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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 monkeypox tests intended to be used in the context of the public health emergency. In particular, the document describes the approach the authority intends to apply to ensure and expand the availability of such tests due to the increasing demand associated with an outbreak of the disease. By the virtue of the guidance, the authority explains the way special temporary, and extraordinary measures will be applied for such devices. At the same time, it is important to mention that provisions of the present guidance are non-binding, nor are intended to introduce new rules or impose new obligations, but rather to provide additional clarifications regarding the applicable regulatory requirements, as well as recommendations to be taken into consideration to ensure compliance thereto. Moreover, the authority explicitly states that an alternative approach could be applied, provided such an approach is in line with existing legislation and has been agreed with the authority in advance. 

Validation of Diagnostic Tests 

The scope of the guidance covers, inter alia, the aspects related to the validation of diagnostic tests intended to be used to identify the monkeypox virus. In this respect, the authority mentions that it is vitally important to ensure the accuracy and reliability of test results since this could impact significantly both the treatment process for a specific patient and also the public health protection in general, resulting in the further spread of the virus. As it is further explained in the document, the authority provides specific recommendations to be taken into consideration concerning validation testing a party responsible for tests should conduct. However, it is explicitly stated that the said recommendations are voluntary, so an alternative approach could be applied, provided it allows to achieve the appropriate result in terms of assessment of analytical and clinical validation principles. According to the guidance, FDA has provided on its website two types of voluntary templates that developers may opt to use to facilitate a EUA request: one is a summary template with recommendations regarding validation testing that should be performed to provide information on the analytical and clinical validity of the test; the other is a voluntary comprehensive template that provides additional details, including study design considerations and fill-in-the-blank responsive test. The authority also mentions that in certain cases, additional studies should be performed – the need for such additional studies should be detrained depending on the characteristics of the device in question. 

Test developers may also make references to other tests intended for the same purpose, already cleared by the FDA. In such a case, it will be necessary to demonstrate that the performance of the new test in question is consistent with the performance of the original one. The scope of assessment should cover the evaluation of the Limit of Detection (LoD). The authority also refers to additional recommendations published on its official website. 

Furthermore, the authority reserves the right to make changes to its recommendations related to validation testing based on the new information it receives during the public health emergency. The availability of new information will allow the authority to make its recommendations more precise and efficient. 

As it was mentioned before, the parties involved in the development of monkeypox tests are allowed to use alternative approaches, provided such approaches are compliant with the respective regulatory requirements. Moreover, alternative approaches should be agreed upon with the FDA before their actual implementation. 

Serology Tests 

According to the guidance, serology tests could be used to collect additional information related to the disease process. At the same time, the authority acknowledges potential issues associated with the misuse of such tests. For instance, it is explicitly stated that serology tests should not be used for diagnostic purposes. As further explained in the guidance, at this time, FDA does not intend to object to the use of monkeypox serology tests that are developed and performed by a high-complexity, CLIA-certified laboratory that is part of an entity that conducts research on diseases and is integrated into the direct medical care of the patient, where the laboratory gives notification of validation to FDA and certain information is included in the test reports. The authority expects that such an approach would reduce the number of cases of misuse, and also facilitate additional research based on the new data available. For instance, testing could be conducted regularly (e.g., daily), while the additional information collected would be useful for further test development. 

The authority also encourages all the parties involved to share the information they collect when using the tests with the FDA. The latter would also consider accepting EUA applications related to serology tests, should it be found reasonable. 

According to the guidance, in case the authority becomes aware of any issues or concerns related to serology tests used in the country, it will get in touch with the respective laboratory and request the appropriate actions to be taken to address such issues. Should the laboratory fail to perform the necessary actions promptly, the tests in question should be no longer used. 

The document also outlines the scope of information to be included in test reports related to serology tests. According to the guidance, this should include the following statements: 

• Not for use to diagnose an active infection;
• Negative results do not preclude monkeypox virus infection, if active infection is suspected, viral testing for monkeypox virus or Orthopoxvirus is necessary;
• Results from antibody testing should not be used to diagnose or exclude Orthopoxvirus infection. 
• The clinical significance of a positive or negative antibody result following smallpox vaccination has not been established. 

Apart from this, the guidance also provides a list of details to be included in the notification to be submitted to the authority upon completion of a validation process. 

In summary, the present FDA guidance provides additional clarifications regarding the specific matters related to monkeypox tests and regulatory requirements associated thereto. The document also highlights the key points related to the use of serology tests. 

Sources:

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/policy-monkeypox-tests-address-public-health-emergency

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