An important issue is the choice for the next step after completion of phase 1 clinical trials—in particular, when there is uncertainty about the reliability of biomarkers in the evaluation of proof of concept, or when the phase 1 trial provides highly promising results. We consider the merits of conducting phase 2b screening trials to evaluate the effect of the treatment regimen on the same clinical endpoint that will be the primary endpoint in a phase 3 trial. Such a trial provides a measured next step to efficiently screen out ineffective regimens, to provide reliable leads regarding promising interventions, and to provide compelling evidence of benefit for highly effective therapies. The phase 2b trial also provides important insights about trial design and infrastructure preparedness if a confirmatory phase 3 trial would be required.