The new article highlights the key points related to molecular diagnostic tests and describes the recommendations provided by the authority in this respect.

The Food and Drug Administration (FDA or the Agency), the UA regulating authority in the sphere of healthcare products, has published a guidance document dedicated to the evaluation of the impact of viral mutations on 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 document provides an overview of the regulatory policy the authority intends to apply, as well as additional clarifications and recommendations to be considered by medical device manufacturers in order to ensure compliance with the applicable regulatory requirements. At the same time, it is also important to mention that guidance documents issued by the FDA 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 can be applied, provided such an approach is in line with the respective legislation and has been agreed with the authority in advance. 

The document provides, inter alia, recommendations to be followed by developers of molecular diagnostic tests. In particular, the guidance outlines the main design considerations to minimize the impact of viral mutations, and also describes the routine monitoring of viral mutations that may impact molecular diagnostic test performance. 


Design Considerations 

First of all, the authority recommends the test developers to consider the performance of their test across all known variants at the time of validation and the potential impact of future genetic variants when considering their test design. In particular, tests should be designed in a way ensuring it remains efficient when used for future potentially foreseeable variations. Multiple different tests can be used to identify the presence of a variant in the sample under review. 

Thus, the Emergency Use Authorization (EUA) request submitted by a test developer should include, inter alia, the details about the measures introduced by the developer in order to mitigate the impact of viral mutations, as well as the assessment of the actual performance of the test in question with respect to all known variants. 

The document also provides recommendations regarding the approach to be followed by test developers when determining targets in order to improve the overall test performance with respect to new genetic variants. 

Routine Monitoring

According to the guidance, apart from taking into account specific design considerations described herein, in order to address properly the issues related to the vital mutations, test developers should also duly implement routine monitoring of viral mutations that may impact molecular diagnostic test performance. In particular, it is stated that test developers should assess the potential impact of variants and mutations observed at a significant frequency on their molecular diagnostic test, as well as the potential impact of those viral mutations detected in a smaller percentage of the population where there are signs of increasing prevalence. 

As further explained by the authority, test developers should assess the performance of the test they are responsible for with respect to variants reflected in the databases, in order to determine the impact such variants could have on the accuracy and reliability of test results.  According to the guidance, should a new viral mutation be identified, test developers should conduct an additional assessment taking into account the following factors:

  • Location of the sequence mismatch within the primers/probes;
  • Whether multiple sequence mismatches could impact a single test; and
  • Whether the aggregate of mutations could impact a particular test to reduce performance by 5% or more from the previously established performance (as reflected in the authorization documents for authorized tests) or drop the test’s performance below the performance recommendations in the applicable EUA template(s) for molecular diagnostic tests for SARS-CoV-2 as discussed in [FDA guidance document dedicated to the revised policy for COVID-19 tests]. 

As it was mentioned by the authority, existing EUA templates already provide basic information and recommendations related to the monitoring to be conducted by test developers, while the authority will revise and update them from time to time based on the new information which becomes available. 

Apart from the above, the authority encourages test developers to pay additional attention to hybridization and the way it could be impacted by viral mutations. According to the guidance, the respective assessment could be conducted in three stages, namely:

  • In silico calculation;
  • Wet testing of genomic material; and 
  • Wet testing of a virus isolate with a mutation. 

Thus, test developers should duly conduct the assessment described hereabove, and then provide the authority with the following information (to be included in the respective EUA request):

  1. Temperature assessment results;
  2. The results of the assessment related to the impact of the viral mutation on the test performance;
  3. Justification for all the actions taken. 

The main purpose of the said assessment is to determine whether the new viral mutation identified could impact significantly the accuracy and reliability of the test results and whether any additional measures are needed to ensure the proper test performance when used for the samples with the new variant. 

It is also important to mention that all the evaluations conducted by a test developer to assess the impact of viral mutations should be duly documented, while the authority is entitled to request such documentation to be provided for review. Furthermore, the authority may also request test developers to conduct additional studies and/or data analysis in order to address specific aspects or concerns. 

In summary, the present FDA guidance describes in detail the approach to be followed in order to ensure the proper performance of molecular diagnostic tests in case of viral mutations. The document outlines the actions to be taken by test developers in this respect, including design considerations and routine monitoring. 



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