Integrating dose estimation into a decision-making framework for model-based drug development.

Model-informed drug discovery and development offers the promise of more efficient clinical development, with increased productivity and reduced cost through scientific decision making and risk management. Go/no-go development decisions in the pharmaceutical industry are often driven by effect size estimates, with the goal of meeting commercially generated target profiles. Sufficient efficacy is critical for eventual success, but the decision to advance development phase is also dependent on adequate knowledge of appropriate dose and dose-response. Doses which are too high or low pose risk of clinical or commercial failure. This paper addresses this issue and continues the evolution of formal decision frameworks in drug development. Here, we consider the integration of both efficacy and dose-response estimation accuracy into the go/no-go decision process, using a model-based approach. Using prespecified target and lower reference values associated with both efficacy and dose accuracy, we build a decision framework to more completely characterize development risk. Given the limited knowledge of dose response in early development, our approach incorporates a set of dose-response models and uses model averaging. The approach and its operating characteristics are illustrated through simulation. Finally, we demonstrate the decision approach on a post hoc analysis of the phase 2 data for naloxegol (a drug approved for opioid-induced constipation).