The Food and Drug Administration (FDA or the Agency), the US regulating authority in the sphere of medical devices and other healthcare products, has published a guidance document dedicated to the policy for evaluating the impact of viral mutations on COVID-19 tests. The recommendations provided therein should be considered by the medical device manufacturers (test developers), as well as by the personnel of the Agency. 

Due to the importance of the issues addressed therein, the present FDA guidance is subject to immediate implementation without the usual procedure of public consultations prescribed under the general rule. At the same time, the industry representatives still may submit their comments and suggestions. It is also important to mention that the guidance itself does not introduce any rule or regulatory requirements to be followed, but provides additional recommendations to be considered instead. The Agency explicitly states that an alternative approach could be applied, providing such an approach complies with the applicable regulatory requirements and was agreed with the FDA in advance. The approach described therein remains applicable within the whole period of the public health emergency.

Regulatory Background 

The present FDA guidance is dedicated to certain specific aspects related to the tests intended to be used in the context of the outbreak of the Coronavirus Disease 2019 (COVID-19) caused by the virus SARS-CoV-2 or the “novel coronavirus”. The provisions of the document are aligned with the emergency framework implemented to address the issues associated with the pandemic. According to the FDA guidance, it is intended to provide a policy and recommendations on evaluating the potential impact of emerging and future viral mutations of SARS-CoV-2 on COVID-19 tests for the duration of the COVID-19 public health emergency. In particular, the document outlines the approach to be utilized by the test developers with regard to the impact of emerging and future variants on the tests they are developing. The scope of the guidance covers the following types of tests:

  • Molecular tests, 
  • Antigen tests,
  • Serology tests intended to detect antibodies. 

The Agency acknowledges that the virus is subject to changes resulting in a situation when numerous variations of the virus are circulating. Some of the new variants disappear, while others exist for a longer period of time. The FDA states that most of the COVID-19 tests used nowadays were initially developed to detect the very first genetic sequence identified earlier in January 2020, while there are many other variations of the virus existing at the moment, and some of them were already detected in the US. 

The document uses such terms as mutation and variation to describe changes in the genetic sequences. According to the document, for the purpose of the present guidance, a mutation stands for the individual genetic change in a SARS-CoV-2 virus sequence when compared with a reference sequence such as Wuhan-Hu1 or USA-WA1/2020, while the variations could be identified by genomic sequences containing such mutations. The Agency mentions that the mutations could impact the features of the virus, including its antigenicity, transmissibility, or virulence. 

Variations and Mutations

The issue addressed in the present FDA guidance is related to the situations when the presence of the aforementioned mutations impacts the accuracy of test results due to the principle of identification employed by the tests. In particular, the molecular tests are based on targeting specific regions of the viral genome to identify the virus. In case if the targeted part of the genome is subject to mutations, this could impact the accuracy of test results and sometimes result in false-negative results. However, the molecular tests initially intended to target multiple regions are less sensitive to the impact potentially caused by mutations. According to the document, the factors impacting the accuracy and reliability of test results include, inter alia, the following ones:

  • The sequence of the variant,
  • The design of the test,
  • The prevalence of the variant in the population. 

Hence, should the test be ineffective in detecting the particular variation of a virus, and the variation becomes widely spread, the percentage of false-negative results would increase accordingly. 

The Agency also mentions that the accuracy of the antigen and serology tests could be impacted by the changes to viral proteins due to the following: 

  • Antigen tests are initially intended to identify particular viral proteins. Should the mutations lead to changes in the structure of a viral protein the test is intended to identify, the accuracy of the results would decrease. Thus, the actual effectiveness of antigen tests is sensitive to the potential changes to the proteins. 
  • Serology tests are initially intended to identify the particular antibodies appearing in the course of the immune response. Should the mutations impact the proteins triggering such a response, the effectiveness of antibody tests could decrease accordingly since the antibodies generated in the course of immune response would be different from those the test is initially intended to identify. 

In order to address the issues described hereabove, the Agency actively collaborates with all the parties involved. For this purpose, the FDA continuously monitored the spreading of new virus variants, as well as the effectiveness of the available COVID-19 tests, including the ones placed on the market under the Emergency Use Authorization (EUA) framework – a special pathway allowing to ensure and expand the availability of medical devices used in the context of an emergency. In this regard, the Agency monitors the performance and effectiveness of COVID-19 tests of all types including molecular, antigen, and serology (antibody) tests. For this purpose, the Agency also analyses the sequence data available and identifies the mutations occurring more often than in 5% during the particular period of time. For the same purpose, the FDA continuously analyses the reports from laboratories and healthcare institutions. On the basis of the aforementioned observations, the FDA has already developed and published the appropriate safety alert to clinical laboratories and healthcare institutions describing the potential impact of variations on test performance. 

Recommendations and Regulatory Requirements 

The recommendations provided in the present FDA guidance should be considered in the context of both already authorized COVID-19 tests and the ones still being under development. At the same time, the Agency also mentions that it may review the recommendations from time to time on the basis of the information available to ensure they cover all the important points.

The Agency mentions that at the moment it considers the option to include the evaluation of the impact of virus mutation on test performance as one of the preconditions for authorization as prescribed under the applicable regulatory requirements. Should the FDA make such a decision, this would become an additional point the medical device manufacturer would have to comply with. 

The FDA also states that in the course of the assessment the performance evaluation should cover all known variants to ensure the sufficient effectiveness of a new test with regard to existing variations. 

Summarizing the information provided here above, the present FDA guidance describes the approach to be applied with regard to existing and potential variations of the virus SARS-CoV-2. In particular, the Agency outlines the most important aspects to be considered and highlights the points requiring the most attention. 

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