Surrogate Markers in Clinical Trials

Surrogate Markers in Clinical Trials

1. Definition & conceptual framework

• A surrogate endpoint (surrogate marker) of a clinical trial is, in Temple's regulatory definition, "a laboratory measurement or a physical sign used as a substitute for a clinically meaningful endpoint that measures directly how a patient feels, functions or survives" — changes induced by therapy on the surrogate are expected to reflect changes in the clinically meaningful endpoint (Ch-74 Surrogate Endpoints, pp.878–9).
• A true (clinical) endpoint unequivocally reflects tangible benefit to the patient — survival, irreversible morbidity, quality of life (QOL); a surrogate is only a replacement for that true endpoint, not a benefit in its own right (Ch-74, pp.878–9).
• Biomarker vs surrogate (hierarchy): a biomarker is any intermediate measurement, typically in a biologic sample, that is associated with a clinical outcome (e.g. a falling white-cell count tracking resolution of pneumonia). A biomarker becomes a surrogate marker only to the extent that treatment-induced changes in the marker have consistently predicted effects on the clinical outcome in previous trials of treatments of the same type — surrogacy is a property of the marker plus a class of interventions, not of the marker alone (Browner 5e Ch.11, p.6–7; Califf, Exp Biol Med 2018 [PMID:29405771]).
• Two criteria should guide primary-endpoint selection: the endpoint must be (i) sensitive to treatment effects and (ii) clinically relevant. Investigators reliably satisfy (i) but frequently neglect (ii); the entire surrogate-endpoint controversy lives in the gap created by chasing sensitivity at the cost of clinical relevance (Ch-74, p.878).
• Stage-dependence of relevance — what counts as a relevant endpoint depends on the phase of experimentation:
  • Phase II (screening for biological activity): tumour shrinkage in cancer, viral load or immune-function measures in HIV, blood pressure or lipid levels in cardiovascular disease are all appropriate biological-activity readouts (Ch-74, p.878).
  • Phase III (defining the therapy's role in practice): the primary objective should be direct clinical efficacy — duration of survival, irreversible morbidity, QOL (Ch-74, pp.878, 885).
• Surrogates are attractive precisely because measures of biological activity are readily available early in a trial and are often strongly correlated with clinical efficacy — but availability + correlation are necessary, not sufficient, for valid substitution (Ch-74, p.879).