Non-signaling protein therapeutics (NSPT) are biological products whose effect consists of ligand neutralization, complement blockade, or other mechanisms without direct signaling action on cells. The 43 FDA-approved products that meet NSPT criteria include anti-TNF, anti-VEGF, and anti-interleukin therapeutics. Analytical and functional characterization of these products is inherently predictive of their therapeutic performance due to the direct relationship between measurable functional activity and clinical effects. The proposed regulatory framework favors comprehensive analytical characterization and mechanistic efficacy tests over clinical trials, which should only be conducted under specific uncertainties. This approach could potentially reduce clinical trial requirements without compromising safety and efficacy. Regulatory agencies should consider creating guidelines for the classification of NSPT and harmonizing international standards for these products.