Proposals for model-based paediatric medicinal development within the current European Union regulatory framework.

The new paediatric European Union (EU) regulation and the consequent demand for paediatric studies on one hand and the ethical need for minimizing the burden of studies in children on the other hand necessitate optimal techniques in the assessment of safety/efficacy and use of drugs in children. Modelling and simulation (M&S) is one way to circumvent some difficulties in developing medicinal products in children. M&S allows the quantitative use of sparse sampling, characterization and prediction of pharmacokinetics/pharmacodynamics (PK/PD), extrapolation from adults to children, interpolation between paediatric age subsets, optimal use of scientific literature and in vitro/preclinical data. Together, industry, academia and regulators recognize the usefulness of modelling and simulation in this setting. However, even if M&S is an emerging science, its integration in the EU regulatory decision making is for the time being deficient and M&S expertise is concentrated in big pharmaceutical companies and academic institutions. The European Medicines Agency, acknowledging all the above conditions, organized and hosted a Workshop on Modelling in Paediatric Medicines. The article presents the personal views of the authors on the issues presented and discussed in the workshop.We attempt to identify the regulatory framework for the use of M&S in paediatric medicinal development and to make proposals for model-based paediatric medicinal development. The objective is to open the discussion between industry, academia, paediatricians and regulators on the optimal use of M&S in paediatric medicinal development.

[1]  Michel Tod,et al.  Facilitation of Drug Evaluation in Children by Population Methods and Modelling , 2008, Clinical pharmacokinetics.

[2]  France Mentré,et al.  Development and implementation of the population Fisher information matrix for the evaluation of population pharmacokinetic designs , 2001, Comput. Methods Programs Biomed..

[3]  James H. Brown,et al.  The fourth dimension of life: fractal geometry and allometric scaling of organisms. , 1999, Science.

[4]  L B Sheiner,et al.  Pharmacokinetic/pharmacodynamic modeling in drug development. , 2000, Annual review of pharmacology and toxicology.

[5]  N. Holford,et al.  Mechanism-based concepts of size and maturity in pharmacokinetics. , 2008, Annual review of pharmacology and toxicology.

[6]  T. Johnson.  Modelling approaches to dose estimation in children. , 2005, British journal of clinical pharmacology.

[7]  R. Gieschke,et al.  Modelling Response Time Profiles in the Absence of Drug Concentrations: Definition and Performance Evaluation of the K–PD Model , 2007, Journal of Pharmacokinetics and Pharmacodynamics.

[8]  M. Karlsson,et al.  Comparison of stepwise covariate model building strategies in population pharmacokinetic-pharmacodynamic analysis , 2002, AAPS PharmSci.

[9]  C. Peck,et al.  Evidence of effectiveness: How much can we extrapolate from existing studies? , 2005, The AAPS Journal.

[10]  L B Sheiner,et al.  Learning versus confirming in clinical drug development , 1997, Clinical pharmacology and therapeutics.

[11]  N H Holford,et al.  Simulation of clinical trials. , 2000, Annual review of pharmacology and toxicology.

[12]  D. Rubin,et al.  Hypothesis: A single clinical trial plus causal evidence of effectiveness is sufficient for drug approval , 2003, Clinical pharmacology and therapeutics.