General Design Considerations in Reproductive and Developmental Toxicity Studies

Developmental and reproductive toxicity studies are conducted with the objective of identifying adverse effects relevant to fertility, pregnancy and development. Many approaches are used to enlighten our understanding of reproductive toxicity. Each segment of the testing paradigm focuses on slightly different objectives, with an overarching goal to understand the mechanistic and exposure relationships of candidate therapeutics that drive toxicity. There are established standard design approaches for these developmental and reproductive toxicity (DART) studies. The DART strategy for each program should carefully consider the intended patient population and existing knowledge regarding the toxicity profile, exposure relationships and expected pharmacology. Overall, mammalian DART studies are large and complex, and require substantial planning and experience for appropriate design and interpretation. DART testing is typically conducted in mammalian rodent species (mouse or rat), with a second non-rodent species used to further evaluate teratogenic potential (often rabbit), but in some cases, studies can be combined, refined, or avoided. In addition, there are non-mammalian tools that can aid in strategy, study design and/or data interpretation. This chapter will explore considerations for the use and design of both ‘standard’ and alternative study types and tools to inform pharmaceutical and biopharmaceutical drug development.