Research Scientist PPD a Part of Thermofisher, United States
Background: In the last decade, development and approval of biologics has increased exponentially. Combined with the FDA’s increased emphasis on monitoring safety during pregnancy and lactation, we anticipate increased post-marketing requirements for lactation studies involving biologics. Though the FDA has released general guidance for lactation studies, there are unique challenges for studies of biologics that are not addressed.
Objectives: To describe design challenges for lactation studies involving therapeutic biologics
Methods: We examined recent lactation studies involving biologics and summarized considerations for study design and implementation.
Results: Biologics have unique characteristics that pose special challenges for the design and conduct of lactation studies.
Long half-life and steady state sampling: The FDA recommends sampling at steady state for medications that are administered chronically. This necessitates the use of patient populations instead of healthy volunteers, which can lead to recruitment challenges. Biologics typically have long half-lives, which extends the time required to reach steady state. This may also hinder recruitment, since steady-state may not be reached by the time the mother planned to stop breastfeeding.
Uncertainty around Cmax and Tmax: The literature to-date on the PK of biologics in breast milk continues to show variation in peak concentration (Cmax) and time to peak concentration (Tmax). The literature suggests that biologics likely transfer to breast milk, but at very low levels. However, higher concentrations and accumulations have also been reported. The variability in the literature may be due to variation in sampling schemes, study populations, therapeutic targets and mechanisms, and/or assay sensitivity. Unfortunately, this uncertainty makes it difficult to estimate optimal sampling time points.
Special risks for breastfed infants: Use of biologics and immunomodulatory medications in breastfeeding mothers poses risks to breastfed infants with developing immune systems. Infants rely on mothers for passive immunity, and maternal immune systems altered by exposure to biologic products can have detrimental secondary impacts on the infant. Infants may also endure direct negative impacts due to contact between breast milk containing biologics and the gut which is an important part of the immune defense system. Lactation studies with biologics are more likely to have additional reporting requirements for the infant and can be more difficult to recruit for.
Conclusions: Lactation studies need to be thoughtfully designed to optimize the data collected. Biologics present several additional challenges that need to be considered.
