Fig. 1

Proposed changes to the antimalarial research and development to better integrate the needs of pregnant individuals in the future. PAST APPROACH (top): Women of non-child-bearing potential (WONCBP) and women of child-bearing potential (WOCBP) with highly effective contraceptive use are included in clinical studies. The timing and extent of non-clinical Developmental and Reproductive Toxicity (DART) studies depends on the intended patient population. Generally, embryofoetal development (EFD) studies start in time to support clinical Phase II but pre-/postnatal development (PPND), as well as fertility and early-embryonic development (FEED) studies may be completed even post-licensure. Data on safety in pregnancy are collected passively in post-licensure registries. Pharmacokinetic (PK) data in pregnant and lactating women are rarely reported at the time of new medicine approval. FUTURE APPROACH (bottom): Lead compounds would be prioritized for progression to clinical development based on their non-teratogenic potential in in vitro assays, e.g., mammalian embryo exposure to compounds in a whole embryo culture (WEC) assay, or a zebrafish foetal development model. By performing the DART studies earlier and in relevant sequence, further selection of drugs for full development would be possible based on the risks identified in animal species. This would support earlier inclusion of WOCBP in clinical trials, with appropriate level of contraception [47], and pregnant women. Inadvertent pregnancies would be followed-up to assess maternal health, growth and development of the child. Utilising physiologically-based pharmacokinetic (PBPK) pregnancy or lactation models would inform on potential human foetal exposure or passage of the tested drug through the placenta and breastmilk, and hence support the justification for starting doses to be tested in clinical PK trials involving pregnant or lactating women. The PK trials would be initiated in parallel to the Phase III development for the general malaria population, once there is sufficient safety and efficacy evidence to derive an acceptable benefit/risk balance to start including pregnant or lactating women in the development of new drugs. Providing appropriate dosage and preliminary safety data in pregnant and lactating women in the first label of the registered medicine would expedite the commencement of further clinical studies and registries to fully characterize safety and efficacy. In particular, active pregnancy registries that capture inadvertent exposures in the first trimester, could help bridge the knowledge gap and provide some confidence to extend studies to this patient population