Use of clinical trial simulation for the optimisation of study designs in rare diseases CRESIM
[EMET Team: N.Bleyzac, C. Cornu, B. Kassaï, P. Nony, P. Reix]
The CRESim project (headed by P. Nony) is a PrioMedChild European project. Its objective is to optimise the study design selection of a randomised controlled trial (RCT) for rare diseases and orphan treatments (Cornu et al.2013).The CRESim project develops a platform performing trial modelling and simulation («cloud computing technology ») (See figure below), initially based on three pathological situations: Dravet Syndrome (rare form of epilepsy), T-cell lymphoblastic lymphoma in children and cystic fibrosis. The common approach is an integrative modelling, using the development and connection between the pathophysiological model of the disease, the pharmacotherapeutic model of the study treatment (i.e. relationship between pharmacokinetics and pharmacodynamics [Ogungbenro et al.2014])) and the clinical trial model with a specific trial design.
The mathematical formalism uses systems of ordinary differential equations (ODE) and reaction-diffusion system of equations (EDP) for most of the models concerned. The project’s central ambitions are divided into the following four main areas:
1) Science: the multidisciplinary integrative modelling (clinicians, pathophysiologists, pharmacologists, therapists, mathematicians, modellers, numerical analysts and computer specialists) meets the very specific needs in the field of rare diseases, with the in silico development and validation of new surrogate endpoints, of “theranostic” approaches, allowing for the implementation of a personalised medicine.
2) Education: with a dissemination of findings to scientific communities, to the pharmaceutical and biotherapeutics industry, and to patient associations.
3) Regulation: The results of the CRESIM project should modify the position of the modelling/simulation in recommendations on developing medicines.
4) Public Health: the expected acceleration of the orphan drug development process and the improvement of the evidence level available on the risk-benefit ratio associated with their use, should transform the world of rare diseases and their therapy.