Table 1.

Considerations for the choice of phase II design for initial validation of predictive marker [Adapted from Mandrekar et al. (32)]

Considerations	Phase II design for initial marker validation
	Enrichment/Targeted	All-comers/unselected	Direct assignment option	Outcome based adaptive randomization
Preliminary evidence
Strongly suggest benefit in marker defined subgroups	Appropriate	Not recommended	Appropriate (with an early single IA, or two IA with option for direct at both IA)	Appropriate (assess multiple treatments/biomarker subgroups)
Uncertain about benefit in overall population versus marker defined subgroups	Not appropriate	Appropriate	Appropriate (direct assignment option within the biomarker positive and negative cohorts)	Appropriate (learn and adapt as the trial proceeds)
Assay performance
Excellent (high concordance between local and central testing; commercially available kits; well established marker cutpoint etc.)	Required	Appropriate	Required	Required
Questionable	Not recommended	Appropriate	Not applicable	Not applicable
Turn-around times
Rapid (2–3 days; without causing delay in the start of therapy)	Optimal	Optimal	Optimal	Optimal
Slow to modest (one week or more)	Not recommended	Appropriate (retrospective marker subgroup assessment)	Appropriate in some cases	Appropriate in some cases
Marker prevalence
Low (<20%)	Optimal	Not recommended	Appropriate (with an early single IA, or two IA with option for direct at both IA)	Appropriate
Moderate (20–50%)	Appropriate	Appropriate (stratified by marker status)	Appropriate, with two IA with direct assignment option only at the second IA	Appropriate
High (>50%)	Appropriate	Appropriate	Appropriate	Appropriate

IA, interim analysis.