Pharmacological therapy for acute ischemic stroke remains limited to one successful, approved treatment: tissue plasminogen activator within 3h of stroke onset. Many neuroprotective drugs and a few other thrombolytics were evaluated in clinical trials, but none demonstrated unequivocal success and were approved by regulatory agencies. The development paradigm for such therapies needs to provide convincing evidence of efficacy and safety to obtain approval by the Food and Drug Administration (FDA). The FDA modernization act of 1997 stated that such evidence could be derived from one large phase III trial with a clinical endpoint and supportive evidence. Drugs being developed for acute ischemic stroke can potentially be approved under this act by coupling a major phase III trial with supportive evidence provided by a phase IIB trial demonstrating an effect on a relevant biomarker such as magnetic resonance imaging or computed tomography assessment of ischemic lesion growth. Statistical approaches have been developed to optimize the design of such an imaging-based phase IIB study, for example approaches that modify randomization probabilities to assign larger proportions of patients to the 'winning' strategy (i.e. 'pick the winner' strategies) with an interim assessment to reduce the sample size requirement. Demonstrating a treatment effect on a relevant imaging-based biomarker should provide supportive evidence for a new drug application, if a subsequent phase III trial with a clinical outcome demonstrates a significant treatment effect.
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