Surrogate End Points in Clinical Trials¶
Fleming, T. R., & DeMets, D. L. (1996). Surrogate End Points in Clinical Trials: Are We Being Misled?. Annals of Internal Medicine, 125(7), 605-613.
Cited by¶
5 citations across 5 artifacts.
Each citation links to the sentence it supports in the citing article.
Primes¶
- Construct Validity
- And in clinical measurement, the question is whether a marker measures the disease or a correlated downstream effect that can respond to treatment without the disease responding — the structure behind many surrogate-endpoint failures.
This sourceShows surrogate endpoints can move while the underlying clinical construct does not, the canonical surrogate-endpoint failure.
SupportedVerified against the publisher's abstract
Fleming and DeMets set the requirement that "effects of the intervention on the surrogate must reliably predict the overall effect on the clinical outcome", and report that "In practice, this requirement frequently fails". They locate the failure in disease processes reaching the clinical outcome through causal pathways not mediated by the surrogate, the intervention's effect on those pathways differing from its effect on the surrogate. That divergence between marker and disease is the structure the sentence names. The work does not put the matter as whether a marker measures the disease or a correlated downstream effect, and gives no count behind the sentence's many.
“In practice, this requirement frequently fails. Among several explanations for this failure is the possibility that the disease process could affect the clinical outcome through several causal pathways that are not mediated through the surrogate, with the intervention's effect on these pathways differing from its effect on the surrogate.”
- And in clinical measurement, the question is whether a marker measures the disease or a correlated downstream effect that can respond to treatment without the disease responding — the structure behind many surrogate-endpoint failures.
- Proxy-Target Divergence
- In medicine, surrogate-endpoint failures occur when a treatment improves a proxy outcome (LDL, HbA1c, tumour response) but fails to improve, or worsens, the patient outcome the proxy was meant to represent.
This sourceCatalogs cases where a treatment improved a surrogate (LDL, arrhythmia suppression) while failing to improve, or worsening, clinical outcomes.
Supported in partVerified against the publisher's abstract
The abstract states surrogate end points must reliably predict the clinical outcome and that this requirement frequently fails, backing the medicine half of the claim; it names cholesterol and tumour shrinkage, not HbA1c.
“In theory, for a surrogate end point to be an effective substitute for the clinical outcome, effects of the intervention on the surrogate must reliably predict the overall effect on the clinical outcome. In practice, this requirement frequently fails.”
- In medicine, surrogate-endpoint failures occur when a treatment improves a proxy outcome (LDL, HbA1c, tumour response) but fails to improve, or worsens, the patient outcome the proxy was meant to represent.
- Proxy–Target Fidelity
- In medicine, surrogate endpoints are proxies for clinical outcomes: a drug that lowers a biomarker (blood pressure, viral load, tumor size, LDL cholesterol) is assumed to improve the outcome the biomarker stands in for (stroke, mortality, survival), and the surrogate-validity literature is a sustained reckoning with cases where the proxy moved but the outcome did not — drugs that improved the biomarker while harming patients.
This sourceDocuments surrogate endpoints (biomarkers) that moved favorably while clinical outcomes did not, sometimes worsening.
Supported in partVerified against the publisher's abstract
The abstract of Fleming & DeMets (1996) states that surrogates such as tumor shrinkage or cholesterol change often fail to predict the clinical outcome and have misled about treatments' real effects on patients' health.
“We use examples from several disease areas to illustrate how surrogate end points have been misleading about the actual effects that treatments have on the health of patients.”
- In medicine, surrogate endpoints are proxies for clinical outcomes: a drug that lowers a biomarker (blood pressure, viral load, tumor size, LDL cholesterol) is assumed to improve the outcome the biomarker stands in for (stroke, mortality, survival), and the surrogate-validity literature is a sustained reckoning with cases where the proxy moved but the outcome did not — drugs that improved the biomarker while harming patients.
- Relevance Substitution
- The same pattern recurs in heuristic substitution (a complex statistical question answered as "does this make me feel comfortable?"), shortcut learning (a model "taking itself" to detect pneumonia while its inference runs through a scanner artefact), surrogate-endpoint substitution (a physician updating on LDL reduction as if it were evidence about cardiovascular mortality),
This sourceShows surrogate endpoints substituted for clinical outcomes can mislead, the medical instance of relevance substitution.
Supported in partVerified against the publisher's abstract
Backs the surrogate-endpoint clause: its abstract says surrogate end points such as cholesterol changes often mislead, but it says nothing of the other two examples.
“We use examples from several disease areas to illustrate how surrogate end points have been misleading about the actual effects that treatments have on the health of patients.”
- The same pattern recurs in heuristic substitution (a complex statistical question answered as "does this make me feel comfortable?"), shortcut learning (a model "taking itself" to detect pneumonia while its inference runs through a scanner artefact), surrogate-endpoint substitution (a physician updating on LDL reduction as if it were evidence about cardiovascular mortality),
Mechanisms¶
- Biomarker Monitoring
- The classic misuse is promoting a candidate surrogate to a decision rule before it is validated — trusting that moving the marker means helping the patient, when a therapy can shift the number without touching the outcome.
This sourceShows why an intervention-induced biomarker change cannot stand in for patient benefit until the surrogate is rigorously validated.
- The classic misuse is promoting a candidate surrogate to a decision rule before it is validated — trusting that moving the marker means helping the patient, when a therapy can shift the number without touching the outcome.
Verification¶
Does it exist? Confirmed. This work's DOI resolves to a registered record, which fixes its identity. That is all it fixes.
Does it back the claim? Read against the text for 4 of 5 citations: 1 supported, 3 supported in part. Each verdict is shown under its citation below, with what in the work backs the sentence.
Support is checked per citation rather than per work — the same source can be cited soundly in one article and wrongly in another. Per-citation recording began recently, so a citation with no recorded check is a gap in the record rather than evidence it went unchecked.
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