The article describes the approach to be applied with respect to viral mutations and their potential impact on the performance of tests intended to identify the virus.

The Food and Drug Administration (FDA or the Agency), the US regulating authority in the sphere of healthcare products, has published a guidance document describing the policy for evaluating the impact of viral mutations on tests intended to be used in the context of Coronavirus Disease 2019 (COVID-19) caused by the virus SARS-CoV-2 or the “novel coronavirus”. The document provides additional clarifications regarding the relevant regulatory requirements, as well as recommendations to be followed by medical device manufacturers and other parties involved in order to ensure compliance thereto. At the same time, the authority explicitly states that its guidance documents are non-binding in their legal nature, nor are intended to introduce new rules or impose new obligations. Moreover, an alternative approach could be applied, provided such an approach is in line with the current legislation and has been agreed with the authority in advance. It is also stated that the present document constitutes a revised version of the guidance document issued previously by the FDA earlier in February 2021. 


Regulatory Background 

During the outbreak of Coronavirus Disease, the authority takes all the steps necessary to ensure the emerging needs of the industry are duly addressed, and all the medical devices that are vitally important during the pandemic are available on the market. By the virtue of this guidance, the authority provides additional explanations regarding the approach to be applied with respect to mutations of the virus and their potential impact on test performance. In particular, this describes a policy to be considered by medical device manufacturers developing COVID-19 tests in order to ensure the accuracy and reliability of the results they provide. The scope of the guidance covers molecular and antigen tests intended to detect the virus itself, as well as serology tests intended to detect antibodies to the said virus. 

It is also important to mention that extraordinary measures introduced by the FDA in order to ensure and expand the availability of vitally important medical devices during the pandemic are temporary in their nature, hence, will remain effective only during the respective public health emergency announced due to the COVID-19 outbreak. Furthermore, the authority reserves the right to make changes to the guidance and/or the policy described therein, should such changes be reasonably necessary based on the new information the authority becomes aware of.

Variants of the Virus: Key Points 

The authority acknowledges that the virus SARS-CoV-2 can mutate over time, creating new variations. Some of these variations exist for a relatively short period of time and then disappear, while others remain for a longer period and sometimes become prevailing. The document provides an overview of mutations of the virus known to the authority on the date the guidance was issued, indicates when each of them has been identified for the first time, and also outlines certain specific aspects and features associated thereto. According to the guidance, the terms mutation (or viral mutation, genetic mutation, etc.) and variant (or virus variant, genetic variant, etc.) are used when describing changes in the genetic sequences of SARS-CoV-2; a mutation is an individual genetic change in a SARS-CoV-2 virus sequence when compared with a reference sequence such as Wuhan-Hu1 or USA-WA1/2020. Each new variation differs in some way from the existing ones, consequently, such a difference could impact the actual performances of tests used to identify the virus. The authority also mentions that different variants of the virus can have different characteristics. 

As further explained in the document, since molecular tests are initially designed to target a specific region(s) of the viral genome, any changes thereto could affect the effectiveness of a molecular test used to identify SARS-CoV-2. At the same time, in case the particular test was initially designed to detect multiple variants of the virus, its performance will be less affected by the differences. According to the guidance, the impact of genetic variants on molecular test performance is influenced by the sequence of the variant, the design of the test, and the prevalence of the variant in the population. Should the test fail to detect a new virus variant that becomes prevailing, the overall percentage of false negative results will increase accordingly. The said changes could affect the performance of an antigen or serology test as well – antigen tests are designed to detect specific viral proteins; if changes in the viral genome alter the structure of a viral protein targeted by an antigen test, the test may not detect the virus, even if the virus is present, leading to false negative results. As in other cases, the new variation becoming prevailing will lead to a significant increase in the percentage of incorrect results. The same applies in the case of serology tests intended to detect antibodies, since genetic variants may also affect the proteins that elect an antibody response. 

In order to address properly the issues described hereabove, the authority collaborates closely with the industry representatives and all the stakeholders involved. In particular, the authority continuously collects and analyses the information which becomes available with respect to the new variants emerging, and also about the actual performances of existing COVID-19 tests when used for new variants of the virus. The FDA intends to evaluate the impact such variants and changes could have on the effectiveness of tests allowed for marketing and used in the country during the pandemic under the different frameworks including the Emergency Use Authorization (EUA) and 510(k) pathway. 

In summary, the present FDA guidance provides an overview of the situation with changes to the virus that happen from time to time in the context of the effectiveness of COVID-19 tests, and the reliability of their results. The authority explains the key factors to be taken into consideration when assessing the potential impact of such changes to the virus and its specific characteristics. 



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