Goldilocks' Determination of What New In Vivo Data are "Just Right" for Different Common Drug Development Scenarios,...

As alternative models and scientific advancements improve the ability to predict developmental toxicity, the challenge is how to best use this information to support safe use of pharmaceuticals in humans. While in vivo experimental data are often expected, there are other important considerations that drive the impact of developmental toxicity data to human risk assessment and product labeling. These considerations include three key elements: (1) the drug's likelihood of producing off-target toxicities, (2) risk tolerance of adverse effects based on indication and patient population, and (3) how much is known about the effects of modulating the target in pregnancy and developmental biology. For example, there is little impact or value of a study in pregnant monkeys to inform the risk assessment for a highly specific monoclonal antibody indicated for a life-threatening indication against a target known to be critical for pregnancy maintenance and fetal survival. In contrast, a small molecule to a novel biological target for a chronic lifestyle indication would warrant more safety data than simply in vitro studies and a literature review. Rather than accounting for innumerable theoretical possibilities surrounding each potential submission's profile, we consolidated most of the typical situations into eight possible scenarios across these three elements, and present a discussion of these scenarios here. We hope that this framework will facilitate a rational approach to determining what new information is required to inform developmental toxicity risk of pharmaceuticals in context of the specific needs of each program while reducing animal use where possible.