The Erosion of Proof in Paradigm Transitions: The Rise of Narrative Rationality in Health Technology Assessment.

OBJECTIVE: To describe and characterize three partly coexisting evidentiary configurations in drug regulation and health technology assessment (HTA), and to examine the inferential consequences of the progressive shift from replication-based to coherence-oriented standards of proof. STUDY DESIGN AND

SETTING: Conceptual and methodological commentary drawing on regulatory history, published methodological and epidemiological literature, documented empirical trends in regulatory approval patterns, and illustrative regulatory cases. Three evidentiary configurations are formally defined and compared: the two-trial paradigm, the one-trial paradigm, and a narrative regime characterized by coherence-based justification when independent experimental replication is limited or absent.

RESULTS: The two-trial paradigm emerged from the post-Kefauver-Harris regulatory emphasis on adequate and well-controlled investigations and was consolidated in U.S. FDA regulatory practice in the late 1980s and 1990s. Under realistic prior assumptions, this configuration may yield a posterior probability of false positive finding (PPFP) of approximately 0.3%. The one-trial paradigm was further legitimized by the FDA Modernization Act (1997), which allowed one adequate and well-controlled trial to be supported by confirmatory evidence, with estimated PPFPs of approximately 4-9% under comparable assumptions. A third configuration, here termed the narrative regime, has expanded progressively through accelerated approval pathways, surrogate endpoint reliance, single-arm trial designs, external controls, real-world evidence, and extrapolation strategies; under this configuration, PPFP may increase further (potentially >15-20%), depending on the prior probability, endpoint validity, and study design. Published trends document a decline in FDA approvals supported by at least two pivotal randomized trials, from 80.6% in 1995-1997 to 52.8% in 2015-2017. The development pathway of subcutaneous belimumab in pediatric systemic lupus erythematosus illustrates how replication-based evidence may be supplemented by pharmacokinetic bridging and extrapolation in selected settings. Regulatory agencies, HTA bodies, and guideline-development organizations operate under partly distinct institutional mandates and apply these configurations with different evidentiary thresholds and decision purposes.

CONCLUSION: Maintaining the critical function of HTA requires flexible evidentiary frameworks to preserve independent comparative evaluation, analytical transparency, and explicit management of uncertainty. Without such safeguards, coherence-based inference may shift evidentiary standards toward plausibility and institutional acceptability rather than empirical testing. This shift should therefore be understood as a transformation in evidentiary standards, not merely as a technical adaptation of study designs.