Surrogate outcomes

Revised and reviewed 19 May 2014

OVERVIEW

Surrogate outcomes are biomarkers intended to substitute for a clinical endpoint and expected to predict clinical benefit or harm based on epidemiologic, therapeutic, pathophysiologic, or other scientific evidence

• surrogate outcomes are not clinically important, but are used because they are thought to predict clinically important outcomes
• much of the evidence for clinical interventions is based on surrogate outcomes, rather than outcomes that actually matter to patients
• in some cases surrogate outcomes morph into actual disease entities (e.g. hypertension)
• patient-centered outcomes are those that reflect the way a patients “feels, functions and survives”

TYPES

Surrogate outcomes may use biomarkers that are:

• causal factors — biomarkers that are involved directly in the chain of events leading to disease
• subclinical indicators – preclinical manifestations of organ damage
• correlated factors — bystanders not directly involved in the cause of a disease process, but correlate with the development, or regression, of disease

ADVANTAGES

• cheap
• available
• easily measured and monitored
• may show larger intervention effects than clinical outcomes
• may respond to interventions more quickly that clinical outcomes

DISADVANTAGES

• predicted correlation with clinically important outcomes is often not found in subsequent studies nor in the real world setting
• limited by an incomplete understanding of disease pathogenesis
• treatment of the surrogate outcome may have unintended consequences (e.g. affect other disease processes, adverse effects of medications)
• can lead to over-medicalisation of pre-disease or non-disease states
• may be misused as part of a composite outcome measure, together with clinically important outcomes, to create larger intervention effects in trials (allowing smaller, faster trials to be conducted)

USE IN HEALTH POLICY

• the use of surrogate endpoints to guide health policy is hazardous as they may not reflect what is the best interests of patients
• they may lead to distraction from patient-centered outcomes and may be subject to ‘gaming’ to meet performance indicators
• e.g. 4 hour rule, readmission rates, CLABSI rates

PROBLEMS WITH PATIENT-CENTERED OUTCOMES

• can be difficult to measure
• includes a subjective component (the way patients feel)
• they are contingent (e.g. the benefit of longevity is contingent on the quality of life associated with it)
• there may be a time lag between the intervention and the benefits (e.g. increase in lifespan)

References and Links

Journal articles

• Yudkin JS, Lipska KJ, Montori VM. The idolatry of the surrogate. BMJ. 2011 Dec 28;343:d7995. PMID: 22205706.