Abstract
PurposeThe current study aimed to illustrate how a non-linear mixed effect (NLME) model-based analysis may improve confidence in a Phase III trial through more precise estimates of the drug effect.MethodsThe FULFIL clinical trial was a Phase III study that compared 24 weeks of once daily inhaled triple therapy with twice daily inhaled dual therapy in patients with chronic obstructive pulmonary disease (COPD). Patient reported outcome data, obtained by using The Evaluating Respiratory Symptoms in COPD (E-RS:COPD) questionnaire, from the FULFIL study were analyzed using an NLME item-based response theory model (IRT). The change from baseline (CFB) in E-RS:COPD total score over 4-week intervals for each treatment arm was obtained using the IRT and compared with published results obtained with a mixed model repeated measures (MMRM) analysis.ResultsThe IRT included a graded response model characterizing item parameters and a Weibull function combined with an offset function to describe the COPD symptoms-time course in patients receiving either triple therapy (n = 907) or dual therapy (n = 894). The IRT improved precision of the estimated drug effect compared to MMRM, resulting in a sample size of at least 3.64 times larger for the MMRM analysis to achieve the IRT precision in the CFB estimate.ConclusionThis study shows the advantage of IRT over MMRM with a direct comparison of the same primary endpoint for the two analyses using the same observed clinical trial data, resulting in an increased confidence in Phase III.
Highlights
The primary reason for Phase III clinical drug development failure is insufficient drug efficacy (55%), followed by safety (14%) and strategic reasons (14%) [1]
The development of “ineffective” or “unsafe” compounds should stop during early stages of drug development, the proportion of failure owing to insufficient efficacy is currently larger in Phase III compared to Phase II (55% vs. 48%) [1]
Item characteristic curves that illustrate the relationship between disease status and probability of giving a certain score for all items are shown in Supplementary Fig. 3
Summary
The primary reason for Phase III clinical drug development failure is insufficient drug efficacy (55%), followed by safety (14%) and strategic reasons (14%) [1]. The development of “ineffective” or “unsafe” compounds should stop during early stages of drug development, the proportion of failure owing to insufficient efficacy is currently larger in Phase III compared to Phase II (55% vs 48%) [1]. Chronic Obstructive Pulmonary disease (COPD) is an inflammatory disease of the respiratory system, accounting for 54.9% of chronic respiratory diseases in 2017 [5]. It was the third leading cause of death in 2016 and is projected to remain among the five leading causes of death by 2030 [6]. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy [7] states that commonly used maintenance medications in COPD are short or long acting β2 agonists
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