Abstract
This review characterizes clinical development that supported the label dose in 60 drug indications recently approved by the US Food and Drug Administration. With Lewis B. Sheiner's Learning vs. Confirming clinical drug development paradigm as a reference point, the clinical development paths, the design of dose-ranging trials, and the dose-exposure-response characterization were examined using US Food and Drug Administration approval packages. It was found that 89% of clinical development programs included several doses in the first-in-patient trial, 43% proceeded directly to confirmatory trials after the first-in-patient trial, and 52% included multiple doses in confirmatory development. A low number of doses and narrow dose ranges were generally included in dose-ranging trials, with only 20% including at least four doses over an at least 10-fold dose range. In a third of approval packages, no dose-response or exposure-response evaluation was identified, and model-based dose-exposure-response characterization was rarely alluded to, as only 2 of 60 approval packages mentioned the use of a model-based approach. The findings suggest that confirmatory development may often be guided more toward learning than confirming, and furthermore that dose exposure response is robustly assessed in only a minority of clinical drug development programs, indicating that there may be room left for optimizing the benefit/risk profile of confirmatory/marketed dose(s). Significant deviation from Learning vs. Confirming may exist in clinical development practice on several levels, and the reasons for why this may be the case are discussed in light of contemporary literature.