TY - JOUR
T1 - Extrapolating evidence of antiepileptic drug efficacy in adults to children ≥2 years of age with focal seizures
T2 - The case for disease similarity
AU - the Pediatric Epilepsy Academic Consortium for Extrapolation
AU - Pellock, John M.
AU - Arzimanoglou, Alexis
AU - D'Cruz, O'Neill
AU - Holmes, Gregory L.
AU - Nordli, Douglas
AU - Shinnar, Shlomo
N1 - Publisher Copyright:
Wiley Periodicals, Inc. © 2017 International League Against Epilepsy
PY - 2017/10
Y1 - 2017/10
N2 - Expediting pediatric access to new antiseizure drugs is particularly compelling, because epileptic seizures are the most common serious neurological symptom in children. Analysis of antiepileptic drug (AED) efficacy outcomes of randomized controlled trials, conducted during the past 20 years in different populations and a broad range of study sites and countries, has shown considerable consistency for each drug between adult and pediatric populations. Historically, the majority of regulatory approvals for AEDs have been for seizure types and not for specific epilepsy syndromes. Available data, both anatomical and neurophysiological, support a similar pathophysiology of focal seizures in adults and young children, and suggest that by age 2 years the structural and physiological milieu upon which seizures develop is similar. Although the distribution of specific etiologies and epilepsy syndromes is different in children from in adults, this should not impact approvals of efficacy based on seizure type, because the pathophysiology of focal seizures and the drug responsiveness of these seizure types are quite similar. Safety and pharmacokinetics cannot be extrapolated from adults to children. The scientific rationale, clinical consensus, and published data support a future approach accepting efficacy data from adult trials and focusing exclusively on prospective pharmacokinetic, tolerability, and safety studies and long-term follow-up in children. Whereas tolerability studies can be compared easily in children and adults, safety studies require large numbers of patients followed for many years.
AB - Expediting pediatric access to new antiseizure drugs is particularly compelling, because epileptic seizures are the most common serious neurological symptom in children. Analysis of antiepileptic drug (AED) efficacy outcomes of randomized controlled trials, conducted during the past 20 years in different populations and a broad range of study sites and countries, has shown considerable consistency for each drug between adult and pediatric populations. Historically, the majority of regulatory approvals for AEDs have been for seizure types and not for specific epilepsy syndromes. Available data, both anatomical and neurophysiological, support a similar pathophysiology of focal seizures in adults and young children, and suggest that by age 2 years the structural and physiological milieu upon which seizures develop is similar. Although the distribution of specific etiologies and epilepsy syndromes is different in children from in adults, this should not impact approvals of efficacy based on seizure type, because the pathophysiology of focal seizures and the drug responsiveness of these seizure types are quite similar. Safety and pharmacokinetics cannot be extrapolated from adults to children. The scientific rationale, clinical consensus, and published data support a future approach accepting efficacy data from adult trials and focusing exclusively on prospective pharmacokinetic, tolerability, and safety studies and long-term follow-up in children. Whereas tolerability studies can be compared easily in children and adults, safety studies require large numbers of patients followed for many years.
KW - AMPA
KW - GABA
KW - NMDA
KW - Pharmacokinetics
KW - Potassium channels
KW - Sodium channels
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U2 - 10.1111/epi.13859
DO - 10.1111/epi.13859
M3 - Review article
C2 - 28755452
AN - SCOPUS:85026491500
SN - 0013-9580
VL - 58
SP - 1686
EP - 1696
JO - Epilepsia
JF - Epilepsia
IS - 10
ER -