Extrapolation of efficacy and other data to support the development of new medicines for children: A systematic review of methods

Abstract

Abstract:Objective: When developing new medicines for children, the potential to extrapolate from adult data to reduce the experimental burden in children is well recognised. However, significant assumptions about the similarity of adults and children are needed for extrapolations to be biologically plausible. We reviewed the literature to identify statistical methods that could be used to optimise extrapolations in paediatric drug development programmes. Methods: Web of Science was used to identify papers proposing methods relevant for using data from a `source population' to support inferences for a `target population'. Four key areas of methods development were targeted: paediatric clinical trials; trials extrapolating efficacy across ethnic groups or geographic regions; the use of historical data in contemporary clinical trials; and using short-term endpoints to support inferences about long-term outcomes. Results: Searches identified 626 papers of which 52 met our inclusion criteria. From these we identified 102 methods comprising 58 Bayesian and 44 frequentist approaches. Most Bayesian methods (n=54) sought to use existing data in the source population to create an informative prior distribution for a future clinical trial. Of these, 46 allowed the source data to be down-weighted to account for potential differences between populations. Bayesian and frequentist versions of methods were found for assessing whether key parameters of source and target populations are commensurate (n=34). Fourteen frequentist methods synthesised data from different populations using a joint model or a weighted test statistic. Conclusions: Several methods were identified as potentially applicable to paediatric drug development. Methods which can accommodate a heterogeneous target population and which allow data from a source population to be down-weighted are preferred. Methods assessing the https://mc.manuscriptcentral.com/smmr Statistical Methods in Medical Research F o r P e e r R e v i e w commensurability of parameters may be used to determine whether it is appropriate to pool data across age groups to estimate treatment effects. Page 2 of 66https://mc.manuscriptcentral.com/smmr 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 Abstract Objective: When developing new medicines for children, the potential to extrapolate from adult data to reduce the experimental burden in children is well recognised. However, significant assumptions about the similarity of adults and children are needed for extrapolations to be biologically plausible. We reviewed the literature to identify statistical methods that could be used to optimise extrapolations in paediatric drug development programmes. Methods: Web of Science was used to identify papers proposing methods relevant for using data from a 'source population' to support inferences for a 'target population'. Fou...

Power gains by using external information in clinical trials are typically not possible when requiring strict type I error control

“…For comprehensive overviews, see, for example, Viele et al. () and Wadsworth, Hampson, and Jaki (). The rationale for using such dynamic borrowing mechanisms is often given by the desire to take into account external information only when it improves inference.…”

“…These include Bayesian dynamic borrowing methods such as hierarchical models, adaptive power priors, and robust mixture priors, and frequentist approaches such as test-then-pool. For comprehensive overviews, see, for example, Viele et al (2014) and Wadsworth, Hampson, and Jaki (2018). The rationale for using such dynamic borrowing mechanisms is often given by the desire to take into account external information only when it improves inference.…”

Bayesian sequential integration within a preclinical pharmacokinetic and pharmacodynamic modeling framework: Lessons learned

“…In some areas of drug development, prior elicitation constitutes a crucial phase since the specification of highly informative prior distributions compensates the small data, thus avoiding convergence issues in parameter estimation . For example, in pediatric studies Bayesian methods are typically used to explicitly borrow information from other adult trials or previous pediatric studies . See also Viele et al, Ibrahim et al, Takeda et al, and Li et al for a more general overview of benefits resulting from borrowing historical information in the analysis of the current trial.…”

A Quantitative Framework to Inform Extrapolation Decisions in Children

“…Wadsworth et al . (2016a) reported the findings of a systematic review of statistical methods that are relevant for extrapolating efficacy and other data from adults to children. Gamalo‐Siebers et al .…”

“…We focus on the extrapolation of adult efficacy data to children. Wadsworth et al (2016a) reported the findings of a systematic review of statistical methods that are relevant for extrapolating efficacy and other data from adults to children. Gamalo-Siebers et al (2017) illustrated methods that use adult data to design improved paediatric programmes and Petit et al (2018) proposed a method for the design and analysis of paediatric dose-finding trials, with the dose range calculated by extrapolating from adult pharmacokinetic data.…”