The Food and Drug Administration (FDA) has published a guidance document dedicated to the mouse embryo assay (MEA) for assisted reproduction technology (ART) devices. Due to its legal nature, the document does not introduce mandatory rules and requirements the parties involved shall follow, but only provides certain clarifications and recommendations to be considered in order to ensure compliance with the applicable regulations. The Agency also mentions that an alternative approach could be applied, providing that such an approach has been agreed upon with the regulating authority in advance. 

Regulatory Background

The present FDA guidance describes the regulatory approach to be applied for MEA used to assess the potential for embryotoxicity of devices contacting gametes and/or embryos. In accordance with the classification regulations under 21 CFR part 884, testing or additional information is required for MEA. As it is stated in the document, the present guidance is intended to provide recommendations for conducting the MEA to support premarket submissions for devices that are intended to contact gametes and/or embryos and to comply with the special controls for those devices classified under 21 CFR 884 that require MEA testing or information. The Agency also mentions that at the moment there are no voluntary consensus standards medical device manufacturers may refer to in order to demonstrate compliance with the applicable requirements. 

Thus, the scope of the present FDA guidance covers only medical devices subject to regulation under 21 CFR part 884 that have direct or indirect contact with gametes and/or embryos. The recommendations provided therein could be also applied in case of other medical devices for which MEA testing or information could be applied.

MEA Testing 

The FDA provides certain recommendations regarding MEA testing. For instance, the Agency states that it finds suitable both one-cell and two-cell systems for assessing embryotoxicity. With regard to testing, the regulating authority emphasizes the following points: 

  • Testing should be performed using final finished devices,
  • It is important to use a sufficient number of devices for testing (at least three),
  • In the case of testing performed in the context of premarket submission, such testing should include both newly manufactured devices and ones at the end of the shelf-life indicated by the manufacturers, providing that all devices subject to testing are from the same lot.

The FDA also describes specific approaches to be applied depending on the type of medical device subject to review and its intended use, namely:

  1. Liquid-based devices for MEA should be tested as provided without extraction or dilution.
  2. Oil indicated for oocyte/embryo culture should be evaluated under the intended use conditions.
  3. Plates and dishes that are indicated for embryo culture should be tested directly without extraction.
  4. Solid devices that are not indicated for embryo culture (e.g. embryo transfer catheters, cryopreservation devices) should be extracted before use. 

The guidance additionally provides recommendations regarding the temperature regime to be used in order to ensure the accuracy and reliability of testing results. 

MEA Test Procedure

The FDA also describes in detail the test procedure itself. According to the guidance, culture media and labware used should be initially intended to be used in ART procedures. For this purpose, the Agency recommends medical device manufacturers check the information about culture media and labware via the appropriate official database operated by the regulating authority. Such information about culture media and labware used in testing should be also provided to the FDA in the course of premarket submission. 

According to the document, at least 21 embryos should be used in testing, providing that at least 15 embryos are being exposed to the control medium in each MEA. Moreover, each MEA should include a control group.  In terms of duration of exposure, the guidance provides the following:

  • In a standard MEA, embryos should be incubated in the test article extract under normal culture conditions for 96 hours if a one-cell system is used or 72 hours for a two-cell system. 
  • If the device is a plate or dish intended for embryo culture, the embryos should be directly incubated in the device in a standard embryo culture medium under normal culture conditions until the end of MEA culture time,
  • If the device is a one-step medium, MEA should be conducted using the test articles until the end of the intended incubation period under normal culture conditions. 
  • If the device is a media product with a shorter intended contact duration than a standard MEA, MEA should be conducted by exposing the embryos to the device for the total intended use duration provided in the labeling of the device. 

The guidance also provides additional rules regarding test duration to be considered by the party responsible for MEA.

In terms of test reports, the Agency refers to the appropriate guidance “Recommended Content and Format of Complete Test Reports for Non-Clinical Bench Performance Testing in Premarket Submissions”. The authority also recommends supplementing the test report with additional information regarding the MEA test method used (e.g. mouse strain, number of embryos, culture conditions, etc.). 

Additional Recommendations 

Besides the aforementioned points, the FDA guidance on mouse embryo assay also highlights other important aspects to be considered by the medical device manufacturers, such as labeling requirements or applicable certificates. For instance, the Agency requires the manufacturers to indicate the applicable acceptance criteria, as well as lot-specific pass/fail results. 

Summarizing the information provided here above, the present guidance outlines the main points related to the mouse embryo assay in the context of assisted reproduction technologies when assessing the potential for embryotoxicity of devices. In particular, the document describes the testing procedures to be performed by the medical device manufacturer before submitting an application for marketing approval, the methods of such testing, as well as the applicable path/fail criteria to be considered. The document is intended to provide additional clarifications and recommendations that are important to ensure compliance with the applicable requirements. The guidance also contains references to related documents and regulations, such as guidelines dedicated to similar matters, for instance, the FDA guidance “Use of International Standards ISO 10993-1, Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process”.

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