Male premating treatment in FEED studies: Length is not everything

Abstract

The ICH S5(R3) guideline recommends that male rodents in a FEED study are treated for ≥2 weeks before mating, which has frequently been criticized as being too short for the detection of all effects on sperm maturation, mating behavior and male fertility. In a FEED study, males generally continue for ≥5 weeks after the start of cohabitation. This review determines how often a 2-week premating treatment period for males was used in FEED studies of novel drugs approved by the FDA in 2022 and 2023. The male premating treatment duration was specified for 44 drugs. Only 16 % of these had a 2-week male premating treatment period. 52 % of drugs had a 4-week period. No examples were found in the literature of drugs for which male-mediated reproductive toxicity could have been detected using a 4-week, but not a 2-week, premating treatment period. Repeat dose studies in 2 species, with a duration of treatment at least equivalent to that in patients, are generally completed before the FEED study is planned. Providing no effects on male reproductive organs are detected in the repeat dose studies, a 2-week premating treatment period appears sufficient for the detection of effects on male mating performance. If toxic effects on spermatogenesis are detected in the repeat dose studies, a male FEED study serves little regulatory purpose. Even in the absence of effects on mating performance and fertility in the FEED study, a drug-related disruption of spermatogenesis would likely be considered pertinent to the human.