Perspectives on Biomarker and Surrogate Endpoint Evaluation Discussion Forum Summary (2011) / Chapter Skim
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7 Presentation by Thomas Fleming: Biomarkers and Surrogate Endpoints in Chronic Disease
7 Presentation by Thomas Fleming: Biomarkers and Surrogate Endpoints in Chronic Disease
Pages 75-86
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From page 75... ...
Fleming focused on two main issues, the first of which he described as "digging deeper" into the reasoning behind his statement that "a correlate does not a surrogate make." He identified three main criteria for choosing endpoints in clinical trials in order to best determine
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From page 76... ...
"Unfortunately," he added, "that's often not the case." He proceeded to discuss the various reasons why a biomarker might fail as a surrogate endpoint, each of which are illustrated diagrammatically in Figure 7-1. The first reason for a biomarker to fail as a surrogate endpoint is that the biomarker does not lie in the causal pathway by which the disease influences the clinical endpoint, so an intervention's effect on the bio marker will not provide a reliable estimate of the intervention's clinical efficacy (as shown in Figure 7-1A)
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From page 77... ...
Examples include carcinoembryonic antigen, a biomarker for ovarian cancer, and prostate-specific antigen (PSA) ; such biomarkers are useful for disease diagnosis and assessing prognosis,
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From page 78... ...
However, a biomarker used as a surrogate endpoint must lie in the pathophysiologic causal pathway of the disease. A second scenario for biomarker failure as a surrogate endpoint occurs when multiple pathways influence outcome.
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From page 79... ...
Indeed, he said, "there are many aspects of the ultimate effect of antimicrobials on the clinical endpoint that may not be captured by the biomarker [VRE decolonization] ." Even for interventions that affect all causal pathways leading to a clinical endpoint, there are potential off-target effects through which the intervention can directly influence the true clinical endpoint, and which the biomarker does not capture (Figure 7-1D)
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From page 80... ...
to be due to off-target effects, likely based in part on a thrombosis off-target mechanism," he said. "A valid surrogate is one where the effect of the intervention on the surrogate is reliably telling us what the effect of the intervention is on the clinical endpoint," Dr.
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From page 81... ...
However, determination of the net effect of an intervention on a surrogate endpoint does not exclude the possibility that the intervention produces off-target effects on the clinical endpoint, he noted. If an intervention for type 2 diabetes provided a 20 percent reduction in the rate of cardiovascular death, stroke, and MI, and that level effect exactly matched what is predicted based on its effect on hemoglobin A1c, it does not mean that is the only way that treatment influenced outcome, Dr.
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From page 82... ...
One example of this is in the adjuvant colon cancer setting, when cancer is detected early enough to permit curative surgery. Among patients whose excised tissue contains positive nodes, about half will experience recurrence of cancer, due to microscopic undetected residual disease, and will die within 5 years, Dr.
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From page 83... ...
He said that validated surrogate endpoints, the second level in the hierarchy, are relatively rare and include the earlier example of colon cancer recurrence and survival, as well as blood pressure, as a surrogate for clinical endpoints in antihypertensive interventions. Both of these surrogates were validated based on large amounts of data from multiple clinical trials, and they were validated for specific types of interventions used in those trials and for specific clini cal endpoints, he said.
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From page 84... ...
Fleming to comment on the variable utility of clinical endpoints, since some clinical endpoints suffer from many of the same measurement issues that biomarkers and surrogate endpoints do, as well as similar unintended consequences. For example, a PRO can measure how depressed patients feel, but it cannot capture the effect of a treatment on blood pressure or on suicide.
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From page 85... ...
Fleming noted that it is important to understand the net effect of an entire food on both biomarkers and clinical endpoints. Thus, he said, if the food in question has more than one experi mental ingredient, it would be important to understand how each ingredient affects relevant biomarkers and clinical endpoints.
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From page 86... ...
. The new intervention appears more beneficial than it is if investigators solely judge it by the effect on LDL, because biomarkers used as surrogate endpoints may not take into effect the multiple causal pathways involved in a disease process, he said.
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