Maximizing Return on Investment in Phase II Proof-of-Concept Trials

Abstract

Phase II proof-of-concept (POC) trials play a key-role in oncology drug development, determining which therapeutic hypotheses will undergo definitive Phase III testing according to predefined Go–No Go (GNG) criteria. The number of possible POC hypotheses likely far exceeds available public or private resources. In this chapter, we propose to find the optimal decisions by explicitly maximizing benefit–cost ratio (aka return on investment), which is often the implicit objective in an otherwise qualitative decision-making process. The numerator of the function, in its simplistic form, represents expected number of truly active drugs identified for Phase III development, and the denominator represents the expected total sample size in the Phase II/III development so that the utility function directly measures how much a patient contributes to the development of an active drug (and its inverse measures how many patients it takes to develop an active drug). The method is easy to explain and simple to implement. Optimization of the benefit-cost ratio leads to type I/II error rates (and therefore sample size) for a trial that is most cost-effective. This in turn leads to cost-effective Go–No Go (GNG) criteria for development decisions.