The new article highlights the aspects related to the way the impact of viral mutations can be addressed when developing tests.
The Food and Drug Administration (FDA or the Agency), the US regulating authority in the sphere of healthcare products, has published a guidance document dedicated to the policy for evaluating the impact of viral mutations on tests intended to be used in the context of the outbreak of Coronavirus Disease 2019 (COVID-19) caused by the virus SARS-CoV-2 or the “novel coronavirus”. The document provides additional clarifications regarding the applicable regulatory requirements, as well as recommendations to be taken into consideration by medical device manufacturers and other parties involved in order to ensure compliance thereto. At the same time, provisions of the guidance are non-binding in their legal nature, nor are intended to introduce new rules or impose new obligations. Moreover, the authority explicitly states that an alternative approach could be applied, provided such an approach is in line with the existing legislation and has been agreed with the authority in advance.

In particular, the document describes the way viral mutations taking place from time to time could impact the accuracy and reliability of test results. The authority explains that changes to the virus and its specific features could impact the ability of in vitro diagnostic devices (tests) to identify it, resulting in an increasing number of false negative results, that creates additional hazards for public health.


Regulatory Background 

First of all, the authority provides general information about viral mutations and also outlines specific measures it takes to monitor them. For instance, the FDA regularly monitored EUA-authorized molecular tests, as well as molecular tests that were authorized or cleared under the de novo or 510(k) pathway, respectively, by aligning the tests’ primer/probe sequences (or equivalent if the test uses an alternative amplification approach) with the U.S. SARS-CoV-2 genomes published in the GISAID  and other databases to determine whether there are any mutations in the region(s) of the viral genome targeted by the tests, as that may impact their performance. Should it be identified that certain mutations occur in the area where tests are used, the authority will collect additional information to evaluate the test performance and assess the impact caused. In this respect, the authority also closely cooperates with test laboratories and healthcare institutions. The authority collects additional information that becomes available, conducts the analysis, and shares its findings with all the parties involved. Thus, the respective FDA policy could be subject to changes intended to address emerging needs.

Recommendations provided in the present revised guidance should be taken into consideration by the parties involved in the development of various types of tests used in the context of novel coronavirus covered by the scope of the respective guidance document.

Recommendations in Detail 

As it was mentioned before, the document is intended to provide additional recommendations to be taken into consideration by COVID-19 test manufacturers when assessing the impact caused by viral mutations on the performance of tests and the accuracy of the results they provide. The authority additionally emphasizes that the said recommendations apply to all the tests irrespective of their regulatory status (i.e., whether they are authorized or not). 

Furthermore, it is also stated that certain conditions related to viral mutations are included in the scope of Emergency Use Authorization (EUA). Hence, the parties responsible for COVID-19 tests are obliged to comply with the said conditions in order to be allowed to make their products available for use during the public health emergency. Furthermore, according to the guidance, during the FDA’s review of an EUA request or a marketing submission for a COVID-19 test, FDA intends to consider the performance of the test across all known variants, as well as the developer’s plans for post-authorization monitoring. The authority also encourages medical device manufacturers to make sure the labeling used includes statements regarding any applicable limitations with respect to the period during which the specimens used to evaluate the performance of the device were collected and the respective territories. Apart from that, labeling could contain a statement that the actual performance of the test could greatly depend on specific variants for which the test is used. The information about the impact viral mutations can have on the accuracy of test results will also be published on the authority’s website. 

The document also provides specific recommendations to be taken into consideration by test developers depending on the particular type of tests they are dealing with. For instance, in terms of molecular diagnostic tests, the authority recommends to:

  1. Design [the] test to minimize the impact of viral mutations on test performance;
  2. Routinely monitor for viral mutations that may impact test performance; and
  3. Clearly convey any test limitations in the test’s labeling as discussed above.

The authority further explains that the tests intended to detect a specific viral mutation will be limited in use and become obsolete quite quickly due to the new variations appearing. Hence, the authority emphasizes the importance of developing COVID-19 tests in a way ensuring they can be used for detecting a wide range of viral mutations, including both known and emerging ones.

In summary, the present FDA guidance provides an overview of the regulatory policy the authority applies with respect to viral mutations in order to mitigate the impact they cause on the accuracy and reliability of test results. The authority outlines the key considerations to be taken into account by medical device manufacturers and healthcare institutions when developing COVID-19 tests.



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