Re-orienting anti-malarial drug development to better serve pregnant women

Abstract

Malaria is one of the most serious infectious diseases affecting predominantly low- and middle-income countries, where pregnant women are among the populations at risk. There are limited options to prevent or treat malaria in pregnancy, particularly in the first trimester, and existing ones may not work optimally in areas where the threat of drug resistance is rising. As malaria elimination is a key goal of the global health community, the inclusion of pregnant women in the adult population to protect from malaria will be key to achieving success. New, safe, and effective options are needed but it can take decades of evidence-gathering before a medicine is recommended for use in pregnancy. This is because pregnant women are typically not included in pre-registration clinical trials due to fear of causing harm. Data to support dosing and safety in pregnancy are subsequently collected in post-licensure studies. There have been growing calls in recent years that this practice needs to change, amplified by the COVID-19 pandemic and increasing public awareness that newly developed medicines generally cannot be administered to pregnant women from the onset. The development of new anti-malarials should ensure that data informing their use in pregnancy and breastfeeding are available earlier. To achieve this, a mindset change and a different approach to medications for pregnant women are needed. Changes in non-clinical, translational, and clinical approaches in the drug development pathway, in line with recent recommendations from the regulatory bodies are proposed in this Comment. The new approach applies to any malaria-endemic region, regardless of the type of Plasmodium responsible for malaria cases. By incorporating intentional and systematic data collection from pre-registration stages of development through post-licensure, it will be possible to inform on the benefit/risk balance of a new anti-malarial earlier and help ensure that the needs of pregnant individuals are addressed in a more timely and equitable manner in the future.

Keywords: Antimalarial drugs; Equity in R&D; Inclusion of women; Malaria in pregnancy; New medicines.

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