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. 2013 Nov;36(2):597-604.
doi: 10.1016/j.cct.2013.05.001. Epub 2013 May 8.

A Review of Phase II Trial Designs for Initial Marker Validation

Free PMC article

A Review of Phase II Trial Designs for Initial Marker Validation

Sumithra J Mandrekar et al. Contemp Clin Trials. .
Free PMC article


Phase II clinical trials aim to identify promising experimental regimens for further testing in phase III trials. In this review article, we focus on phase II designs for initial predictive biomarker validation to determine if a drug should be developed for an unselected patient population or for a biomarker-defined patient subset only. Several prospective designs for biomarker-directed therapy have been proposed, differing primarily in the study population, or randomization scheme, or both. The design choice is driven by scientific rationale, marker prevalence, strength of preliminary evidence, assay performance, and turn-around times for marker assessment. The enrichment design is most appropriate when compelling preliminary evidence suggests treatment benefit in only certain marker-defined subgroups, the all-comers design is useful when preliminary evidence regarding treatment effects in marker subgroups is unclear, and adaptive designs have the most potential in the setting of multiple treatment options and multiple marker-defined subgroups. We recently proposed a 2-stage phase II design that has the option for direct assignment (i.e., stop randomization and assign all patients to the experimental arm in stage 2) based on interim analysis (IA) results. This design not only recognizes the need for randomization but also acknowledges the possibility of promising but inconclusive results after pre-planned IA. Simulation studies demonstrated that the direct assignment-option design has minimal power loss, marginal increase in type I error rates, and reasonable robustness to population shift effects. Systematic evaluation and implementation of these design strategies in the phase II setting are essential for accelerating the clinical validation of biomarker guided-therapy.

Keywords: Adaptive design; All-comers design; Biomarker; Direct assignment; Enrichment design; Interim analysis.

Conflict of interest statement



Figure 1
Figure 1. Example of a Biomarker strategy Phase II design
*Stratification factors: ECOG performance status (0,1 versus 2); Age (≤75 versus > 75)
Figure 2
Figure 2. Direct Assignment option Design with a single pre-planned interim analysis for one biomarker defined subgroup
Square brackets [] indicate number of patients enrolled at the given stage. R: randomize; N: total number of patients allocated at start of trial; p1: p-value based on interim analysis patient data; c1, c2, and d: O’Brien-Fleming stopping boundaries (d is the overall trial efficacy boundary)
Figure 3
Figure 3. Direct Assignment option Design with 2 planned interim analyses (IA), with an option for direct assignment at each analysis for one biomarker defined subgroup
Fut: futility; eff: efficacy; dir: direct; rand: randomize c1, c2, c3, c4 (=c2), c5 (=c7), c6, c7: O’Brien-Fleming stopping boundaries

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