The Food and Drug Administration (FDA), the US authority responsible for medical device regulation, issued guidance for clinical laboratories dedicated to Coronavirus Disease-2019 during the public health emergency. The document covers the aspects related to molecular diagnostics tests concerning the novel coronavirus (COVID-19). In particular, the main purpose of the guidance is to accelerate the process of development, validation, and authorization for emergency use of in vitro diagnostics tests used to determine the aforementioned virus.
COVID-19 Situation Overview
Earlier in February 2020, the Secretary of Health and Human Services announced the public health emergency, providing that additional measures are needed to accelerate the development and use of in vitro diagnostic devices for identification of the novel coronavirus (2019-nCoV). The present guidance provides a policy to be used by laboratories developing and using their own tests for the purpose of detection of the aforementioned virus.
It is also important to mention that due to the situation with the infection, the guidance should be implemented immediately without any public discussion procedure usually applicable when issuing new guidance.
The document covers aspects related to the disease named “Coronavirus Disease 2019” (COVID-19) caused by the virus named “SARS-CoV-2”. The new virus could be characterized by the significant speed of spreading, so it is crucial to implement measures aimed at efficient detection of the novel virus in order to ensure public safety and health protection. The guidance is intended to assist healthcare institutions and laboratories with the development of their own approach to testing and diagnostics. At the present time, most of the tests are developed by the Centers for Disease Control and Prevention (CDC) laboratories, but the FDA emphasizes that it is necessary to extend the engagement of other laboratories in the development of in vitro diagnostic tests. It is important to mention that tests developed by the CDC have already obtained an emergency use authorization from the FDA.
In accordance with section 564 of the Federal Food, Drug, and Cosmetics Act, the agency is entitled to allow using medical products without prior approval under emergency circumstances that should be confirmed by the declaration of emergency. In this case, the agency initiates the emergency use authorization (EUA) procedure. The EUA framework allows the agency to take action aimed at the implementation of the medical countermeasures initiatives (MCMs) against chemical, biological, radiobiological, radiological, and nuclear (CBRN) threats.
Some of the US laboratories certified to perform high-complexity testing are already engaged in the process of test development and later will apply for the EUA. To create a favorable regime for such entities, the FDA announced that they would be allowed to use such tests before obtaining the emergency use authorization. In particular, the laboratories would have 15 days to prepare the submissions for validated tests.
Thus, the guidance document is addressed to all laboratories certified to perform high-complexity testing, engaged in the process of development and validation of own in vitro diagnostics tests, intended to apply for approval via the emergency use authorization framework.
Policy in Detail
The guidance covers both cases when laboratories develop and manufacture their own test, and also the cases of using the “research use only” (RUO) products developed and created by other manufacturers as the basis for their own research. In particular, the document describes the following steps of the process:
- Validation. Before being used, any clinical test should pass the validation procedure, which becomes especially important in the period of emergency. The agency provides the details regarding the approach to the validation to be used by laboratories to ensure the safety and quality of the tests being used. Thus, the FDA outlines the minimum requirements to be fulfilled in the course of providing the confirmation of the clinical validity of tests developed by the laboratories. First of all, the laboratories should provide information on the limit of detection (LoD) related to the novel coronavirus, which states for the lowest concentration the test could determine. This information should be included in the EUA submission. Due to the reasonable difficulties in using known positive samples to evaluate the effectiveness and accuracy of sample tests, the authority requires to perform a clinical evaluation based on at least 30 contrived reactive specimens and 30 non-reactive specimens. The concentration used should be 1x-2x LoD. It is also required to provide the documents on the accuracy of identification, including the details on an in silico analysis and cross-reactivity testing.
- Notification of the agency. Upon the successful completion of the validation process, the laboratory should duly notify the agency using the appropriate email address. The notification should be accompanied by the information on the name of the laboratory and its director, its address and the contact person`s details. An automated reply provided by the agency constitutes the acknowledgment that the FDA has received the notification. According to the guidance, the EUA request should follow the initial notification within 15 business days.
- Reporting. It is also required to provide detailed testing reports allowing the agency to review the validation process itself and the reliability of its results. The information on any positive results achieved should be provided to healthcare agencies of all levels without any undue delay.
- Filing the emergency use authorization request. The agency will provide the laboratories intended to apply for the EUA with the appropriate template which takes into consideration the specific of COVID-19. The agency also announces that it would actively cooperate with the laboratory during the submission and review processes, provide the applicants with all the information needed to submit a request and properly notify the laboratory in case of refusal in the authorization. In such a case, the laboratory would have to provide updated and corrected testing results.
- Requirements related to clinical testing provide that the laboratories should obtain the information on the first 5 positive and 5 negative clinical specimens and provide them to the independent laboratory to obtain additional confirmation. This procedure should be performed before obtaining the emergency use authorization from the FDA. In case if the laboratory applying for the EUA fails to fulfill this requirement and confirm the accuracy of testing results, it should notify the agency and issue a corrected test report.
Summarizing the information provided above, the FDA issued guidance describing the most important aspects related to the validation of tests developed by authorized laboratories to determine the novel coronavirus SARS-CoV-2.
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