Table 1. Main study designs for predictive marker validation.

Design	Description
Unselected or all-comers
Sequential testing strategy	The compound is first tested in the overall population and then in the marker-defined subpopulation or vice versa, according to the strength of preliminary data
Marker by treatment interaction	The marker is used as a stratification factor upfront: the overall study population is divided into two groups according to the marker status and each subpopulation is equally randomised to the experimental versus control arm
Marker-based strategy	Patients are randomly assigned to receive their treatment either based on the biomarker status or not; thus, determining a significant overlap of patients treated with the same regimen in both the biomarker-based and non-biomarker-based arm
Targeted or enrichment	All patients are screened for molecular alteration but only the subpopulation who either express a specific molecular alteration or not are enrolled in the clinical trial to assess the safety, tolerability and clinical benefit of a specific treatment
	This design requires well-established assay reproducibility and accuracy and early evidence of benefit
Hybrid	Only the marker-defined subgroup is randomly assigned to have the treatment based on that marker, the others subgroups are assigned to the standard of care
	It is similar to the enrichment design but also includes the non-marker-defined subgroup; thus, being the preferable choice when there is prior evidence of marker-based treatment