Sensitivity of male reproductive endpoints in nonhuman primate toxicity studies: a statistical power analysis

Area of Science:

• Toxicology
• Reproductive Toxicology
• Non-human Primate Studies

Background:

• Assessing male reproductive toxicity is crucial in non-human primate (NHP) safety studies.
• Standard endpoints may lack the sensitivity to detect subtle adverse effects.
• Understanding the power of existing endpoints informs study design and interpretation.

Purpose of the Study:

• To evaluate the statistical power of routine and triggered male reproductive toxicity endpoints in NHPs.
• To determine the group size required for detecting specific effect sizes with adequate power.
• To assess the sensitivity of various endpoints, including organ weights, testicular volume, seminal parameters, and hormone levels.

Main Methods:

• Power analysis was conducted using control data from sexually mature Asian and Mauritian NHPs.
• The analysis focused on the ability to detect a 50% change from control values.
• Evaluated endpoints included male reproductive organ weights, testicular volume, seminal analyses, and serum hormone levels.

Main Results:

• Power to detect a 50% change was low across most endpoints with a group size of 3 NHPs (e.g., 13-30% for organ weights, ~30% for testicular volume).
• Seminal analyses (6-66%) and male hormone levels (10-78%) showed variable but generally insufficient power.
• Overall, current male reproductive endpoints exhibit poor power (<80%) to detect significant changes with small group sizes.

Conclusions:

• Standard male reproductive toxicity endpoints in NHPs have limited sensitivity for detecting adverse effects, especially with small group sizes.
• Confidently identifying male reproductive toxicity likely necessitates specialized study designs with larger sample sizes.
• Triggering non-routine endpoints in specific cases may not substantially enhance the sensitivity for detecting adverse male reproductive effects.