Male premating treatment in FEED studies: Length is not everything

Area of Science:

• Reproductive toxicology
• Drug development
• Regulatory science

Background:

• The ICH S5(R3) guideline suggests a minimum 2-week premating treatment for male rodents in FEED studies.
• This duration is considered potentially inadequate for detecting all male reproductive effects.
• Longer treatment periods are often employed in practice.

Purpose of the Study:

• To evaluate the frequency of 2-week male premating treatment periods in recent FDA-approved drug FEED studies.
• To assess the adequacy of the 2-week period based on regulatory and scientific considerations.

Main Methods:

• Review of FDA drug approvals in 2022 and 2023.
• Analysis of specified male premating treatment durations in Fertility and Embryo-fetal Development (FEED) studies.
• Literature search for studies comparing different premating treatment durations.

Main Results:

• Only 16% of 44 reviewed drugs used a 2-week male premating treatment.
• 52% of drugs utilized a 4-week premating treatment period.
• No evidence found that a 4-week period detected effects missed by a 2-week period, suggesting potential redundancy.

Conclusions:

• A 2-week premating treatment may be sufficient if repeat-dose studies show no male reproductive organ effects.
• If repeat-dose studies reveal spermatogenesis toxicity, the FEED study's utility is limited.
• Disruptions in spermatogenesis are considered relevant to human health regardless of FEED study outcomes.