As part of a UK Medical Research Council-funded project on innovative designs for paediatric drug development programmes, we ran a one-day meeting on extrapolation in paediatric medicine development.

Extrapolation in Paediatric Medicine Development (17th May 2018) brought together researchers and practitioners to discuss methods for extrapolation and comprised of invited talks on extrapolation in paediatric drug development.

Speakers

• Ron Portman (Novartis, US) - Slides (Portman)
• Ian Wadsworth (Lancaster University, UK) - Slides (Wadsworth)
• Sarah Zohar (INSERM, France)
• Foteini Strimenopoulou (UCB, UK) - Slides (Strimenopoulou)
• Andy Kenwright (Roche, UK) - Slides (Kenwright)
• Franz König (Medical University of Vienna, Austria) - Slides (Koenig)
• Graeme Sills (University of Liverpool, UK) - Slides (Sills)

Schedule

09.00	Registration and coffee
09.30	Introduction to meeting
09.45	Ron Portman - Extrapolation: A Person’s a Person, No Matter How Small, Dr Seuss
10.30	Ian Wadsworth - Using historical data to inform extrapolation decisions in children
11.15	Coffee break
11.30	Sarah Zohar - Extrapolation and bridging between populations in early phase clinical trials
12.15	Foteini Strimenopoulou - Our experience at UCB in building priors for paediatric studies
13.00	Lunch
14.00	Andy Kenwright - Extrapolation: Lessons In Advising Across Therapeutic Areas/the Big Pond
14.45	Franz Koenig - Adaptive paediatric investigation plans – how to exploit extrapolation in drug development for children
15.30	Graeme Sills - Clinical drug development for epilepsy; risks and rewards of extrapolation
16.15	Summary and close

Abstracts

Andy Kenwright

Extrapolation: Lessons In Advising Across Therapeutic Areas/the Big Pond

Andy will highlight some key aspects of internal Roche/Genentech advice on how to make the most of extrapolation within clinical development programs, and some differences between FDA and PDCO.

Franz Koenig

Adaptive paediatric investigation plans - how to exploit extrapolation in drug development for children

Different arguments have been put forward why drug developers should commit themselves early for what they are planning to do for children. By EU regulation, paediatric investigation plans (PIP) should be agreed on in early phases of drug development in adults. A full independent drug development programme to demonstrate efficacy may not be ethical and/or feasible in such a highly vulnerable population as children. Here, extrapolation [1] from adults to children can be applied to reduce the burden and avoids unnecessary clinical trials in children, but early regulatory decisions on how far extrapolation can be used may be highly uncertain. Under special circumstances, the regulatory process should allow for adaptive paediatric investigation plans [2] explicitly foreseeing a re‐evaluation of the early decision based on the information accumulated later from adults or elsewhere. A small step towards adaptivity and learning from experience may improve the quality of regulatory decisions in particular with regard to how much information can be borrowed from adults. However, such an adaptive PIP would require some more flexibility from both regulatory authorities and sponsors. We will discuss how an adaptive PIP would fit considering the EU legislation and its implementation in EMA procedures. Furthermore, frequentist and Bayesian approaches [3] for extrapolation are discussed.

[1] EMA Draft Reflection paper on the use of extrapolation in the development of medicines for paediatrics (2017). EMA/199678/2016. European Medicines Agency, London, UK.[2] Bauer, P., & König, F. (2016). Adaptive paediatric investigation plans, a small step to improve regulatory decision making in drug development for children? Pharmaceutical Statistics, 15(5), 384-386.[3 Hlavin, G., Koenig, F., Male, C., Posch, M., & Bauer, P. (2016). Evidence, eminence and extrapolation. Statistics in Medicine, 35(13), 2117-2132.

Ron Portman

Extrapolation: A Person’s a Person, No Matter How Small, Dr Seuss

Abstract to follow.

Graeme Sills

Clinical drug development for epilepsy; risks and rewards of extrapolation

Data from clinical trials in adults, extrapolated to predict benefits in paediatric patients, could result in fewer or smaller trials being required to obtain a new drug licence for paediatrics. This talk outlines the place of such extrapolation in the development of drugs for use in paediatric epilepsies. Based on consensus expert opinion, a proposal is presented for a new paradigm for the clinical development of drugs for focal epilepsies. Phase I data should continue to be collected in adults, and phase II and III trials should simultaneously recruit adults and paediatric patients aged above 2 years. Drugs would be provisionally licensed for children subject to phase IV collection of neurodevelopmental safety data in this age group. A single programme of trials would suffice to license the drug for use as either adjunctive therapy or monotherapy. Patients, clinicians and sponsors would all benefit from this new structure through cost reduction and earlier access to novel treatments. Further work is needed to elicit the views of patients, their parents and guardians as appropriate, regulatory authorities and bodies such as the National Institute for Health and Care Excellence (UK).

Foteini Strimenopoulou

Our experience at UCB in building priors for paediatric studies

Abstract to follow.

Ian Wadsworth

Using historical data to inform extrapolation decisions in children

When developing new medicine for children, the potential to extrapolate from adult efficacy data is well recognised. However, significant assumptions about the similarity of adults and children are needed for extrapolations to be biologically plausible. One such assumption is that pharmacokinetic-pharmacodynamic (PK-PD) relationships are similar in these different groups. In this presentation, we consider how ‘source’ data available from historical trials completed in adults and adolescents treated with a test drug, can be used to quantify prior uncertainty about whether PK-PD relationships are similar in adults and younger children. A Bayesian multivariate meta-analytic model is used to synthesise the PK-PD data available from the historical trials which recruited adults and adolescents. The model adjusts for the biases that may arise since these existing data are not perfectly relevant to the comparison of interest, and we propose a strategy for eliciting expert prior opinion on the size of these external biases. From the fitted bias-adjusted meta-analytic model we derive prior distributions which quantify our uncertainty about the similarity of PK-PD relationships in adults and younger children. These prior distributions can then be used to calculate the probability of similar PK-PD relationships in adults and younger children which, in turn, may be used to inform decisions as to whether complete extrapolation of efficacy data from adults to children is currently justified, or whether additional data in children are needed to reduce uncertainty. Properties of the proposed methods are assessed using simulation, and their application to epilepsy drug development is considered.

Sarah Zohar

Extrapolation and bridging between populations in early phase clinical trials

Abstract to follow.