Opportunities and pitfalls in clinical proof-of-concept: principles and examples.

Clinical proof-of-concept trials crucially inform major resource deployment decisions. This paper discusses several mechanisms for enhancing their rigour and efficiency. The importance of careful consideration when using a surrogate endpoint is illustrated; situational effectiveness of run-in patient enrichment is explored; a versatile tool is introduced to ensure a strong pharmacological underpinning; the benefits of dose-titration are revealed by simulation; and the importance of adequately scheduled observations is shown. The general process of model-based trial design and analysis is described and several examples demonstrate the value in historical data, simulation-guided design, model-based analysis and trial adaptation informed by interim analysis.