%0 Journal Article
%T Early Clinical Development Can Be Designed Around Mechanistic Falsification Instead of Sequential Confirmation
%A Emily Johnson
%A Robert Smith
%A Laura Brown
%A Kevin Miller
%J International Journal of Pharmaceutical Research and Allied Sciences
%@ 2277-3657
%D 2026
%V 15
%N 4
%R 10.51847/1dVeYH5v5F
%P 132-140
%X Early clinical development is commonly organized as an accumulation of favorable observations: adequate exposure, target engagement, pharmacodynamic activity, tolerability, and eventually evidence of clinical benefit. That sequence is operationally useful but can create an inferential problem when each positive result is treated as another layer of confirmation without specifying which mechanistic claim has actually survived a credible opportunity to fail. This Perspective proposes a different design principle. Early human development can be structured around explicit mechanistic claims that are interrogated at separable levels: whether relevant exposure is achieved; whether the intended target is engaged at the relevant site and time; whether engagement produces the predicted pharmacodynamic consequence; and whether that consequence remains meaningful in the biological and clinical context of the treated population. Under this approach, discordant evidence is used to localize uncertainty rather than being absorbed into a generally favorable narrative. Failure may implicate delivery, target engagement, pathway sufficiency, biomarker validity, disease context, dose, timing, or the therapeutic hypothesis itself. The proposed falsification-centred architecture does not constitute a prospectively validated development algorithm. Its purpose is to make early clinical programs more explicit about what individual observations can falsify, what they cannot establish, and why mechanistically positive evidence may still leave the central therapeutic hypothesis unresolved.
%U https://ijpras.com/article/early-clinical-development-can-be-designed-around-mechanistic-falsification-instead-of-sequential-co-r9qhtlcvotscyex