Table 2—

Phases of marker validation process for therapeutic trials(modelled on 35)

Phase 1Natural history markerDemonstration of relationship between frequency/magnitude of marker and clinical outcomes
Reflect underlying disease mechanisms
Predict clinical outcomes independent of treatment
Phase 2Biological activity markerPhase I/II trials demonstrating appropriate effects on the marker with therapeutic intervention
Responds to therapy
Change in frequency/magnitude of marker corresponds with therapeutic potencyDose-dependent effects of treatment on the marker
Phase 3Marker of therapeutic efficacyDemonstration that the marker predicts clinical outcomes and responds to therapy in outcome trials
An early change in the marker predicts clinical outcome in the context of active therapy
Ideally, marker could be used as a surrogate endpoint for clinical outcomesValidation should establish whether the marker is applicable to all disease stages and all interventions