Optimising Design In Paediatric Regulatory Studies
Oscar Della Pasqua(1) and Eliane Fuseau(2)
(1)GlaxoSmithKline, Greenford, UK (2)EMF,Aix-en-Provence, France
Most societies define children population by age group and/or by sexual activity. However, these definitions do not support current PKPD understanding of pharmacological response and physiology. Obvious differences exist between adult and children, which are relevant to the treatment of their disease. These may encompass changes in pharmacokinetics, pharmacodynamics, safety and efficacy assessments.
Pharmaceutical companies do not usually assess the dose-response in the children population, but rather rely on empirical practices and off-label extrapolation. Techniques exist which would allow a rational dose selection in children, based on PKPD bridging studies. Yet, the approach requires the adequate use of children-specific assessment of the disease and treatment. Regulatory organs have attempted to encourage companies to retain the initiative of paediatric development for their compounds and issued a number of guidance documents over the last 5 years: FDA (1998), ICH E11 (2000), EMEA (draft 2002). These documents have addressed the issue of drug development for paediatric use only and redefined the timing of the paediatric studies relative to the adult studies.
Current guidelines do not address all relevant issues concerning study design and data analysis. In addition to recruitment issues, examples will be presented that illustrate difficulties in dose selection, sampling scheme, pharmacokinetic disposition and differences in delivery systems and absorption. The use of simulation and extrapolation from adult data is not simple and may lead to bias and imprecision.
Population PKPD modelling is a tool to optimise paediatric drug development program and meet regulatory requirements. Implementation of bridging strategy will allow coherent label for paediatric indication.