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Despite their foundational role, these studies are increasingly marginalised in today\u2019s drug development environment due to economic pressures, regulatory conservatism, and an overemphasis on statistical endpoints from large-scale trials. This article traces the historical roots and enduring value of experimental medicine, distinguishes it from current early phase drug development studies, and explores the structural forces behind its decline. N-of-1 trials are discussed as a systematic extension of these principles, offering precision insights at the individual level. We apply this discussion to chronic kidney disease (CKD), a field where slow progression and heterogeneous pathophysiology make early mechanistic studies especially valuable. We argue that bypassing such studies in favour of speed represents a strategic gamble that may misdirect costly late-phase trials. Integrating mechanistic insights with statistical power is not superfluous, but essential, particularly in complex diseases like CKD where understanding why and how interventions work may matter as much as whether they do. We acknowledge that achieving this vision necessitates overcoming significant structural, economic, and cultural barriers within the current drug development environment; however, the costs of inaction, manifest as trial failures, patient harm, and missed therapeutic opportunities, are potentially much greater.<\/jats:p>","DOI":"10.1007\/s00424-026-03184-x","type":"journal-article","created":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T03:32:49Z","timestamp":1780543969000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["First-in-human to proof-of-concept: why experimental medicine studies remain essential in human physiology and drug development"],"prefix":"10.1007","volume":"478","author":[{"given":"Robert J.","family":"Unwin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Challis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carsten","family":"Wagner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovambattista","family":"Capasso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Carlsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,4]]},"reference":[{"key":"3184_CR1","doi-asserted-by":"publisher","first-page":"2219","DOI":"10.1056\/nejmoa2025845","volume":"383","author":"GL Bakris","year":"2020","unstructured":"Bakris GL, Agarwal R, Anker SD, Pitt B, Ruilope LM, Rossing P, Kolkhof P, Nowack C, Schloemer P, Joseph A, Filippatos G, Investigators F-D (2020) Effect of Finerenone on Chronic Kidney Disease Outcomes in Type 2 Diabetes. 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