Surrogate Markers in Clinical Trials

Definition & conceptual framework

• Surrogate endpoint — (Temple) a laboratory measurement or physical sign used as a substitute for a clinically meaningful endpoint that measures directly how a patient feels, functions or survives — a therapy-induced change in the surrogate is expected to reflect change in the true endpoint.
• True (clinical) endpoint — unequivocally reflects tangible patient benefit — survival, irreversible morbidity, quality of life; a surrogate is only a replacement for it, not a benefit in its own right.
• Biomarker vs surrogate — a biomarker is any intermediate measurement merely associated with a clinical outcome; it becomes a surrogate marker only when treatment-induced changes in it have consistently predicted effects on the outcome in previous trials of treatments of the same type — surrogacy is a property of the marker plus a class of interventions, not the marker alone.
• Two endpoint criteria — a primary endpoint must be (i) sensitive to treatment effect and (ii) clinically relevant; investigators reliably satisfy (i) but neglect (ii) — the whole surrogate controversy lives in chasing sensitivity at the cost of relevance.
• Stage-dependence — relevance is phase-dependent: Phase II (screening biological activity) tolerates surrogate readouts — tumour shrinkage, viral load, BP, lipids; Phase III (defining the therapy's role) should target direct efficacy — survival, irreversible morbidity, QOL.