FDA Labeling Of Antiepileptic Drugs (AEDs) For Partial Onset Seizures (POS) Challenges The European Medicines Agency`s (EMA) Pediatric Investigation Plan (PIP) Concept

Background: Without a PIP, new drugs cannot be EU-registered. The EMA website lists 7 epilepsy PIPs. In 2016, the FDA decided that AED efficacy in adults can be extrapolated to children down to 4 years, making separate safety & efficacy (S&E) trials unnecessary.

Objective: To investigate whether PIP-demanded pediatric trials are scientifically justified.

Methods: All epilepsy PIPs on the EMA website were analyzed. Relevant FDA documents and literature were reviewed.

Results: The 7 epilepsy PIPs (brivaracetam, EMA-00332-PIP01-08-M11; carisbamate, EMEA-000360-PIP01-08; esclicarbazepine, EMEA-000696-PIP02-10-M05; ethosuximide, EMEA-001617-PIP01-14; lacosamide, EMEA-000402-PIP02-11-M03; retigabine, EMEA-000116-PIP01-07-M08; vigabatrin, EMEA-000717-PIP02-13-M02) demand for POS in total 32 studies, 7 modeling & simulation (M&S) studies, and one literature review. Patients` ages vary between birth to 17 years, one month to 17 years, 2-17 years, 6-15 years, 1 month to

Conclusion: Since the efficacy of AEDs can be extrapolated from adults, most PIP-demanded epilepsy POS trials are medically unjustified and therefore unethical. Children do not need as many clinical trials as possible, only those that truly advance treatment. Clinicians should refuse to participate in such trials or, if already participating in, should reconsider, discuss the FDA’s approach with the sponsoring company or clinical research organisation, and ask the responsible ethics committee to consider trial suspension.