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Novel methodologic approaches to phase I, II, and III trials.

Among the future directions of stroke research identified by the Stroke Progress Review Group was a call for improved trial design, conduct, and outcome assessment. This demand is underscored by recent trial findings. Of the >100 clinical trials in ischemic stroke published during the first decade of the 21st century, only 5 of 31 phase III trials demonstrated efficacy on the primary outcome.1 As the number of experimental therapies undergoing clinical investigation in stroke increases, there is a rising need for more efficient statistical designs to (1) determine the optimal dose, (2) identify interventions with therapeutic potential, and (3) evaluate clinically relevant treatment effects.

The correct selection of the optimal dose, via a thorough understanding of the dose–toxicity and dose–efficacy relationships, is critical for establishing the efficacy of a potential therapeutic agent.2 Traditional rule–based dose-escalation designs,3 such as the 3+3 design and its variations, have suboptimal statistical operating characteristics. The inefficiency in the 3+3 design is that it stems from the decision to escalate or de-escalate, a decision is based solely on event data from the current dose, without considering event information available from neighboring doses. An alternative design called the Continual Reassessment Method4 is an adaptive dose-finding algorithm, wherein escalation or de-escalation through the dose region is determined by continuous re-estimation of the dose–toxicity curve, and each cohort of subjects is treated at the dose currently believed to be the maximum tolerated dose. Although computationally more intensive than the 3+3 design, the Continual Reassessment Method and its variations use all available toxicity data in the estimation of the maximum tolerated dose, and thus are statistically more efficient. Ethical considerations also favor the Continual Reassessment Method, because the Continual Reassessment Method typically treats fewer patients at subtherapeutic doses.

Once the appropriate dose has been determined through …