Physical feasibility gating in early drug discovery: a decision framework for identifying predictable physical failures, with retrospective illustration

Abstract

Clinical drug development is characterized by high attrition rates: approximately 90% of candidates entering Phase I fail to obtain approval. Inadequate efficacy accounts for 40 to 50 percent of terminations in Phase II and Phase III, while safety concerns account for roughly 30 percent. Most efficacy failures result from incorrect biological hypotheses rather than physicochemical deficiencies: drugs frequently bind their intended targets but fail to alter disease progression because the mechanistic assumptions underlying their action are invalid. This perspective introduces a feasibility-gating framework that utilizes physical constraints as explicit, early-stage filters. The framework does not claim that physics alone can predict therapeutic success; rather, it asserts that a systematic evaluation of thermodynamic, kinetic, transport, and microenvironmental constraints can identify candidates likely to fail on physical grounds prior to substantial investment in synthesis and translational research, thereby conserving resources for the inherently experimental validation of biological hypotheses. The individual constraints are based on well-established pharmacological principles; their contribution lies in organizing these principles into a checklist-style decision logic with specific thresholds, explicit guidance on interpreting each threshold, and a clear connection to quantitative systems pharmacology (QSP) and physiologically based pharmacokinetic (PBPK) modeling. We position this framework relative to these established quantitative disciplines, implement each gating criterion, and demonstrate the logic retrospectively using documented development histories. Physical reasoning serves as an essential yet limited filter: it identifies certain predictable physical risks early in the development process without guaranteeing success for candidates that pass through.