Surrogate markers in clinical trials--challenges and opportunities
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Updated: Jun 24, 2026
Preparation of Peripheral Blood Mononuclear Cell Pellets and Plasma from a Single Blood Draw at Clinical Trial Sites for Biomarker Analysis
Published on: March 20, 2021
Raphaël Duivenvoorden1, Eric de Groot, Erik S G Stroes
1Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands.
Insights
Plasma biomarkers like LDL-c, HDL-c, and HbA1c may not fully predict cardiovascular drug efficacy due to disease complexity. Vascular imaging offers a more comprehensive assessment of atherosclerosis progression and treatment effects.
Area of Science:
- Cardiovascular Medicine
- Pharmacology
- Biomarker Research
Background:
- Surrogate markers (LDL-c, HDL-c, HbA1c) are increasingly scrutinized for failing to predict clinical benefit in cardiovascular drug trials.
- The complex, multifactorial nature of atherosclerotic vascular disease limits the predictive power of single circulating biomarkers.
Purpose of the Study:
- To review the challenges and limitations of using plasma biomarkers as surrogate endpoints for cardiovascular drug efficacy.
- To highlight the potential of vascular imaging modalities in assessing atherosclerosis and treatment response.
Main Methods:
- Literature review focusing on plasma biomarkers and vascular imaging in cardiovascular drug efficacy assessment.
- Discussion of the limitations of soluble endpoints versus the continuous variable assessment provided by vascular imaging.
Main Results:
- Plasma biomarkers offer a limited view, reflecting only a fraction of the disease and unable to monitor side effects or novel pathways.
- Vascular imaging directly assesses the arterial wall, providing a continuous measure of atherosclerosis from early stages to complications.
Conclusions:
- Relying solely on plasma biomarkers for cardiovascular drug efficacy is insufficient due to the inherent complexity of atherosclerosis.
- Vascular imaging presents a more robust approach to evaluating the true impact of therapies on the atherosclerotic disease process.
Abstract:
Surrogate markers have recently come under scrutiny since a few of the considered most reliable intermediate endpoints (LDL-c, HDL-c and HbA(1c)) have failed to predict clinical benefit following pharmacological intervention in the causal pathway. However, it follows that comprehending the pathophysiological complexity of atherosclerotic vascular disease, no single surrogate is likely to be omniscient in the translation of benefit or harm of a certain therapy. Especially surrogates that are assessed in the circulation merely reflect a part of the complex multipathway disease. Such markers do not have the ability to monitor potential side effects of interventions or assess the activation of unknown pro-atherogenic pathways. Contrary to such soluble endpoints, vascular imaging data can provide information on atherosclerosis as a continuous variable, since the disease process of the vascular wall itself is assessed. Understanding this continuity from the earliest stages through to the vascular complications is essential, as the arterial wall reflects the net effect of either known or yet to be discovered hereditary as well as environmental factors. In this review we will focus on challenges and pitfalls using plasma biomarkers as surrogate endpoints for the assessment of cardiovascular drug efficacy. Subsequently, we will focus on vascular imaging modalities as tools to investigate atherosclerosis.
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