Doubly randomized delayed-start design for enrichment studies with responders or nonresponders.

High placebo response has been a major source of bias and is difficult to deal with in many central nervous system (CNS) clinical trials. This bias has led to a high failure rate in mood disorder trials even with known effective drugs. For cancer trials, the traditional parallel group design biases the inference on the maintenance effect of the new drug with the traditional time-to-treatment failure analysis. To minimize bias, we propose a doubly randomized delayed-start design for clinical trials with enrichment. The design consists of two periods. In the first period, patients can be randomized to receive several doses of a new drug or a control. In the second period, control patients of the first period of an enriched population can be rerandomized to receive the same or fewer doses of the new drug or to continue on the control. Depending on the clinical needs, different randomization ratios can be applied to the two periods. The essential feature is that the design is naturally adaptive because of the randomization for the second period. As a result, other aspects of the second period, such as the sample size, can be modified adaptively when an interim analysis is set up for the first period. At the end of the trial, response data from both randomizations are combined in an integrated analysis. Because of the enrichment in the second period, the design increases the probability of trial success and, in addition, reduces the required sample size. Thus, for clinical development, the design offers greater efficiency.

A meta-analytic approach to an integrated summary of efficacy: a case study of becaplermin gel.

This paper presents a case study involving a meta-analytic approach for an integrated summary of efficacy based upon four phase II and III clinical trials that comprised the basis for a Biologics License Application to the U.S. Food and Drug Administration for approval of becaplermin gel. There were substantial variations in observed response rates across the four studies that were of concern to regulatory agencies. Due to these variations and because there were various treatment combinations in the four trials, standard statistical methods for an integrated analysis of efficacy were problematic. A meta-analytic model that focused on the variations of concern was employed to permit a suitable integrated analysis. The resulting integrated analysis clarified response rate variability and provided accurate estimates of treatment effects based upon the four clinical trials. While this meta-analysis was viewed by neither regulators nor the sponsor as a confirmatory analysis, it was seen by both regulators and sponsor as strongly supportive of the efficacy of becaplermin gel.