Role of Modelling and Simulation (M&S) in Paediatric Investigation Plans (PIPs)

Efthymios Manolis (1)

1 Scientific Advice

Ethical and practical constraints encourage the optimal use of resources in paediatric drug development. In this context, modelling and simulation (M&S) has emerged as a promising methodology acknowledged by industry, academia and regulators. We previously proposed a paradigm for use of M&S in paediatric medicinal development. In this publication M&S was identified as decision tool, study optimisation and/or data analysis tool. Three and a half years since the entry into force on 26 January 2007 of the Paediatric Regulation the European Medicines Agency has gained substantial experience on the use of M&S in paediatric medicinal development. In this review we present examples on how the proposed paradigm applies in real case scenarios of planned pharmaceutical developments. We also report the results of a paediatric database search to further "validate" the paradigm. 47 out of 210 positive PIP opinions make reference to M&S (data included all positive opinions issued up to January 2010). However further search in the summary reports identified that opinions report approximately half of the M&S approaches used in PIPs. M&S is used as data analysis, dose prediction and sampling optimisation tool but not as a tool to navigate in the paediatric decision tree as was previously proposed. Population pharmacokinetic (POP-PK) and pharmacodynamics (POP-PK/PD) and physiological based pharmacokinetic models (PBPK) are widely used by industry and accepted by regulators as a way to circumvent some difficulties in developing medicinal products in children. The knowledge of the effects of age and size on PK is improving and models are widely employed to make optimal use of this knowledge. However based on the PIP experience, less is known on the effects of size and maturation on pharmacodynamics (PD), disease progression and safety. Extrapolation of efficacy from different age groups is often used in paediatric medicinal development as another means to alleviate the burden of clinical trials in children. In the current regulatory thinking, M&S provides a quantitative framework for the extrapolation but the main weight of evidence comes from clinical data. The regulators are eager to discuss further the integration of M&S in paediatric medicinal development and the development of safety, disease and mechanistic "bottom up" models that could help shift the current medicinal development paradigm.

Mots clés: Medicine

Efthymios Manolis. Role of Modelling and Simulation (M&S) in Paediatric Investigation Plans (PIPs). Pediatric Anesthesia, 2011, 15 (s3 DP), pp.214. ⟨10.1111/j.1460-9592.2011.03523.x⟩. ⟨hal-00609057⟩