Should Randomized Clinical Trials Remain the Primary Evidence for Evaluating New Therapeutic Regimens in Leprosy? Introducing Deep Phenotyping Real-World Evidence (DP-RWE) as a Methodological Framework

Leprosy remains a major cause of peripheral neuropathy and permanent disability, with current multidrug regimens challenged by toxicity, treatment duration, and relapse. Although therapeutic innovation is an urgent priority, conventional Phase III randomized controlled trials (RCTs) face substantial economic, logistical, and ethical constraints in neglected diseases, while routine Real-World Evidence (RWE) lacks granular biological resolution. To bridge this gap, this Perspective introduces Deep Phenotyping Real-World Evidence (DP-RWE), a standardized clinical research framework integrating Deep Phenotyping and RWE into a prospective, longitudinal architecture for therapeutic evaluation under routine clinical conditions. Built upon four core principles: Standardization, Deep Phenotyping (DP), Longitudinal Assessment, and Real-World Applicability, the framework organizes prospective clinical, microbiological, histopathological, molecular, immunological, neurophysiological, and imaging domains tailored to specific therapeutic questions. Grounded in over two decades of reference-center cohort research, DP-RWE demonstrates that longitudinally integrating multimodal biomarkers captures distinct biological dimensions of therapeutic response, therapeutic failure, and relapse under real-world practice. Ultimately, DP-RWE does not replace RCTs but complements them, establishing a reproducible, biologically informative pathway to evaluate innovative therapeutic regimens and advance precision medicine in endemic regions.