Evidence from biomarkers and surrogate endpoints

Abstract

Summary:The use of physiological, anatomical, and other biological tests is commonplace in the practice of medicine. In neurology, objectively measured tests termed biomarkers (BMs) are playing an increasing role in diagnosis and management of disease, both in clinical practice and in experimental therapeutics. This article will discuss the various applications of BMs to the assessment of therapies for neurological diseases and will use examples from neurological diseases to elucidate the strengths and potential weaknesses of BMs. As the understanding of the pathophysiology of many neurological diseases has improved, new BMs have been developed, and efforts have been made to use these as proxies for clinical endpoints. A BM used in this manner is referred to as a surrogate endpoint (SE). There are many potential advantages and disadvantages of using SEs in the evaluation of new therapies, and these will be reviewed as well. Furthermore, the evidence required for the development of an SE and the nature of the evidence that can be derived from the use of BMs and SEs will be discussed.

NMR‐based metabolomic analysis of cerebrospinal fluid and serum in neurological diseases – a diagnostic tool?

“…Disease treatment in neurology is predicted to advance over the next decade with the development of genetic, stem cell and immunomodulatory therapies. Biomarkers will be essential in the development and deployment of these therapies to facilitate diagnosis, guide prognosis and therapy, evaluate experimental pharmacotherapy and in addition provide surrogate endpoints and markers for clinical research (43)(44)(45). Single biomarkers will rarely achieve these ideals and it is likely that composite endpoints will be required.…”

The validity of biomarkers as surrogate endpoints in Alzheimer's disease by means of the Quantitative Surrogate Validation Level of Evidence Scheme (QSVLES)

“…The development of a biomarker relies on the understanding of the pathological basis, biochemical, anatomical or even molecular, of the disease under study. The potential applications of a biomarker include their use as a diagnostic tool, staging instrument, prognostic tool, and predictor of clinical response to an intervention (7)(8)(9)(10).…”

Treatment effect of natalizumab on relapse outcomes in multiple sclerosis patients despite ongoing MRI activity

“…However, it is not yet clear that MRI evidence of disease activity should be accepted as a clinical endpoint since changes observed with this imaging technique may not be invariably correlated with disease progression, as measured by disability scales or relapses in treated MS patients 12. Results from MRI evaluations might potentially serve as a surrogate endpoint but would be required to meet the following criterion: prediction of clinical benefit (or harm, or lack of benefit or harm) based on epidemiological, therapeutic, pathophysiological or other scientific evidence 13. It has recently been emphasised that surrogate endpoints, including MRI measures, must be validated against clinical outcomes in trials of patients with MS14; and it has also been emphasised that the validation of surrogate endpoints is treatment specific 15.…”