Possible dose response relationships between a biomarker and clinical status. Understanding the biomarker-disease relationship is important and can be established to some degree in preclinical studies, with support from cross-sectional or natural history studies. The graph shows how different shapes of the curve can provide very different interpretations of the change in clinical status (C1, C2 and C3) for a similar change in the biomarker (b1, b2). In C1, the biomarker only covers a small range of the clinical disease change very early in the disease process, providing the potential error of associating change in the biomarker without much real change in clinical status. In C3, the biomarker is measuring a process too late in the clinical progression leading to most of the clinical decline occurring before the biomarker really changes. In C2, the biomarker dynamic range is covering a larger part of the major decline process, and would therefore express a better response relationship with the clinical status. Establishing this relationship is an important part of interpreting the change in a biomarker in a clinical study setting and understanding the predictive value of the biomarker; having this data is therefore important in the qualification process. This figure and discussion was taken from a presentation by Marc Walton at the Workshop Series on this white paper development in 2012 (See www.EveryLifeFoundation.org for the slide presentation).