The past is the future: innovative designs in acute stroke therapy trials.

Section Editors: Marc Fisher MD Antoni Davalos MD More than 74 000 patients with acute ischemic stroke have been randomized into clinical trials over the past 35 years to investigate new therapies.1 Only one treatment, thrombolysis with recombinant tissue plasminogen activator, has emerged from these investigations.2 Efforts to establish acute neuroprotectant therapies have yet to succeed.3,4 Have we squandered our resources? Has methodological rigidity delayed development of a new treatment or prolonged investigation of an ineffective therapy? Here we present a flexible and more efficient approach to clinical trial design and analysis. We have the potential to improve the use of scarce patient resources and to accelerate development of promising agents. In medical practice, we respond to a patient if a dosage seems inadequate by either changing the dosage or switching to another medication. We cautiously change treatment after reviewing new evidence: side effects, intractable symptoms, and poor adherence. We might express our estimate of how much the change may improve the patient’s condition in terms of probability. We repeat this process every time we update the treatment plan in light of new important information. Why not take the same approach to clinical trials? The proposed approach to the design and conduct of clinical trials uses Bayesian methods that make careful use of high-quality available past (prior) evidence to refine the inference from accumulating evidence in the ongoing clinical trial. This approach may: (1) enhance investigation of single agents or combination therapies; (2) make earlier and more reliable choices of dose for use in pivotal trials; (3) accelerate the progression from phase II into phase III trials all the way to a potentially seamless switch; and (4) treat trial participants more effectively by adaptively allocating more resources to therapies that are performing well while reducing support for …