Manolis Efthymios, Osman Tariq Eldirdiry, Herold Ralf, Koenig Franz, Tomasi Paolo, Vamvakas Spiros, Saint Raymond Agnes
European Medicines Agency, Canary Wharf, London, UK.
Paediatr Anaesth. 2011 Mar;21(3):214-21. doi: 10.1111/j.1460-9592.2011.03523.x. Epub 2011 Jan 18.
Ethical and practical constraints encourage the optimal use of resources in pediatric drug development. Modeling and simulation has emerged as a promising methodology acknowledged by industry, academia, and regulators. We previously proposed a paradigm in pediatric drug development, whereby modeling and simulation is used as a decision tool, for study optimization and/or as a data analysis tool. Three and a half years since the Paediatric Regulation came into force in 2007, the European Medicines Agency has gained substantial experience in the use of modeling and simulation in pediatric drug 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 pediatric database search to further 'validate' the paradigm. There were 47 of 210 positive pediatric investigation plan (PIP) opinions that made reference to modeling and simulation (data included all positive opinions issued up to January 2010). This reflects a major shift in regulatory thinking. The ratio of PIPs with modeling and simulation rose to two in five based on the summary reports. Population pharmacokinetic (POP-PK) and pharmacodynamics (POP-PD) and physiologically based pharmacokinetic models are widely used by industry and endorsed or even imposed 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 but less is known about the effects of size and maturation on PD, disease progression, and safety. Extrapolation of efficacy from different age groups is often used in pediatric medicinal development as another means to alleviate the burden of clinical trials in children, and this can be aided by modeling and simulation to supplement clinical data. The regulatory assessment is finally judged on clinical grounds such as feasibility, ethical issues, prioritization of studies, and unmet medical need. The regulators are eager to expand the use of modeling and simulation to elucidate safety issues, to evaluate the effects of disease (e.g., renal or hepatic dysfunction), and to qualify mechanistic models that could help shift the current medicinal development paradigm.
伦理和实际限制因素促使儿科药物研发中资源的优化利用。建模与模拟已成为一种受到业界、学术界和监管机构认可的、颇具前景的方法。我们之前提出了一种儿科药物研发范式，即将建模与模拟用作决策工具以优化研究和/或用作数据分析工具。自2007年《儿科法规》生效三年半以来，欧洲药品管理局在儿科药物研发中使用建模与模拟方面积累了丰富经验。在本综述中，我们列举了所提出的范式如何应用于计划中的药物研发实际案例的示例。我们还报告了一项儿科数据库检索结果，以进一步“验证”该范式。在210项积极的儿科研究计划（PIP）意见中，有47项提及了建模与模拟（数据包括截至2010年1月发布的所有积极意见）。这反映了监管思维的重大转变。根据总结报告，涉及建模与模拟的PIP比例升至五分之二。群体药代动力学（POP-PK）和药效学（POP-PD）以及基于生理的药代动力学模型被业界广泛使用，并得到监管机构的认可甚至强制要求，作为规避儿童药品研发中一些困难的一种方式。关于年龄和体型对药代动力学影响的知识正在不断完善，模型被广泛用于充分利用这一知识，但对于体型和成熟度对药效学、疾病进展及安全性的影响了解较少。在儿科药物研发中，常常采用从不同年龄组外推疗效的方法，作为减轻儿童临床试验负担的另一种手段，而建模与模拟可以辅助补充临床数据。监管评估最终基于可行性、伦理问题、研究优先级和未满足的医疗需求等临床依据进行判断。监管机构渴望扩大建模与模拟的应用，以阐明安全性问题、评估疾病（如肾功能或肝功能障碍）的影响，并使有助于改变当前药物研发范式的机制模型得到验证。
