Reproductive and developmental toxicity testing: from in vivo to in vitro

On April 16, 2012, the U.S. Food and Drug Administration (FDA) held a workshop cosponsored by the National Institute of environmental Health Sciences, the Center for Alternatives to Animal testing (CAAt) at the Johns Hopkins Bloomberg School of Public Health, and the Middle Atlantic Reproduction and teratology Association to discuss emerging in vitro tools for predicting reproductive and developmental toxicity. this workshop, with 350 registered participants including those participating via webstream, provided an opportunity to discuss the evidence needed to evaluate and validate new test methods and to integrate these methods into regulatory decision making. During drug development, pharmaceutical companies use a variety of in vivo and in vitro developmental and reproductive toxicology (DARt) tests to predict the safety of new compounds. the results inform internal decision making and labeling, helping companies determine, for example, whether a compound would be safe for particular populations (e.g., women of childbearing age). In vivo testing for effects on embryofetal development in two animal species – one rodent species (usually rats or mice) and one nonrodent species (typically rabbits) is generally required by FDA to support clinical trials and labeling for use in pregnancy, explained Ed Fisher (FDA). Currently, companies employ in vitro tests using humanor animal-derived cells or cell lines or different animal models (e.g., zebrafish) only as a way to rapidly screen compounds prior to, or in conjunction with, in vivo testing, added Abigail Jacobs (FDA). For a variety of reasons, animal toxicity is sometimes a poor predictor of human toxicity, noted David Gerhold (National Institutes of Health – NIH) and other participants. Validated in vitro tests have the potential to increase the relevance of toxicity testing for humans and to reduce, refine, or replace in vivo animal testing. In fact, Gerhold continued, the National Research Council (NRC) report, Toxicity Testing in the 21st Century: A Vision and Strategy (NRC, 2007), envisions a future in which toxicity testing relies primarily on the in vitro study of human-derived cells or cell lines. Furthermore, the in vivo DARt methods used for regulatory purposes have changed little in the past few decades, explained Jesse Goodman (FDA), despite dramatic advances in basic scientific research. Modernizing toxicology to improve preclinical predictions of product safety, continued Goodman, is one of the priorities identified in FDA’s strategic plan for regulatory science (US FDA, 2011). But how should scientists validate emerging in vitro assays or batteries of tests? And what is the current status of ongoing validation efforts? Participants addressed these and related questions, focusing on the ability of in vitro test methods to predict in vivo outcomes and the potential to incorporate these new methods into regulatory decision making. Ultimately, Fisher and other participants said, to be accepted by both pharmaceutical companies and regulators, new methods must provide protection that is equivalent to, or better than, existing in vivo approaches.