Visualizing Dose–Response When the Signal to Noise Ratio Is Low: The Bronchodilatory Response in Chronic Obstructive Pulmonary Disease
Spirometry is a safe, cheap, and easy-to-use methodology for the assessment of lung function. Spirometry biomarkers such as the forced expiratory volume in 1 second (FEV1) and the forced vital capacity (FVC) are commonly used in the diagnosis of conditions such as asthma and chronic obstructive pulmonary disease. In recent years, FEV1 in particular has also been used to support dose selection in bronchodilator drug development programs. Despite its convenience and objectivity as a measure of pulmonary function, FEV1 has a very low signal to noise ratio (SNR) as a marker of bronchodilator response. This problem is exacerbated when the biomarker is analyzed using traditional dose ranging study designs that do not provide an explicit and precise estimate of the dose response relationship. The combination of low SNR and imprecise methodology means that traditional dose finding activities for bronchodilators are inefficient and may lead to the selection of sub-optimal doses. Using graphics produced during the development of the novel long-acting β2-agonist, indacaterol, the issues outlined above are described and an alternative approach, built on a model-based characterization of the bronchodilatory dose response relationship is presented.
KeywordsPlacebo Covariance Corticosteroid Salmeterol Formoterol
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