evaluate the real-world performance of SARS-CoV-2 diagnostic tests and antibody tests.

Evidence generated by the Accelerator project is intended to be complementary to other studies that have been conducted or are underway as well as to provide actionable information about the prevalence of SARS-CoV-2 in specific populations and highlight individual risk factors for patients. This helps improve our understanding of the disease, tailor public health interventions and strategies to mitigate risks for individuals and communities and help stop the spread of SARS-CoV-2.

Taken together, these actions will, and already are, providing the clinical, patient and consumer communities with more accurate information about diagnostic test performance and allowing for the rapid availability of new, accurate and reliable tests.

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FDA's Ongoing Work to Support and Advance COVID-19 Diagnostic Test Accuracy and Availability - FDA.gov