When the Gold Standard Meets the Living System: On the Epistemic Limits of RCT-Centered Evidence Architectures in Chronic Adaptive Biology

Abstract Evidence-Based Medicine (EBM) and randomized controlled trials (RCTs) represent one of the most consequential methodological transformations in the history of medicine. Through controlled experimentation, statistical rigor, and systematic reduction of bias, RCT-centered evidence architectures substantially improved pharmacological evaluation, clinical reproducibility, and inferential reliability across biomedical research. Yet the same methodological structures that enabled these advances may also impose selective constraints on the types of biological phenomena that become experimentally visible. This paper argues that RCT-centered evidence systems are exceptionally effective for detecting isolated intervention-dependent causal effects under stabilized experimental conditions, but may exhibit reduced sensitivity to chronic organizational states characterized by distributed causality, adaptive compensation, nonlinear regulation, multiscale feedback, and long-timescale physiological adaptation. The argument is epistemological rather than ideological: the issue is not insufficient scientific rigor, but a partial mismatch between dominant evidence architectures and the structure of chronic adaptive biology itself. Drawing from systems biology, complexity science, network physiology, philosophy of science, and chronic pain research, the paper distinguishes between localized pathological variables and system-level organizational states. It further argues that evidence hierarchies function not merely as evaluative tools, but also as epistemic selection systems that shape which forms of biological organization become experimentally legible, fundable, publishable, and clinically actionable. The paper concludes by proposing that future medical epistemology may require methodological expansion toward systems-compatible evidence architectures capable of capturing organizational dynamics alongside isolated intervention effects.