A methodological framework for drug development in rare diseases. The CRESim program: Epilogue and perspectives

Based on the 'European Child-Rare-Euro-Simulation' (CRESim) project, this article proposes a generalizable strategy utilizing datasets analysis in combination with modeling and simulation, in order to optimize the clinical drug development applied in the field of rare diseases. The global process includes: (i) the simulation of a realistic virtual population of patients (modeled from a real dataset of patients), (ii) the modeling of disease pathophysiological components and of pharmacokinetic-pharmacodynamic relations of the drug(s) of interest, (iii) the modeling of several randomized controlled clinical trials (RCTs) designs and (iv) the analysis of the results (multi-dimensional approach for RCTs durations and precision of the estimation of the treatment effect). However, whereas modeling and numerical simulation may provide supplementary tools for drug development, they cannot be considered as a substitute for RCTs performed in 'real' patients.