“On February 4, 2020, the U.S. secretary of health and human services declared that emergency use of diagnostics for SARS-CoV-2 was justified, triggering emergency authority for the Food and Drug Administration (FDA) to grant an emergency use authorization (EUA) for a device if it reasonably believes that it may be effective, rather than waiting to grant full approval when it has reasonable assurance that the device is safe and effective. This mechanism expedites access to accurate diagnostic tests during emergencies, when information gaps and false results may adversely affect patient care and public health decision making.
The EUA process enabled molecular diagnostic tests to be developed, validated, and deployed within weeks rather than several months to over a year, as traditionally required. [..] By July 31, the FDA had authorized 163 Covid-19 diagnostic tests.
[..] Developers could “spike” human specimens, such as sputum, with different amounts of extracted SARS-CoV-2 RNA or live or inactivated virus to assess viral detection, rather than using patient specimens. Validation could thus be completed rapidly once viral RNA or virus became available. However, this approach was less likely than use of patient specimens to accurately characterize test performance.
[..] Though ideally a standard set of patient samples would be used to establish relative performance among tests, implementing such a scheme is challenging because of the limited amount of sample obtained from each patient. We therefore developed a reference panel of samples with different amounts of inactivated virus and samples whose SARS-CoV-2 status is unknown to developers. We are distributing this panel to makers of EUA-authorized molecular assays to allow determination of relative limits of detection (LODs). Once an international reference standard is finalized, the panel can be anchored to it and assessments can be updated to represent absolute LOD.
[..] No test is 100% accurate, and performance can vary within populations. Covid-19 diagnostic tests may be less accurate in asymptomatic or low-risk populations and in persons who shed little virus or are early or late in the course of illness. Even if a test were 98% sensitive and 99% specific, it would still produce a false negative result in 2 of every 100 people infected. If we test 5 million Americans daily and only 1% of them have Covid-19, a total of 1000 positive cases will be missed, which increases the risk of spread, and another 49,500 people will receive false positive results. False positive results can be burdensome to public health officials who are tasked with contact tracing and other public health activities, and many people may be unnecessarily quarantined. An understanding of the positive and negative predictive value of a test should be factored into clinical decision making and patient counseling. To mitigate the impact of false results, all Covid-19 tests authorized to date have been made available only by prescription, so that clinicians can interpret results for patients. However, several nonprescription tests are currently under development.
[..] we have learned lessons that should inform our response to future outbreaks. First, we believe that the U.S. government should work with international partners to establish a plan for sharing clinical specimens as soon as a public health threat emerges. This effort could be aided by having appropriate international agreements in place in advance.
Second, when a public health threat warrants large-scale testing, it would be more effective to authorize a small number of well-designed, well-developed, and validated tests run on common high-throughput platforms, followed by a few point-of-care tests, all of which are manufactured in large quantities, than to simultaneously develop and authorize scores of diagnostics. Such diffuse efforts are an inefficient use of resources.
[..] Use of contract manufacturers at the outset can greatly increase test availability. The FDA could proactively create validation protocols in collaboration with the test-developer community for commonly anticipated pathogen and sample types before an outbreak and modify them as necessary once an outbreak occurred.
[..] Third, we need common approaches to validating test design and performance, regardless of whether there is an emergency. Our experience with Covid-19 highlights the need for a common legislative framework to ensure that all clinical tests are accurate and reliable.
Fourth, the clinical community should understand test performance and how to use that information in patient care. Tests should be accompanied by clear, standardized, comprehensible information on performance for clinicians and patients. Training and continuing education can enhance physicians’ understanding of test performance, selection, interpretation, and clinical usefulness.”
Full editorial, Shuren J and Stenzel T. New England Journal of Medicine, 2020.10.22