Non-Signaling Protein Therapeutics: A Mechanism-Based Regulatory Framework to Modernize Biosimilar Development and Global Harmonization

Abstract

Non-Signaling Protein Therapeutics (NSPTs) represent a proposed regulatory category for biological products whose therapeutic effects operate through ligand neutralization, complement cascade blockade, or other non-signal-transducing mechanisms rather than receptor-mediated signaling. These products exhibit bounded biological responses, with a direct relationship between measurable functional activity and clinical effects, making analytical and functional characterization inherently predictive of therapeutic performance. Analysis of FDA-licensed biologics identifies 43 products that meet NSPT criteria, including anti-TNF, anti-VEGF, anti-interleukin, and complement-inhibitor therapeutics. While some NSPTs have robust biosimilar competition, many high-value products lack biosimilar development despite patent expiration, creating a development gap that may affect resource allocation and patient access timelines. A comprehensive timeline documenting regulatory evolution from BPCIA enactment in 2010 through FDA draft guidance proposing elimination of default clinical efficacy study requirements illustrates a systematic progression toward evidence-efficient frameworks. The NSPT framework proposes fit-for-purpose evidence packages prioritizing comprehensive analytical characterization and mechanistic potency assays, reserving clinical studies for specific residual uncertainties. This approach aligns with FDA modernization initiatives and historical precedents demonstrating regulatory flexibility. Implementation could potentially reduce clinical trial requirements that may not add commensurate scientific value, while maintaining safety and efficacy standards. The framework proposes that NSPT biosimilars meeting analytical and functional criteria, recognizing that mechanism-based similarity supports therapeutic equivalence, may warrant consideration for interchangeability designation, subject to statutory requirements. Regulatory agencies should consider establishing NSPT classification guidelines, harmonizing international standards, and evaluating whether current evidence requirements are optimally calibrated to scientific uncertainty for these product classes.