Abstracts

Rationale: Prior to June of 2017, VNS Therapy for epilepsy was indicated for use in the United States for adults and adolescents 12 years of age and older with partial onset seizures that are refractory to antiepileptic medications. FDA accepts extrapolation of efficacy from adults to pediatrics for anti-epileptic drugs. Using methodology outlined in FDA’s 2016 guidance document “Leveraging Existing Clinical Data for Extrapolation to Pediatric Uses of Medical Devices”, we investigated whether existing clinical data could be used to extrapolate safety and efficacy of VNS Therapy to include patients 4 to 11 years of age with partial onset seizures that are refractory to antiepileptic medications. Methods: Existing clinical study data were evaluated in addition to the Cyberonics post-market surveillance database. All clinical studies followed good clinical practices to protect study participants. The primary effectiveness endpoint was the percentage of patients 4-11 years of age with =50% reduction from baseline in the frequency of seizures following 12 months of treatment. A Bayesian hierarchical model, which borrowed from adult data, was used to model the 12-month responder rates. The primary safety endpoint was the incidence rate of device-related treatment emergent adverse events for patients 4-11 years of age; this rate was compared to that of patients 12-21 years via a 95% confidence interval for the incidence rate ratio (IRR). Results: Clinical study data from 847 patients and post-market surveillance data from 80,366 patients were included. At baseline, patients were taking an average of 2.6 AEDs (range 0-7). The mean age at epilepsy onset was 9.2 years with an average of 18.2 years passed from the time of diagnosis until VNS implant. In the efficacy population, 582 patients completed 12 months of follow-up. Across all studies, the Bayesian hierarchical model estimate for responder rate (RR) following 12 months of treatment in patients 4-11 years of age is 37% (95% credible interval: 26%, 48%). The response rate was similar to the estimate for patients =12 years (RR: 39%; 95% credible interval: 33%, 46%). In the safety population, 805 patients completed 12 months of follow-up. Based on clinical data, the overall incidence rate of device related treatment emergent adverse events was not different for patients 4-11 years of age compared to patients 12-21 years of age (IRR: 0.44, 95% CI: 0.20, 1.04). Based on post-market surveillance data, the overall incidence rate of device related treatment emergent adverse events was lower for patients 4-11 years of age compared to patients 12-21 years of age (IRR: 0.82, 95% CI: 0.77, 0.88). There were no unanticipated adverse device effects observed in pediatric patients 4-11 years of age. Overall, treatment-emergent adverse events in patients 4-11 years of age were consistent with patients 12-21 years of age treated with VNS Therapy and no new risks were identified. Conclusions: Based on these findings, FDA approved VNS Therapy for drug resistant epilepsy in children = 4 years of age. VNS Therapy is a safe and effective treatment for partial onset seizures that are refractory to antiepileptic medications in adults and pediatric patients = 4 years of age. Funding: LivaNova USA, Inc. is the study sponsor.