Dose Finding in the Clinical Development of 60 US Food and Drug Administration-Approved Drugs Compared With Learning vs. Confirming Recommendations
- This review evaluates the current practice of dose finding in the pharmaceutical industry and assesses the clinical evidence supporting the optimality of the label dose.
- Previous work has focused on dose-ranging trial design, while clinical development paths and dose–exposure–response characterization for label-dose identification have not been reviewed.
- Dose finding is not confined to a single trial, phase, or development stage.
- There is a significant discrepancy between drug development theory (Learning vs. Confirming) and current clinical drug development practice.
- Evidence of this discrepancy includes:
- Frequent inclusion of multiple active doses in FIP trials.
- Common inclusion of multiple active doses in confirmatory development, indicating a learning approach rather than a confirming approach.
- Low number of active doses and narrow dose ranges in dose-ranging trials, which affects the extent of learning and the application of model-based analysis.
- Lack of formal dose–exposure–response characterization by statistical models to inform dose selection, raising questions about the benefit/risk optimality of confirmatory/marketed doses.
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...
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