known to effectively reduce low-density lipoprotein cholesterol (LDL-C), and investigators want to use LDL lowering as a surrogate endpoint for death or MI. The new intervention has a similar effect on LDL, but it has far weaker effects on other positive mechanisms as compared with the original intervention. This could be because the original intervention not only reduced LDL, but also positively affected triglycerides and high-density lipoprotein cholesterol (HDL-C). 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.

Conversely, the new intervention could have unintended adverse effects such as increasing blood pressure through the angiotensin-renin system. Then, the effect on the lipid-based biomarker does not represent the totality of effects. “That is in fact what we saw when we looked at torcetrapib,” he said. “Fortunately we recognized that torcetrapib and atorvastatin … [produced] an adverse [net] effect because we had clinical endpoint studies.”

Dr. Fleming also reminded the audience that the magnitude and duration of the effect of the intervention matters. For example, an intervention that has a modest effect on LDL-C may not produce a clinical benefit. On the other hand, “we’ve also seen with some of the surrogates, that if the effect is particularly profound, more isn’t always better,” he said. Examples of this scenario include hematocrit normalization with ESAs, reducing hemoglobin A1c in type 2 diabetes, and large reductions in blood pressure (Staessen et al., 2003).

In response to the committee’s question—how biomarker evaluation effects the public—Dr. Fleming replied that biomarkers are of great interest because they allow for timely assessment of interventions. However, he added, “it is critically important that [assessments] not just be timely, but reliable.” The ultimate goal of these assessments is not to give the public more choices but rather more informed choices, he said. In that regard, he described the report as “very enlightened” in its discussion of the steps involved in biomarker evaluation: validation, qualification, and utilization. In undergoing such evaluation, he said it happens more frequently than one might expect that the effect of an intervention on a biomarker fails to accurately predict its effect on a clinical endpoint.

“It is not so much the things we don’t know that get us into trouble; it’s the things that we do know that aren’t so,” said Dr. Fleming. He added that for the public, the most problematic aspect of biomarker use results when biomarkers that are not truly validated give us the impression that we understand a treatment effect when we do not.



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