Structural Misalignment Between Regulatory Definitions of BCG-Unresponsive Non-Muscle-Invasive Bladder Cancer and...

Background: Definitions of BCG-unresponsive non-muscle-invasive bladder cancer (NMIBC) have become central to therapeutic decision making and clinical trial eligibility. This perspective synthesizes regulatory frameworks with real-world observations to examine how structural conditions shape the applicability of current definitions. These definitions rely on structural prerequisites-adequate BCG exposure, routine maintenance therapy, standardized surveillance, timely access to early radical cystectomy, and complete tumour-level documentation-that are not consistently achievable across diverse health-care environments. This study examines the structural and operational factors that limit the applicability of current BCG-unresponsive criteria in real-world NMIBC care. Methods: A multilevel analysis was performed and integrated four complementary sources of evidence-regulatory frameworks, national claims datasets, multicenter clinical studies, and real-world practice observation-selected for their ability to capture distinct structural dimensions of NMIBC care. Operational assumptions embedded in contemporary definitions were compared with real-world treatment patterns. Structural barriers were categorized across macro-level system constraints, meso-level institutional practices, and micro-level clinical workflows. Results: As a result, a substantial proportion of patients cannot be classified under existing criteria because the exposure-based and time-dependent conditions required by regulatory definitions are not met in routine practice. Maintenance BCG is infrequently delivered, surveillance intervals vary widely, early radical cystectomy is limited by system-level and institutional factors, and key tumour-level variables required for classification are often missing in large-scale datasets. As a result, many patients cannot be reliably classified using existing criteria-not because of tumour biology or clinician behavior, but because the structural assumptions underlying the definitions are unmet. Conclusions: Current BCG-unresponsive criteria rely on structural conditions that are not universally present in real-world NMIBC care. These findings suggest that context-specific operational definitions, together with complementary strategies such as improving guideline implementation, enhancing data completeness, standardizing surveillance practices, and strengthening healthcare infrastructure, may help align regulatory expectations with real-world practice and support equitable access to bladder-sparing therapies.