Pediatric Extrapolation

Development of effective treatments for rare disease and in pediatric population poses unique scientific and ethical challenges in addition to the small markets. Children as a vulnerable population in clinical research require special considerations to minimize the risk and assure prospect of direct clinical benefit when the risk to the child is more than minimal. In this regard, both the US and EU regulations suggest a complementary strategy based on assessing the relevance of existing information in the adult population to the pediatric population, in terms of the disease, drug pharmacology, and clinical response to treatment in order to identify the gaps or level of uncertainty that need to be addressed to extend conclusion of adequate evidence of efficacy and safety. In this chapter, the aspects on pediatric extrapolation that can contribute to successful drug development of pediatric diseases are extensively discussed, including the sources and quality of data for extrapolation, the applicability of preclinical and nonclinical models, the extrapolation study designs considering choice of control, endpoint and type-I error rate, key approaches and considerations in starting dose selection, and dose-optimization/dose-finding, as well as useful Bayesian approaches. Examples of successful clinical development programs using pediatric extrapolation have been discussed in the chapter.