This guidance provides recommendations to sponsors for assessing risks to embryo/fetal development resulting from administration of an investigational active pharmaceutical ingredient (API) to males, either through an effect on the male germ cell or from seminal transfer of an API that has been shown to be genotoxic or a potent developmental toxicant when administered to pregnant animals or humans.
The guidance presents an overview of FDA’s current approach to assessing the following potential risks associated with pharmaceutical use in male patients:
- Male-mediated developmental risk involving effects of the API on the germ cell
- Developmental toxicity in the conceptus associated with transfer of the API in seminal fluid to pregnant partners
The guidance also applies to a new molecular entity for which the risk has not yet been assessed.
Specifically, the guidance discusses recommendations for examining the potential for API exposure in males to adversely affect offspring development based on the following considerations:
- Evaluation of mechanism of action, genotoxicity, reproductive toxicity, and developmental toxicity studies
- Known effects of API or pharmaceutical class in animals or humans
- Assessment of potential embryo/fetal exposure through transfer and vaginal uptake of reproductive or developmental toxicants secreted into seminal fluid
The guidance also covers overall considerations in assessing male-mediated developmental risk, including factors that investigators should consider when testing a new API in males, and recommendations on risk mitigation (e.g., measures to prevent pregnancy or seminal transfer to a pregnant sexual partner when risk is anticipated).
This guidance does not address the potential risks to partners exposed to seminal fluid transfer of an API from men taking pharmaceutical products, nor does it discuss potential effects on embryo/fetal development resulting from exposure to pregnant women via any route other than seminal transfer. It also does not specifically address potential effects on the ability of the treated population or their partners to conceive.
General guidance on assessing genotoxicity and reproductive and developmental risk is available in appropriate nonclinical guidances.