Preclinical assessment for translation to humans: The PATH approach for assessing supporting evidence for early-phase trials and innovative care

Early-phase trials and innovative care draw support from basic science, preclinical studies, and clinical research. Such evidential diversity presents a challenge for traditional ways of synthesizing evidence. In what follows, we review the limitations of existing approaches for communicating supporting evidence for early-phase trials. We then offer a structured approach, PATH (preclinical assessment for translation to humans). PATH is grounded in the premise that the case for administering novel strategies to patients requires connecting the dots between nine mechanistic steps supporting a clinical claim. Using PATH entails first parsing supporting evidence, assessing the strength of evidence at each step, and then assessing the strength of a chain of evidence linking drug administration to clinical effect. While PATH requires further refinement, the approach reduces some of the opacity, arbitrariness, and biases in current ways of presenting and assessing scientific support for early-phase trials and innovative care. The ethical and scientific basis of early-phase trials rests on supporting evidence from biochemical, preclinical, and clinical studies. By parsing this evidence into nine mechanistic steps, scientists can communicate the strength of support for a trial in a manner that is comprehensive, transparent, and accurate.