Novel Pharmacometric Methods for Design and Analysis of Disease Progression Studies

Abstract: With societies aging all around the world, the global burden of degenerative diseases is expected to increase exponentially. From the perspective drug development, degenerative diseases represent an especially challenging class. Clinical trials, in this context often termed disease progression studies, are long, costly, require many individuals, and have low success rates. Therefore, it is crucial to use informative study designs and to analyze efficiently the obtained trial data. The development of novel approaches intended towards facilitating both the design and the analysis of disease progression studies was the aim of this thesis.This aim was pursued in three stages (i) the characterization and extension of pharmacometric software, (ii) the development of new methodology around statistical power, and (iii) the demonstration of application benefits.The optimal design software PopED was extended to simplify the application of optimal design methodology when planning a disease progression study. The performance of non-linear mixed effect estimation algorithms for trial data analysis was evaluated in terms of bias, precision, robustness with respect to initial estimates, and runtime. A novel statistic allowing for explicit optimization of study design for statistical power was derived and found to perform superior to existing methods. Monte-Carlo power studies were accelerated through application of parametric power estimation, delivering full power versus sample size curves from a few hundred Monte-Carlo samples. Optimal design and an explicit optimization for statistical power were applied to the planning of a study in Alzheimer's disease, resulting in a 30% smaller study size when targeting 80% power. The analysis of ADAS-cog score data was improved through application of item response theory, yielding a more exact description of the assessment score, an increased statistical power and an enhanced insight in the assessment properties.In conclusion, this thesis presents novel pharmacometric methods that can help addressing the challenges of designing and planning disease progression studies.