The 0.7% likelihood of approval for novel analgesics from Phase I represents a systemic crisis hindering resolution of the global opioid epidemic and economic burden. This study identifies causes of this stagnation through a dual–faceted analysis of regulatory trends in Japan and global clinical trial failures between 2015 and 2025. Analysis of the Pharmaceuticals and Medical Devices Agency (PMDA) database revealed approximately 95% of primary endpoints in successful applications rely on unidimensional subjective pain intensity scores, whereas multi–faceted functional indicators represent approximately 5%. Concurrently, global data from Pharmaprojects identified an "Efficacy Wall", with failure rates of 63.4% in Phase II and 56.3% in Phase III. The predominant cause of late–stage discontinuation was a lack of efficacy, suggesting that subjective metrics are insufficient to distinguish therapeutic signals from variable placebo responses amidst high intra–individual variability. To revitalize the pipeline, we propose a paradigm shift focused on four strategic pillars: prioritizing multi–faceted functional outcomes aligned with international bio–psycho–social guidelines, integrating objective biomarkers, such as those monitored via electroencephalography (EEG), to mitigate subjective noise, implementing precision medicine through phenotyping utilizing frameworks such as the ICD–11 to identify high–responder populations, and utilizing real–world data (RWD) to manage the prohibitive costs of extended trials. Furthermore, we emphasize redefining the placebo effect as an endogenous pharmacological mechanism, particularly for evaluating digital therapeutics. Harmonizing these objective and multi–dimensional approaches with regulatory science is essential to bridge the gap between biological innovation and clinical approval, ensuring transformative non–opioid treatments reach patients worldwide.
Nakae et al. (Fri,) studied this question.