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A Revisited Strategy for Antiepileptic Drug Development in Children

Designing an Initial Exploratory Step

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Abstract

Background

Randomized controlled trials (RCTs) in refractory paediatric epilepsy usually involve the two main types of epilepsy shared by children and adults, focal epilepsy and Lennox-Gastaut syndrome (LGS). Most other epilepsy syndromes, specifically paediatric, are excluded from drug development. In order to identify among them the candidate(s) for dedicated RCTs with a new drug, the European Medicine Agency (EMA) recently recommended proceeding in two steps: (1) an exploratory (prospective-observational) trial (POT) including a large variety of paediatric epilepsy syndromes and (2) a subsequent RCT in each of those that disclose a signal for possible efficacy.

Objective

Our objective was to address the three following issues that have not been addressed by the EMA: (1) to determine a minimal threshold for this signal; (2) to establish a list of epilepsies to evaluate; and (3) to estimate the number of patients to include in such POTs.

Methods

We extensively reviewed the POTs (including various syndromes) and RCTs reported in paediatric patients with uncontrolled epilepsy using MEDLINE (from 1990 to 2011) and the Cochrane library. We determined the threshold as the lowest percentage of responders observed in a POT with a positive corresponding RCT. The syndromes that reached this threshold in a POT were those to evaluate in an RCT. The minimal number of patients to include for each syndrome for a POT with a new antiepileptic drug was estimated in order to reach at least this threshold of responders with a 95 % confidence interval.

Results

We found the minimal responder threshold to be 25 %. We identified eight epilepsy types/syndromes reaching this threshold and estimated for each of them the minimal sample needed: refractory focal epilepsy (n = 40), Lennox-Gastaut syndrome (n = 32), infantile spasms (n = 50), Dravet syndrome (n = 32), childhood absence epilepsy (n = 12), other symptomatic generalized epilepsy (n = 38), epileptic encephalopathy with continuous spikes and waves during sleep (n = 7) and epilepsy with myoclonic-astatic seizures (n = 4) [the two last samples may be underestimated due to the lack of RCTs in these conditions].

Conclusion

Among the eight epilepsy types/syndromes that we recommend to systematically include in exploratory trials using the POT procedure, we assume that, for the minimal sample given above, a responder threshold of 25 % will provide a reliable efficacy signal, to be confirmed by a dedicated RCT. This strategy should avoid missing new therapeutic possibilities for children with epilepsy and reduce the off-label use of drugs in paediatric neurology.

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Acknowledgements

We are grateful to Gail Scher who reviewed the manuscript. Dr Chiron has received honoraria from Biocodex, Eisai, Lundbeck, Novartis and Johnson & Johnson, and research support from Biocodex, Eisai, the European Community Sixth and Seventh Framework Thematic Priority Life Sciences, the French Research Agency (ANR), the French Foundation for Research in Epilepsy (FFRE) and the Foundation for Brain Research (FRC). Dr Kassai reports no disclosures. Prof. Dulac has received research support from Biocodex, and the French University. Prof. Pons has received research support from Biocodex, and the French Ministry of Health. Dr Nabbout serves on the scientific advisory board for Novartis and has received research support from Biocodex, Viropharma and the ANR. We confirm that we have read the journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. No funding was received to prepare this manuscript.

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Authors and Affiliations

  1. Inserm, U663, Service de Neurologie et Metabolisme, Hopital Necker, 149 rue de Sevres, 75015, Paris, France

    Catherine Chiron, Olivier Dulac, Gerard Pons & Rima Nabbout

  2. University Paris Descartes, Paris, France

    Catherine Chiron, Olivier Dulac, Gerard Pons & Rima Nabbout

  3. APHP, Department of Pediatric Neurology and Metabolism, Hospital Necker – Enfants Malades, Paris, France

    Catherine Chiron, Olivier Dulac & Rima Nabbout

  4. Department of Clinical Pharmacology, Epicime-CIC 201/Inserm-Hospices Civils de Lyon, RIPPS, UMR 5558 CNRS, University Hospital of Lyon, Lyon, France

    Behrouz Kassai

  5. APHP, Department of Pediatric Clinical Pharmacology, RIPPS, Hospital Cochin – Saint Vincent de Paul, Paris, France

    Gerard Pons

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  1. Catherine Chiron
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Correspondence to Catherine Chiron.

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Chiron, C., Kassai, B., Dulac, O. et al. A Revisited Strategy for Antiepileptic Drug Development in Children. CNS Drugs 27, 185–195 (2013). https://doi.org/10.1007/s40263-012-0035-9

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