The true treatment benefit is unpredictable in clinical trials using surrogate outcome measured with diagnostic tests

Abstract

Background and Objectives-Clinical trials increasingly use results of diagnostic tests as surrogate outcomes. Our objective was to answer the following questions: (1) is the parameter measured by the reference standard a valid surrogate? (2) How does the tests accuracy influence the estimate of the treatment benefit on surrogate? (3) Is it possible to correct the measured treatment effect given by results of inaccurate tests?Methods and Setting-We reviewed the literature on asymptomatic deep venous thrombosis (DVT), detected by the reference standard and other imaging techniques, as surrogate for venous thromboembolism. The influence of test inaccuracy on the measurement of treatment benefit was calculated as a function of the patient baseline risk, the treatment effect model, and test performances.Results-We show that: (1) asymptomatic DVT is correlated with clinical outcomes but is yet to be established as a surrogate; (2) inaccurate diagnostic test underestimates the treatment effect on surrogate; (3) the prevalence of the disease, the treatment effect model, and the accuracy of the test and the reference standard used to evaluate it need to be known to correct this underestimation.Conclusion-Even when the surrogate end point is valid, without a reliable study of the diagnostic test we cannot quantify the true treatment effect.

LDL-cholesterol differences predicted survival benefit in statin trials by the surrogate threshold effect (STE)

“…These decisions are also influenced by patient preference, cost effectiveness, rarity of the condition, and whether there is a large safety database associated with the intervention under consideration [3,69,71]. Finally, the use of a biomarker as a surrogate for the evaluation as a diagnostic test entails additional deliberations as shown by Kassaï et al [72].…”

Evidence-based mechanistic reasoning

“…The evidence linking the surrogate and the clinically relevant outcome is often lacking. [35][36][37] All mechanisms are, at least to some extent, 'partial', in the sense that they are not completely understood.…”

The Application of Biomarkers in Clinical Trials for Motor Neuron Disease

“…For a biomarker to be used as a surrogate marker and clinical end point, it must meet certain criteria including: ■ Well established and validated biological relationship with the accepted clinical end point;■ The ability to derive an estimate of the patients' treatment-induced benefit;■ The treatment effect on the clinical outcome must be entirely explained by the treatment effect on the surrogate [87]. …”

“…■ The treatment effect on the clinical outcome must be entirely explained by the treatment effect on the surrogate [87]. …”