Immune responses to therapeutic protein products have the potential to affect product pharmacokinetics, pharmacodynamics, safety, and efficacy. Detection and analysis of Anti-Drug Antibody (ADA) formation is a helpful tool in understanding potential immune responses. In January 2019, FDA published guidance on the development and validation of ADA assay. This talk will present the newly developed Pfizer-wide best practice for the cut points determination for the screening and confirmatory steps in the multi-tier ADA detection assays. Three innovations incorporated in this new paradigm will be described and justified: 1) instead of relying on statistical outlier procedures, we rely on assay characteristics to identify and remove naive samples with “pre-existing reactivity” or “nonspecific binding”; 2) instead of searching among parametric models via p-values, we use robust modern nonparametric method that takes into consideration that each sample is tested multiple times during cut point experiments; 3) we use specially designed graphs to present the data, along with other scientific context, such as minimum cut point suggested by assay precision and maximum cut point suggested by positive controls, which enables the final discussion with clinical team or regulatory agency to combine clinical context with assay capability. Several real case studies will be used to illustrate the new approach and its benefits.