Recommendation 1:

The biomarker evaluation process should consist of the following three steps:


Analytical validation: analyses of available evidence on the analytical performance of an assay;


Qualification: assessment of available evidence on associations between the biomarker and disease states, including data showing effects of interventions on both the biomarker and clinical outcomes; and


Utilization: contextual analysis based on the specific use proposed and the applicability of available evidence to this use. This includes a determination of whether the validation and qualification conducted provide sufficient support for the use proposed.

The committee recognizes that including analytical validation in the evaluation framework and separating the evidentiary assessment from the utilization analysis is a departure from many previous attempts to develop biomarker evaluation systems, but found that these processes, although distinct, are interwoven in such a way that it is impossible to responsibly consider one without also considering the others. Although biomarker analytical validation and biomarker qualification will often be considered together (the statistical linkages of disease, biomarker, and drugs can depend on the analytical soundness of a biomarker assay) and have been used synonymously in the past (Biomarkers Definitions Working Group, 2001), differentiating these processes is important (Lee et al., 2006). A National Institutes of Health working group recommended the term “validation” be used for analytical methods (Biomarkers Definitions Working Group, 2001). The American Association of Pharmaceutical Scientists (AAPS), the Pharmaceutical Research and Manufacturers of America, and the Biomarkers Consortium, among other organizations, have worked to reinforce the distinction between analytical validation and qualification (Lee et al., 2005; Wagner, 2002). As discussed below, analytical validation is the process of assessing how well an assay quantitates a biomarker of interest; qualification is the evidentiary and statistical process linking a biomarker with biological processes and clinical endpoints (Biomarkers Definitions Working Group, 2001). The committee determined that qualification could be further separated into evidentiary assessment and utilization analysis, so that the different investigative and analytical processes required to evaluate evidence and contexts of use

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