Efficient Study Design and Analysis of Longitudinal Dose-Response Data Using Fractional Polynomials.

ABSTRACT

Correctly characterising the dose-response relationship and taking the correct dose forward for further study is a critical part of the drug development process. We use optimal design theory to compare different designs and show that using longitudinal data from all available timepoints in a continuous-time dose-response model can substantially increase the efficiency of estimation of the dose-response compared to a single timepoint model. We give theoretical results to calculate the efficiency gains for a large class of these models. For example, a linearly growing Emax dose-response in a population with a between/within-patient variance ratio ranging from 0.1 to 1 measured at six visits can be estimated with between 1.43 and 2.22 times relative efficiency gain, or equivalently, with 30% to a 55% reduced sample size, compared to a single model of the final timepoint. Fractional polynomials are a flexible way to incorporate data from repeated measurements, increasing precision without imposing strong constraints. Longitudinal dose-response models using two fractional polynomial terms are robust to mis-specification of the true longitudinal process while maintaining, often large, efficiency gains. These models have applications for characterising the dose-response at interim or final analyses.