In a new perspective article, researchers examined gaps in clinical drug trials that involved lactating women and identified the need for regulatory and research advancements. According to the study, approximately 50% of breastfeeding women worldwide require medication, but limited data exist on drug transfer through breast milk and potential effects on infants.

In their study, published in npj Women's Health, the investigators pointed to a 2016 FDA review, which found that lactation was one of the most frequent exclusion criteria in trials for drugs approved between 2014 and 2017. A separate review of 422 new molecular entities approved by the FDA between 2001 and 2020 showed that only 5% included human lactation data.

Regulatory agencies have taken steps to address these gaps. The FDA's 2019 guidance recommended that clinical lactation studies are conducted when a drug is expected to be used by women of reproductive age. More recently, the 2024 FDA draft guidance on diversity action plans has called for the inclusion of underrepresented populations, including lactating women, in clinical trials. However, most lactation studies continue to be conducted as postmarketing rather than during drug development. An analysis of FDA approval letters from 2000 to 2022 found that only 18 drugs included lactation studies as postmarketing requirements. Nearly 90% of those requests occurred after 2017.

Historically, concerns over potential risks to infants have contributed to the exclusion of breastfeeding women from trials. Although drug exposure via breast milk is generally lower than exposure through placental transfer, notable exceptions exist. In the current study, the researchers cited bedaquiline for the treatment of rifampicin-resistant tuberculosis, which reached concentrations in breast milk that were 14 times higher than in maternal plasma. Breastfed infants exposed to this drug were found to have plasma levels similar to their mothers. While adverse drug reactions in breastfed infants are rare, pharmacovigilance data indicate that nonspecific symptoms such as irritability and respiratory depression are commonly reported and complicate safety assessments.

A key metric in evaluating drug safety during lactation is the Relative Infant Dose (RID), which represents the percentage of the weight-adjusted maternal dose consumed by an infant through breast milk. A World Health Organization Working Group proposed that drugs with an RID greater than 10% may not be safe in infants, and those exceeding 25% should be avoided by nursing mothers. However, the researchers noted that these are arbitrary thresholds that lack pharmacological basis and do not necessarily predict adverse clinical events.

Advances in pharmacokinetics have introduced modeling and simulation methods to estimate infant drug exposure without requiring direct clinical trials. Physiologically based pharmacokinetic and population pharmacokinetic (Pop-PK) modeling are being increasingly used to predict drug transfer into breast milk and evaluate potential risks. The study presents case studies of drugs, including zuranolone (for postpartum depression), moxidectin (for river blindness), and primaquine (for malaria), in which modeling informed safety recommendations. In these cases, pharmacokinetic models were used to determine RID and assess the likelihood of adverse effects.

The researchers also noted disparities in lactation research between high-income and low- and middle-income countries (LMICs). Many LMIC regulatory agencies lack the resources to mandate lactation studies, which may lead to a reliance on data from Western populations that do not fully reflect diverse patient needs. The Maternal and Infant Lactation PharmacoKinetics program in Uganda has sought to address this gap by conducting lactation pharmacokinetic studies on antiretrovirals, tuberculosis medications, and antimalarials. Findings from these studies have contributed to World Health Organization guidelines on breastfeeding and medication use.

In the current study, investigators identified the need for early-stage lactation studies during drug development, rather than as postmarketing requirements, along with standardized methodologies for milk sampling and expanded regulatory frameworks to ensure that breastfeeding women receive evidence-based medication guidance. The researchers described the growing role of pharmacokinetic modeling in bridging data gaps, while noting that continued efforts from regulators, pharmaceutical companies, and clinical researchers will be necessary to ensure that lactating women are included in drug research.

"Breastfeeding women will continue to form a key part of all societies in the world, and remain at risk of a wide range of medical conditions requiring medication use," wrote Karen Rowland Yeo of Certara U.K. Limited (CPT Division) in Sheffield, U.K., with colleagues. The investigators further explained that "studies must be designed with the communities in mind, bring together diverse skill sets and be underpinned by strong stakeholder and community engagement."

Disclosures can be found in the study.