Cut point validation vs. real-world performance: the ultra-low cut point dilemma

Cut point determination is a critical component in the development and validation of antidrug antibody (ADA) assays, directly influencing the assessment of immunogenic responses. Removal of analytical and biological outliers from employing Tukey's outlier test may lead to reduced variability and consequently low or ultra-low cut points (ULCPs, defined here as signal-to-noise ratios ≤1.10). Such ULCPs raise concerns about assay reliability and the potential for elevated false-positive rates. To evaluate this, we analyzed ADA studies from two contract research organizations employing ULCPs. Given the heightened assay sensitivity from modern platforms and reagents, our findings indicate that ULCPs do not inherently compromise ADA assay performance or reliability. These results support the continued use of ULCPs when appropriately validated and statistically justified.