On Saturday, 29 February 2020, the U.S. Food and Drug Administration (FDA) issued an “immediately in effect guidance” to swiftly expand testing for the novel coronavirus (2019-nCoV, formally named SARS-CoV-2), the causative virus for COVID-19 disease. The policy expedites use of molecular diagnostics tests developed and used in laboratories certified to perform high-complexity testing under the Clinical Laboratory Improvement Amendments (CLIA) in advance of issuance of emergency use authorizations (EUA) for the tests. The new policy allows CLIA-certified laboratories to deploy a validated test immediately, while submitting a completed EUA within 15 business days.
In an unusual move prompted by the acute need for COVID-19 testing capacity, FDA issued a new policy in the form of an “immediately in effect guidance,” Policy for Diagnostics Testing in Laboratories Certified to Perform High Complexity Testing under CLIA prior to Emergency Use Authorization for Coronavirus Disease-2019 during the Public Health Emergency, dispensing with a public comment period.
Critically, the new policy allows CLIA-certified laboratories to implement a validated test for the novel coronavirus without the delay of securing an EUA. The policy requires laboratories to notify the agency following completion of assay validation based on specific, FDA provided parameters, and “recommends” that laboratories submit a completed EUA request within 15 business days of notifying the agency of the successful validation.
In addition to providing for immediate use of validated assays, the new guidance specifies minimum testing necessary to ensure that assays are valid. The new policy includes recommendations for the minimum level of expected validation studies for qualification of these laboratory developed tests, consisting of limit of detection, clinical evaluation in the absence of known positive samples, documentation of in silico analyses, and cross-reactivity.
While an EUA request is pending, laboratories’ test reports should include a general statement that the test has been validated but that FDA’s review is pending. If FDA determines that the validation data is not sufficient to support issuance of an EUA, the laboratory will need to stop patient testing and issue a corrected report stating the previously reported results may not be valid.
During the agency’s review and prior to the determination of the EUA request, FDA recommends that clinical laboratories obtain confirmation of the first five positive and first five negative clinical specimens using an EUA-authorized assay, which may require sending the specimens to another laboratory for confirmation, and that discrepancies be reported to patients and healthcare providers.
On 2 March 2020, Timothy Stenzel, Director, Office of In Vitro Diagnostics and Radiological Health at FDA, led a webinar with the Center for Devices and Radiological Health (CDRH) personnel to review the policy stated in the guidance and take questions from industry. The webinar presenters stated that the test validation procedures outlined in the guidance are to be taken as suggestions and recommendations, and they encouraged laboratories pursuing alternative approaches, such as different technologies or alternative specimen types, to reach out directly to work with the agency to resolve questions around alternative pathways to assay validation. CLIA-certified laboratories are encouraged to contact FDA with questions about modifications or alternatives to the suggested protocols by calling the Division of Microbiology Devices at (301) 348-1778 or emailing the EUA request submissions address.
FDA reiterated that the policy allowing use of molecular diagnostic LDT validated tests prior to EUA approval only applies to CLIA-certified laboratories. Traditional IVD manufacturers are still required to complete the EUA process prior to marketing tests for COVID-19. However, FDA reiterated that the agency will diligently wok with these entities to develop and approve IVDs for CORVID-19 viral assays through the EUA process, but without pre-EUA marketing. The FDA officials also confirmed that laboratories using kit lots qualified by the Centers for Disease Control and Prevention (CDC) to conduct testing are not required to submit EUA requests, as these kits have already been authorized. Currently there is only one such lot available, although additional lots are undergoing qualification by CDC.
The webinar presenters strongly encouraged labs conducting testing to contact local and state public health authorities as soon as they begin validation efforts so that public health laboratories can be prepared to respond to positive findings.
As recently as 2 March 2020, two additional tests, besides the CDC assay, a New York State Laboratory test and an IDT Laboratory test, have been granted a FDA EUA for testing suspected COVID-19 patients.
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