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Rare disease: use of clinical trial simulation for the choice and optimization of study design

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1. Description of the scientific ideas Rare diseases are defined as diseases occurring in less than one in 2,000. It is estimated that 5,000 to 8,000 distinct rare diseases exist today, corresponding to 24 to 36 million people in the European Community. The most frequent rare diseases are either chronic degenerative life-threatening or disabling diseases where quality of life is compromised. Orphan drug evaluation issue: Whereas RCTs (randomized controlled clinical trials) are currently used for the evaluation of non-orphan drugs, no general validated approach for the assessment of orphan drugs exist. Particularly, there is a need for investigation and assessment of specific alternative RCTs designs for the evaluation of orphan drugs in rare diseases, because of the small numbers of patients likely to be enrolled. 2. Research hypotheses In addition to the traditional ‘parallel group’ design, alternative designs are usually considered for small clinical trials, e.g. crossover, factorial, withdrawal, and early-escape designs. Innovative designs have been also developed such as single subject (n-of-1) designs, sequential designs (e.g. sequential monitoring triangular design), and adaptive designs. The Bayesian and the meta-analytic approaches have also to be considered. ‘In silico’ RCTs simulations can be defined as the generation of a response for virtual patients obtained by modeling trial design, human behavior, disease progress and drug behavior using numerical methods and specific mathematical models. The CRESim (‘Child-Rare-Euro-Simulation‘) project belongs to the framework of an ‘in silico’ approach, with the use of RCTs modelling and Monte Carlo simulation in order to evaluate various clinical trial designs in different rare diseases. 3. Objectives and methods The main objective is to investigate ‘in silico’ various experimental designs of RCTs dealing with the evaluation of drugs in children presenting with a rare disease. Three categories of diseases will be considered: neurology (e.g. epilepsy), pneumology (e.g. cystic fibrosis) and onco-hematology. For each category, several RCTs will be simulated using different experimental designs and the results will be compared in terms of trial duration (e.g. for the patient, the investigator and the sponsor) and precision of the estimation of the treatment effect. The project also includes the rational use of already available databases in the field of some rare diseases in order to validate the models proposed for RCTs simulations. 4. Workpackages and scientific participants WP1– Methodology, scientific coordination and management (P. Nony, C. Cornu, B. Kassai, Lyon, FRANCE) WP2 to 4–Epilepsy (R. Guerrini, Florence, ITALY), Cystic fibrosis (H. Tiddens, Rotterdam, NL), Hemato-oncology (Y. Bertrand, Lyon, FRANCE) WP5– Modelling (L. Aarons, Manchester, UK) WP6– RCTs simulation and statistical analysis (S. Chabaud, D. Perol, Lyon, FRANCE WP7– Dissemination and exploitation (G. Pons, F. Dufour, Paris, FRANCE) Industry Partner– NOVARTIS (F. Bretz, Basel, SWITZERLAND) 5. Relevance to the PRIOMEDCHILD research theme The CRESim project corresponds to a multidisciplinary work aiming at more effective treatments of children affected by rare diseases. The development of an innovative methodology in medicine for childhood research is proposed, to facilitate the performance of clinical research and to improve the feasibility of studies in children. 6. Methodological aspects Scientific innovation: New approaches to protocol designs are actually needed for trials with small sample sizes that can assess the potential therapeutic efficacies of drugs. Such an ‘in silico’ approach has never been widely applied neither in the field of RCTs designs nor in the therapeutic evaluation of orphan drugs. Impact and excellence: The project will provide a new environment for more effective healthcare, i.e. an ‘in silico’ platform for RCTs simulation in rare diseases. 7. Potential social significance of the project Patients affected with rare diseases and their families are confronted with the lack of scientific knowledge, resulting from difficulties in developing therapeutic tools and defining adequate therapeutic strategies. The CRESim project will contribute to speed-up the process of orphan drug development, and will transform the practice of medicine in this domain. 8. Added value of the international collaboration CRESim is a multi-disciplinary project involving physicians, pharmacologists, mathematicians and computer scientists belonging to the academic or private sector. Finding a solution for a complex disease implies a transversal approach. CRESim study will pave the way for investigation of numerous drugs under development in rare diseases and will leverage European existing strengths as a world leader in this scientific area.

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Projectnummer:
113205008
Looptijd: 100%
Looptijd: 100 %
2011
2014
Onderdeel van programma:
Projectleider en penvoerder:
Dr. C.C. Cornu
Verantwoordelijke organisatie:
Université Claude Bernard Lyon 1