PerspectiveOptimizing phase II of drug development for disease-modifying compounds

Phase II proof of concept (POC) (IIa) and dose-finding (IIb) studies represent major challenges in drug development. Prolonged development times delay effective therapies from reaching patients in need and adversely affect industry goals of decreasing time to market. Biomarkers including magnetic resonance imaging, cerebrospinal fluid tau and amyloid β, and amyloid positron emission tomography have been considered as alternative outcomes to clinical measures. None of these is yet validated. Population enrichment is another possible solution to POC studies. More rapid progression to prespecified milestones can be achieved by enriching the population with risk factors. Conclusions based on enriched populations must be extrapolated with caution. Clinical measures with greater sensitivity than standard trial instruments might represent another strategy applicable to POC studies. Adaptive dose-response designs are being considered as a means of shortening phase IIb studies and creating a seamless interface with phase III. None of these strategies have been validated in a successful drug development program; all have some promise for reforming phase II and answering the central question of “how much information is sufficient to proceed to phase III without excessive risk for failure?”