Abstracts

Rationale: Epilepsy clinical trials have difficulty recruiting young children. The RRE is an initiative of the Epilepsy Foundation, bringing together industry and academic scientists and clinicians, patient representatives, and regulators to address current scientific and regulatory challenges. The 2017 RRE topic was "Pediatric drug development: Moving toward a framework for antiepileptic drug (AED) use in children." Methods: During the meeting, participants: Reviewed the current landscape of pediatric epilepsy trialsConsidered the current role of extrapolation, and where this may be applied more broadly or in new areasDiscussed the scientific value and limitations (technical and ethical) of pediatric regulatory requestsIdentified trial data most valued by pediatric neurologistsHeard from patient and caregiver stakeholders about outcome measures they most valueMade proposals to improve the structure of pediatric epilepsy trials Results: Pediatric regulatory requirements from the Food and Drug Administration (FDA) and European Medicines Agency (EMA) are often not aligned. Current requirements emphasize the pursuit of placebo-controlled efficacy data from trials in young children. Such data is virtually impossible to obtain, and delays acquisition of safety, tolerability, dosing and pK data. Difficulties in conducting required pediatric trials include low incidence of some seizure types or epilepsy syndromes in young children (particularly for Lennox-Gastaut syndrome (LGS) and primary generalized tonic-clonic seizures (PGTCS)), caregiver and clinician reluctance to enroll participants in placebo-controlled trials (particularly for focal seizures), high rates of placebo-response and comorbidities, small numbers of patients determined refractory by the ages included for study, competition for patients due to other studies in the field, and ethical concerns when a marketed product can be used off-label. Conclusions: Clinicians value safety, tolerability and dosing data over efficacy data in young children. Possible regulatory solutions include expanding extrapolation of efficacy to younger ages (such as in children with focal seizures from the current extrapolation of age 4 years down to age 2 years), and exploring extrapolation use for indications in LGS (down to age 3 years) and PGTCS. Additionally, waivers from study of young children may be appropriate under the Pediatric Research Equity Act (PREA) for "impossible or highly impractical" placebo-controlled efficacy studies (such as infants and toddlers from 1 month to 2 years with focal seizures). Alternate study designs such as observational cohort studies, retention rate trials or comparative trials of newer AEDs could provide valuable safety, tolerability, dosing and pK data. Non-seizure outcome measures are valued by patients and families, and should be explored. Funding: RRE member companies participate via sponsorship agreement for each annual meeting.