Bridging the gap:using extrapolation to reduce the experimental burden in children

When developing a new drug product for children, it is important to provide safe and effective medicines whilst minimising the experimental burden where possible. Extrapolating data from clinical trials in adults or other relevant populations has the potential to reduce the number or size of clinical trials required to obtain a licence for a new drug in the paediatric population. The ethical and practical benefits extrapolation can provide, such as speeding up access to medicines, reducing drug development costs and avoiding replication of existing information, have to be balanced against potential risks i.e. if extrapolation from adults is incorrectly deemed to be appropriate, children could be exposed to a harmful or ineffective treatment. Extrapolation is therefore a challenging but important aspect for future paediatric medicine development. The work presented in this thesis is broadly interested in approaches for reducing the experimental burden in the paediatric population by leveraging external information, such as existing adult data or the opinion of clinical experts. The concept of extrapolation, especially in the context of paediatric clinical trials, is explored over the thesis, beginning with a literature review of extrapolation methodology in Chapter 3, particularly aiming to identify potentially relevant methods for performing extrapolations to children. Extrapolation can be a potentially controversial approach to take in drug development, so the opinion of experts within a target clinical setting is incredibly valuable. Chapters 4 and 5 describe the process and outcome of seeking the opinion of clinical experts regarding extrapolation in epilepsy drug development. Based on this expert opinion, an outline for a new drug development paradigm is presented allowing for simultaneous recruitment of adults and paediatric patients aged 2 years and older, from Phase II onwards. In order for the extrapolation of efficacy data from adult trials to the paediatric population to be plausible and appropriate, strong assumptions regarding similarity between these populations are required. One important assumption is whether adults and children can be said to have similar pharmacokinetic-pharmacodynamic (PK-PD) relationships. In Chapter 6, an approach is developed to use data from existing studies of adults and adolescents, along with expert opinion, to quantify prior uncertainty regarding the similarity of PK-PD relationships in adults and younger children. A bias-adjusted meta-analysis of existing adult and adolescent data allows the derivation of prior distributions quantifying our uncertainty about the extrapolation assumption and calculation of the prior probability that the extrapolation assumption holds. This approach could be extended to quantifying prior uncertainty in other contexts; here we consider PK-PD relationships in adults and younger children to provide a clear focus. Within the paediatric population itself, there may exist distinct age groups with different PK-PD relationships requiring separate dosing rules to account for pharmacological differences. Chapter 7 considers model-based approaches to quantify how parameters of PK-PD models differ over age. Based on this, an approach for deriving optimal dosing rules accounting for differences between age groups is developed