The contribution of clinical pharmacology surrogates and models to drug development—a critical appraisal

Rolan, Paul

doi:10.1046/j.1365-2125.1997.t01-1-00583.x

Cited by 88 publications

(43 citation statements)

References 4 publications

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“…With a new marker it is unlikely that reproducibility and predictive power will be clearly established, but its relevance to an underlying disease mechanism may promise an improved understanding and more comprehensive assessment of the disorder that can be established over time. As noted above, the degree of novelty in a marker is inversely related to the extent to which it is validated [4].…”

Section: Selection and Validation Of New Markers In Copdmentioning

confidence: 95%

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Outcomes and markers in the assessment of chronic obstructive pulmonary disease

Jones

Agustí²

2006

European Respiratory Journal

219

157

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The clinical presentation of chronic obstructive pulmonary disease (COPD) is highly variable, reflecting the interaction of a complex range of pathological changes including both pulmonary and systemic effects.The consequences of COPD experienced by the patient (i.e. its outcomes) include: symptoms, weight loss, exercise intolerance, exacerbations, health-related quality of life, health resource use and death. No single measure can reflect the variety of pathological effects or adequately describe the nature or severity of COPD.Currently, there are few validated markers for assessing COPD and evaluating the effectiveness of treatment. The forced expiratory volume in one second has been used as a global marker of COPD, but it does not fully reflect the burden of COPD on patients. New markers are needed to better characterise the full clinical spectrum of the disease and to guide the development and assessment of new and more effective therapies.This article considers the distinction between outcomes and markers, the various ways in which markers are used and the need for new markers in the management of chronic obstructive pulmonary disease. The process of marker selection and validation is reviewed and potential new biological, physiological and symptomatic markers for chronic obstructive pulmonary disease are assessed.

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Section: Selection and Validation Of New Markers In Copdmentioning

confidence: 95%

“…A marker has been defined as a clinical measurement that is associated with, and believed to be related pathophysiologically to, a clinical outcome [4,5]. The term marker is used in a number of ways, so it is important that there is clarity in its use, since its meaning may change with its context.…”

Section: Defining Outcomes and Markersmentioning

confidence: 99%

Outcomes and markers in the assessment of chronic obstructive pulmonary disease

Jones

Agustí²

2006

European Respiratory Journal

219

157

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“…The concept of mechanism-based PK/PD modeling adds a novel dimension to the selection, evaluation, and validation of biomarkers, with a strong emphasis on Bconstruct validityâ s defined by Rolan (40). Within the context of mechanismbased PK/PD modeling, we define a biomarker as a measure that characterizes, in a strictly quantitative manner, a process, which is on the causal path between drug administration and effect.…”

Section: Biomarkers and Pk/pd Modelingmentioning

confidence: 99%

Mechanism-Based Pharmacokinetic–Pharmacodynamic Modeling—A New Classification of Biomarkers

et al. 2005

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In recent years, pharmacokinetic/pharmacodynamic (PK/PD) modeling has developed from an empirical descriptive discipline into a mechanistic science that can be applied at all stages of drug development. Mechanism-based PK/PD models differ from empirical descriptive models in that they contain specific expressions to characterize processes on the causal path between drug administration and effect. Mechanism-based PK/PD models have much improved properties for extrapolation and prediction. As such, they constitute a scientific basis for rational drug discovery and development. In this report, a novel classification of biomarkers is proposed. Within the context of mechanism-based PK/PD modeling, a biomarker is defined as a measure that characterizes, in a strictly quantitative manner, a process, which is on the causal path between drug administration and effect. The new classification system distinguishes seven types of biomarkers: type 0, genotype/phenotype determining drug response; type 1, concentration of drug or drug metabolite; type 2, molecular target occupancy; type 3, molecular target activation; type 4, physiological measures; type 5, pathophysiological measures; and type 6, clinical ratings. In this paper, the use of the new biomarker classification is discussed in the context of the application of mechanism-based PK/PD analysis in drug discovery and development.

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“…The extent of rigor in the development of an outcome measure is dependent on its intended usage within the drug development process (30,86,87), and differs between clinical efficacy measures, surrogate endpoints, and biomarkers. Even established outcome measures can be further developed with the ongoing accumulation of new data.…”

Section: Key Principles For the Ongoing Evaluation Of Cf Outcome Measmentioning

confidence: 99%

Advancing Outcome Measures for the New Era of Drug Development in Cystic Fibrosis

Mayer-Hamblett

Ramsey

Kronmal

2007

Proceedings of the American Thoracic Society

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The growing pipeline of candidate drugs for cystic fibrosis (CF) is challenging clinical trial research. There has been a shift from evaluating drugs aimed at treating the secondary manifestations of CF to evaluating drugs targeted toward the primary prevention of chronic lung disease. As CF is an orphan disease, there is a fundamental need to assess new therapies efficiently and accurately by mechanisms that best use the number of available patients. This need can be addressed with the continued advancement and refinement of CF outcome measures. We begin by presenting an overview of the outcome measures currently used in CF clinical studies, defined and categorized in terms of one of the three main classes of endpoints: clinical efficacy measures, surrogate endpoints, and biomarkers. To move forward efficiently, clinical research in CF is dependent on the development of new outcomes able to capture biologic and clinical response to novel therapeutic approaches. We conclude with a discussion of the criteria by which all new outcome measures should be evaluated. A systematic, rigorous approach to outcome measure development is needed to provide the tools necessary for evaluating new therapies and moving drugs out of the pipeline and into the CF clinic.

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The contribution of clinical pharmacology surrogates and models to drug development—a critical appraisal

Cited by 88 publications

References 4 publications

Outcomes and markers in the assessment of chronic obstructive pulmonary disease

Outcomes and markers in the assessment of chronic obstructive pulmonary disease

Mechanism-Based Pharmacokinetic–Pharmacodynamic Modeling—A New Classification of Biomarkers

Advancing Outcome Measures for the New Era of Drug Development in Cystic Fibrosis

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