Targeting population entering phase III trials: A new stratified adaptive phase II design

Abstract

The primary goal of phase II studies is to assess the efficacy of the new treatment in order to decide whether it has sufficient activity to warrant further evaluation in a phase III comparative trial. However, many adequately conducted phase II trials are negative leading to termination of drug development. Heterogeneity of the population is often considered to be a cause of treatment effect dilution. One approach to determine the sensitive subpopulation is to conduct several phase II trials, one in each specific subset of patients. This option might unethically increase the number of non-sensitive patients under evaluation. Adaptive two-stage designs have been recently proposed. London and Chang proposed a global one-sample test for response rates for stratified phase II clinical trials, whereas Jones and Holmgren proposed an adaptive design that allows preliminary determination of efficacy that may be restricted to a specific subpopulation defined by biomarker status. These two methods do not allow early termination for efficacy in one or several subgroups as they are extensions of the Simon design. The authors propose an alternative method to deal with stratification in phase II clinical trials and identification of the best target population. This method is based on the multiple-stage Fleming design allowing for early stopping rules for either efficacy or inefficacy. It also integrates a procedure testing whether treatment effects are similar or heterogeneous between the two groups. The operating characteristics of this method were compared with those of a standard Fleming design using exact binomial probabilities.

A New Adaptive Simon-Based Design Focusing on Subpopulation Heterogeneity

“…In these trials, one reason for the lack of success is the inclusion of heterogeneous subpopulations [11]. When the drug fails to show efficacy, analyses of subgroups are performed to detect a potentially drug sensitive subpopulation.…”

“…A few adaptive designs are available, based on Fleming's design [11] and Simon's design [12]. The adaptive Simon's design developed by Jones and Holmgren is built why two hierarchical subpopulations.…”

Clinical trials in the age of personalized medicine

“…Subsequent analysis suggested that the drug might have had some success with a selected sub-population [49,50]. In light of this and other well-known phase III failures, the Task Force recommended that investigators consider stratified, adaptive designs that allow phase II trials to select a population in the course of a trial and continue study of the subpopulation in order to provide more precise indications for phase III trials [51,52].…”

Systems pharmacology, pharmacogenetics, and clinical trial design in network medicine

“…A number of statistical papers have appeared providing tools for investigators who wish to use an adaptive design in a confirmatory trial 60, 61, 68, 69 . Various classification schemes have been proposed, such as whether the adaptation affects the trial conduct or the statistical procedures; or whether the adaptation is planned prospectively, occurs in an ad hoc fashion concurrent with the ongoing trial, or is a retrospective maneuver implemented prior to database lock and unblinding of the treatment codes 62, 70, 71 .…”