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Abstract:
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Phase II proof-of-concept (POC) trials determine which therapeutic hypotheses will undergo definitive Phase III testing. The number of possible POC hypotheses likely far exceeds available public or private resources. We propose a design strategy for maximizing efficiency of POC trials that obtains the greatest knowledge with the minimum patient exposure. We compare efficiency using the benefit-cost ratio, defined to be the risk-adjusted number of truly active drugs correctly identified for Phase III development divided by the risk-adjusted total sample size in Phase II and III development. It is most cost-effective to conduct smaller POC trials which are powered at 80% on an effect size 50% larger than that of minimal clinical interest, allowing more possible POC hypotheses to be investigated under a finite POC budget constraint. We also consider parallel arrays of POC trials with multiple indications or drugs, and sequential two-stage POC trial arrays where all drugs get an initial allotment of POC trials and only those which achieve a POC get further investment. These strategies can improve the output of successful drugs by up to 30% at a constant budget.
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