New FDA guideline for the mouse embryo assay enhances rigor for assessment of ART Devices
Denny Sakkas, PhDa, Alan S. Penzias, MDa,b, Eli Y. Adashi, MD, MSc
a Boston IVF
bBeth Israel Deaconess Medical Center, Harvard Medical School
cWarren Alpert Medical School, Brown University
In January 2021, the Food and Drug Administration (FDA) issued a guidance to outline recommendations on conducting the mouse embryo assay (MEA) to support premarket submissions and lot release of Assisted Reproduction Technology (ART) media and devices (https://www.fda.gov/media/127874/download). This innocuous governmental act has created a landmark moment after a long history of ART development.
The first attempts at human artificial insemination by the Scottish surgeon/scientist John Hunter are believed to have occurred in 1785, with a baby born the same year. Early reports of successful donor insemination, in turn, were published in the 1940s and 1950s. It was 1944 when Rock and Menkin (Rock and Menkin, 1944) reported the first case of In Vitro Fertilization (IVF) and embryo development in the human. In the decades that ensued, many of the different clinical and laboratory procedures that were employed in “proof of concept” IVF evolved. One component in particular, embryo culture media, improved significantly (Whittingham, 1971;Brinster, 1974;Biggers and Borland, 1976). It was 1973 when the first IVF pregnancy in the world was reported by a team in Melbourne, Australia. Sadly, the pregnancy ended in early embryo death (De Kretser et al., 1973). Finally, in 1978, the application of accumulated knowledge to the advancement in the technologies associated with IVF culminated in the first IVF birth in the world (Steptoe and Edwards, 1978).
Since these incredible milestones, we also saw paradigm shifts in ART with the introduction of techniques such as Intracytoplasmic Sperm Injection (ICSI) and the use of vitrification to cryopreserve gametes and embryos. With many of these changes, the art of ART was driven by innovation and supported by new products. It was only in the last decade or so that many products and innovations have been more closely regulated. ART is now a global endeavour with thousands of IVF centers each seeking to apply the most advanced techniques. We must remember that in our pursuit of success, we also have a serious responsibility to “do no harm” to the families we are helping to create.
The FDA guidance document, which standardizes the conduct of the MEA to support premarket submissions and lot release of ART devices, adds rigor. The FDA recommended that MEA testing be used to assess the embryotoxicity of ART devices that have direct and/or indirect contact with gametes and/or embryos. The FDA also proposed that blastocyst development from either one-cell or two-cell stage embryos (i.e., one-cell system or two-cell system) can be used to assess embryotoxicity and considers both methods acceptable. Granted, even prior to this FDA regulation, the MEA has been used as a staple to provide IVF clinics with assurance that the many products and devices implicated in the IVF process have passed some level of quality assurance. Many IVF laboratories that made their own culture media in the early days of IVF, used the MEA as their internal quality control. The large majority of clinics now rely solely on MEA testing certificates provided by companies when they purchase media or devices. The new MEA guidelines now provide for a uniform testing system and assessment for the IVF community in the US, and hopefully one that may be applicable worldwide. Briefly, the one-cell system must achieve ≥80% of embryos developing to expanded blastocyst at 96 hours of culture. The two-cell system, in turn, must achieve ≥80% embryos developing to expanded blastocyst at 72 hours of culture. A minimum of 21 embryos should be exposed to the test article, while a minimum of 15 embryos should be exposed to the control medium in each MEA. The FDA also recommends that a minimum of 3 individual devices be evaluated in each test to account for potential variability between devices.
The question remains of whether the MEA is sensitive enough to detect problems in products related to IVF treatment. One could argue that a stronger emphasis on replicates and greater testing numbers would provide an even better assurance. For embryology purists, the greatest test remains the transfer and birth of live mouse pups. This, in some ways, is a better way to expose subtle toxicities that may be present in the products being tested. However, obtaining live pups may be more complex so other approaches could be looked at, including the use of time-lapse imaging to compare sensitivity of the MEA. This has already been shown to have improved sensitivity when examining clinical grade mineral oil with known peroxide concentrations and comparing it to standard MEA (Ainsworth et al., 2017). The IVF companies and community may, in the future, need to be more proactive in improving the standards required for testing in partnership with the FDA.
The FDA guidance on the MEA for ART Devices is a great step forward and serves two purposes for the IVF community as a whole. First, it provides standardized criteria so that any solid device or liquid coming in contact with gametes or embryos is tested. Second, it rebuffs the notion that the field of IVF is poorly overseen and regulated.
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