Use of Biomarkers and Surrogate Endpoints in Drug Development and Regulatory Decision Making: Criteria, Validation, Strategies

Lj, Lesko; Aj, Atkinson

doi:10.1146/annurev.pharmtox.41.1.347

Cited by 422 publications

(266 citation statements)

References 45 publications

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“…The sixth examines factors, both genetic and somatic, mediating overall and age-specific risk for dementia. Investigations of biomarkers, physical signs or laboratory measurements that occur in association with the development of a specific disease or disease process (Lesko & Atkinson, 2001) are discussed in the seventh section of this chapter. Finally, the eighth part of this chapter will discuss implications of future research to improve the health and well being of people with Down syndrome.…”

Section: Chapter Organizationmentioning

confidence: 99%

“…Biomarkers are physical signs or laboratory measurements that occur in association with the development of a specific disease or disease process (Lesko & Atkinson, 2001). They can help confirm diagnoses, especially in conditions like Alzheimer's disease where, with currently available technology, the "gold standard" diagnosis can only be determined by direct examination of brain tissue (rarely from a biopsy, but more usually based upon postmortem findings).…”

Section: Biomarkersmentioning

confidence: 99%

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Chapter 4 Alzheimer's Disease in Adults with Down Syndrome

Zigman¹,

Devenny²,

Krinsky‐McHale³

et al. 2008

International Review of Research in Mental Retardation

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Section: Chapter Organizationmentioning

confidence: 99%

Section: Biomarkersmentioning

confidence: 99%

Chapter 4 Alzheimer's Disease in Adults with Down Syndrome

Zigman¹,

Devenny²,

Krinsky‐McHale³

et al. 2008

International Review of Research in Mental Retardation

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“…Of course, the entire field of 'inborn errors of metabolism' is based on seeking diagnostic changes in the metabolome, and these are now measured routinely [65,66]. Such diagnostic biomarkers can of course be surrogates [67], as well as being genuinely diagnostic. However, studies that seek novel biomarkers are not without their difficulties, and bias is an everpresent danger [68,69].…”

Section: What Is the Metabolome Potentially Useful For? Biomarker Detmentioning

confidence: 99%

Systems biology, metabolic modelling and metabolomics in drug discovery and development

Kell

2006

Drug Discovery Today

265

163

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Unlike signalling pathways, metabolic networks are subject to strict stoichiometric constraints. Metabolomics amplifies changes in the proteome, and represents more closely the phenotype of an organism. Recent advances enable the production (and computer-readable encoding as SBML) of metabolic network models reconstructed from genome sequences, as well as experimental measurements of much of the metabolome. There is increasing convergence between the number of human metabolites estimated via genomics ( 3000) and the number measured experimentally. It is thus both timely, and now possible, to bring these two approaches together as an integrated (if distributed) whole to help understand the genesis of metabolic biomarkers, the progress of disease, and the modes of action, efficacy, off-target effects and toxicity of pharmaceutical drugs. Systems biology and metabolic modelling in the 21st CenturyAlthough there are many individual definitions, most commentators (including this one [1,2]) take it that systems biology involves an iterative interplay between more or less high-throughput and high-content 'wet' experiments, technology development, theory and computational modelling, and that it is the involvement of computational modelling, in particular, in the process that sets systems biology apart from the more traditional and more reductionist molecular biology. Metabolomics illustrates this amply. There is also the view that the perceived decrease in the effectiveness of the target-based drug discovery process [3][4][5], including the still-high levels of attrition [6], means that we must move towards understanding organisms at something more akin to a whole-system level [7][8][9][10][11].The question then arises as to what part of a system one might first beneficially model? Although there has, unsurprisingly, been considerable interest in modelling the major signalling pathways (e.g. Refs [12,13]), there are several reasons why it is timely to turn our attention to the level of small molecule metabolism, which is the focus of this review. Metabolism is more discriminatingIt has long been known, and proven through the formalism of metabolic control analysis [7,10,[14][15][16], that whereas small changes in the concentrations of enzymes (and the transcripts that encode them) have only small effects on the fluxes through metabolic pathways, they have substantial effects on the concentrations of metabolic intermediates. Because the metabolome (nominally the concentrations of 'all' the metabolites measured in a system of interest [17]) is downstream of the proteome, it is thereby 'amplified' both in theory [18] and in practice [19,20] and represents a more sensitive level of organisation than do the macromolecular 'omes for understanding a complex biological system, and the changes in it that might be occasioned by disease or pharmaceutical intervention [21,22]. Metabolic reconstruction is now mature and timelyAn attractive feature for the purposes of modelling is that metabolism, in contrast to signalling pathways, ...

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“…More important is patient management: the time lost for a patient, who is not responsive to treatment, can be significantly reduced. A biomarker that substitutes a clinical endpoint is called a surrogate endpoint [30][31][32][33]. The most important criteria for valid surrogates are biological plausibility, a documented statistical relationship between the surrogate and an accepted clinical endpoint in epidemiological studies, and demonstration that treatment effects on the surrogate correspond to the clinical outcome.…”

Section: E Clinical Studiesmentioning

confidence: 99%

In Vivo magnetic resonance techniques and drug discovery

Beckmann¹

2006

Braz. J. Phys.

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The long and resource intensive process of drug discovery and development is confronted with the basic challenge of providing effective and safe therapies at reasonably low costs. The better the mechanism of a disease is known, the higher the probability to find an appropriate therapy. Also, the better and earlier a disease can be diagnosed and characterized, the higher the chance to be able to interfere in this process with a chemical entity. This reasoning sets the framework for the use of imaging in drug discovery. We discuss the relevance of magnetic resonance imaging and spectroscopy to derive anatomical, functional, metabolic and target-related information in the context of pharmacological research in vivo.

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Use of Biomarkers and Surrogate Endpoints in Drug Development and Regulatory Decision Making: Criteria, Validation, Strategies

Cited by 422 publications

References 45 publications

Chapter 4 Alzheimer's Disease in Adults with Down Syndrome

Chapter 4 Alzheimer's Disease in Adults with Down Syndrome

Systems biology, metabolic modelling and metabolomics in drug discovery and development

In Vivo magnetic resonance techniques and drug discovery

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