Clinical Drug Development in Epilepsy Revisited: A Proposal for a New Paradigm Streamlined Using Extrapolation

Abstract

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 article 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).

Ethical Issues in Pediatric Regulatory Studies Involving Placebo Treatment

“…6,9-11 Other authors went even further with the question if pediatric patients are just small adults, and answered this positively for AEDs: the underlying pathophysiological process is the same for patients 2 years, who will respond similarly to AEDs, provided the dosing is correct. 12 With these positions published in international peerreviewed journals, epileptology was and is the first clinical discipline to openly challenge the concept of children as "therapeutic orphans" which, since 1968, is the backbone of first U.S. and then European Union (EU) pediatric legislation. 13,14 In the United States, each member state decides about the age of majority.…”

Role of observational studies in supporting extrapolation of efficacy data from adults to children with epilepsy — A systematic review of the literature using lacosamide as an example

“…2,3 In epilepsy, however, differences in syndromes, aetiology and natural history between adults and children add further layers of complexity to analyses. 4,5 According to the Pediatric Epilepsy Academic Consortium for Extrapolation (PEACE), if antiepileptic drugs (AEDs) have been shown to be effective in adults with focal epilepsy, they can be considered effective in children !2 years of age with focal epilepsy. 4 During development, the evidence base for a candidate AED is typically built in the adult focal epilepsy setting; building the evidence base in primary generalized epilepsy (PGE; or idiopathic or generalized genetic epilepsy) however, is more complex and challenging.…”

A Quantitative Framework to Inform Extrapolation Decisions in Children

“…Throughout we illustrate the proposed extrapolation framework with applications to antiepileptic drug development. In this setting, there is broad agreement about the acceptability of extrapolating efficacy data in adults with partial onset seizures to older children with partial onset seizures, although there is some uncertainty about what age one can extrapolate down to (European Medicines Agency, 2010;Pediatric News, 2016;French et al, 2004;Wadsworth et al, 2016b). This paper proceeds as follows.…”