Nonclinical Considerations for Support of Pregnancy and Lactation in Clinical Trials

Pregnant and breastfeeding individuals remain underrepresented in clinical drug development, leaving health care providers and patients with limited data to inform treatment decisions. Current practice relies heavily on nonclinical developmental and reproductive toxicity (DART) studies in animals, while clinical trials typically exclude pregnant and breastfeeding populations or require highly effective contraception for women of childbearing potential. Consequently, medications may be used during pregnancy or lactation despite limited supporting evidence, which can lead to treatment interruption, suboptimal dosing, and increased maternal or fetal risk. Emerging regulatory guidance, including draft ICH Guideline on Inclusion of Pregnant and Breastfeeding Individuals in Clinical Trials (E21), highlights the ethical and clinical need to generate data directly in these populations.

This paper evaluates the current regulatory framework for nonclinical studies described in ICH S5(R3) and M3(R2) and examines how these studies can support the enrollment of pregnant and breastfeeding individuals in clinical trials. It proposes pragmatic adaptations to align nonclinical testing with the anticipated clinical context of use and considers the role of new approach methodologies (NAMs) and alternative study designs.

Potential DART strategies are described that could enable the inclusion of pregnant individuals in clinical trials based on factors such as dosing duration, route of administration, and study type (e.g., pharmacokinetic studies). The paper also considers the use of NAMs, including physiologically based pharmacokinetic modeling and in vitro assays, as well as alternative study designs such as preliminary pre- and postnatal development or extended embryo-fetal development studies. Approaches to inform studies in breastfeeding populations, including milk-plasma ratio modeling and translation from nonclinical data, are also discussed.

These approaches support a shift from routine exclusion toward proactive and ethical inclusion of pregnant and breastfeeding individuals in clinical research, helping address longstanding evidence gaps and improving therapeutic decision-making.