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. 2022 Oct;63(10):2664-2670.
doi: 10.1111/epi.17366. Epub 2022 Aug 12.

Considerations for determining the efficacy of new antiseizure medications in children age 1 month to younger than 2 years

Jacqueline A French  1 , Elena Cleary  2 , Dennis Dlugos  3 , Gail Farfel  4 , Kathleen Farrell  5 , Barry Gidal  6 , Caitlin L Grzeskowiak  5 , Rachel Gurrell  7 , Cynthia Harden  8 , Tracy J Stalvey  9 , Julia Tsai  10 , Elaine C Wirrell  11 , David Blum  12 , Nathan Fountain  13
Affiliations

Considerations for determining the efficacy of new antiseizure medications in children age 1 month to younger than 2 years

Jacqueline A French et al. Epilepsia. 2022 Oct.

Abstract

Objectives: Drug treatment for children with epilepsy should, ideally, be governed by evidence from adequate and well-controlled clinical studies. However, these studies are difficult to conduct, and so direct evidence supporting the informed use of specific drugs is often lacking. The Research Roundtable for Epilepsy (RRE) met in 2020 to align on an approach to therapy development for focal seizures in children age 1 month <2 years of age.

Methods: The RRE reviewed the regulatory landscape, epidemiology, seizure semiology, antiseizure medicine pharmacology, and safety issues applicable to this population.

Results: After reviewing evidence, the conclusion was that pediatric efficacy trials would be impracticable to conduct but a waiver of the regulatory requirement to conduct any study would lead to an absence of information to guide dosing in a critical population. Review of available data and discussion of RRE attendees led to the conclusion that the requirements for extrapolation of efficacy from older children down to infants from age 1 month to <2 years old appeared to be met. After the RRE, the US Food and Drug Administration (FDA) approved brivaracetam for use in children with focal epilepsy above the age of 1 month in August 2021 and lacosamide in October 2021, both based on the principle of extrapolation from data in older children.

Significance: These recommendations should result in more rapid accessibility of antiseizure medications for infants.

Keywords: antiseizure medications; clinical trials; extrapolation; pediatric epilepsy.

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Conflict of interest statement

J. French receives salary support from the Epilepsy Foundation and for consulting work and/or attending Scientific Advisory Boards on behalf of the Epilepsy Study Consortium for Aeonian/Aeovian, Alterity Therapeutics Limited, Anavex, Arkin Holdings, Angelini Pharma S.p.A, Arvelle Therapeutics, Inc., Athenen Therapeutics/Carnot Pharma, Autifony Therapeutics Limited, Baergic Bio, Biogen, Biohaven Pharmaceuticals, BioMarin Pharmaceutical Inc., BioXcel Therapeutics, Bloom Science Inc., BridgeBio Pharma Inc., Camp4 Therapeutics Corporation, Cerebral Therapeutics, Cerevel, Clinical Education Alliance, Coda Biotherapeutics, Corlieve Therapeutics, Crossject, Eisai, Eliem Therapeutics, Encoded Therapeutics, Engage Therapeutics, Engrail, Epalex, Epihunter, Epiminder, Epitel Inc, Equilibre BioPharmaceuticals, Greenwich Biosciences, Grin Therapeutics, GW Pharma, Janssen Pharmaceutica, Jazz Pharmaceuticals, Knopp Biosciences, Lipocine, LivaNova, Longboard Pharmaceuticals, Lundbeck, Marinus, Mend Neuroscience, Merck, NeuCyte Inc., Neumirna Therapeutics, Neurocrine, Neuroelectrics USA Corporation, Neuronetics Inc., Neuropace, NxGen Medicine Inc., Ono Pharmaceutical Co., Otsuka Pharmaceutical Development, Ovid Therapeutics Inc., Paladin Labs Inc., Passage Bio, Pfizer, Praxis, PureTech LTY Inc., Rafa Laboratories Ltd, SK Life Sciences, Sofinnova, Stoke, Supernus, Synergia Medical, Takeda, UCB Inc., Ventus Therapeutics, Xenon, Xeris, Zogenix, Zynerba. J. French has also received research support from the Epilepsy Study Consortium (Funded by Andrews Foundation, Eisai, Engage, Lundbeck, Pfizer, SK Life Science, Sunovion, UCB, Vogelstein Foundation) Epilepsy Study Consortium/Epilepsy Foundation (Funded by UCB), GW/FACES and NINDS. She is on the editorial board of Lancet Neurology and Neurology Today. She is Chief Medical/Innovation Officer for the Epilepsy Foundation. She has received travel reimbursement related to research, advisory meetings, or presentation of results at scientific meetings from the Epilepsy Study Consortium, the Epilepsy Foundation, Angelini Pharma S.p.A., Clinical Education Alliance, NeuCyte, Inc., Neurocrine, Praxis, Xenon. E. Cleary is an employee of UCB Biosciences. D. Dlugos has received salary support from the National Institutes of Health (NIH), Commonwealth of Pennsylvania Department of Health, Pediatric Epilepsy Research Foundation, and The Epilepsy Study Consortium. He is an investigator on research grants awarded to Children's Hospital of Philadelphia (CHOP) from Takeda, Zogenix, Greenwich Biosciences, Stoke Therapeutics, Neurelis, Aquestive, Bio‐Pharm, SK Life Sciences, Encoded Therapeutics, Xenon and Longboard Pharmaceuticals. He received honoraria and/or travel support for continuing medical education (CME) and other educational programs from Wake Forest University School of Medicine, American Epilepsy Society, Epilepsy Foundation of America, Medscape, Ministry of Health of the United Arab Emirates, Seoul National University, and the Chinese Pediatric Society. G. Farfel is Executive Vice President and Chief Development Officer of Zogenix, a wholly owned subsidiary of UCB Pharma. She is also a member of the Board of Directors of Durect Corporation, and of AvroBio Inc. K. Farrell is an employee of the Epilepsy Foundation. B. Gidal receives Speaking or Consulting honorarium from UCB, Eisai, SK Life Science, Greenwich Biosciences, and Aquestive. C. Grzeskowiak is an employee of the Epilepsy Foundation. R. Gurrell is or was an employee of Pfizer Ltd and Cerevel Therapeutics and may own stock in the company. C. Harden is a full‐time employee of Xenon Pharmaceuticals Inc and owns stock in this company. T. Stalvey was a paid employee of Aquestive Therapeutics and Neurelis. T. Stalvey is currently a paid employee of Imagion Biosystems and is on the Board of Directors for the Epilepsy Foundation of Central and South Texas. J. Tsai is a paid employee of Ovid Therapeutics. E.C. Wirrell has received consulting fees from Encoded Therapeutics, Eisai, and Biomarin. D. Blum receives compensation from Eliem Pharmaceuticals, GW Pharmaceuticals, Neuroelectrics Corporation, Neurona Therapeutics, ProUnlimited, Sunovion Pharmaceuticals, Takeda, and XW Pharmaceuticals. N. Fountain is principal investigator for clinical trial grants or consulting awarded to the University of Virginia from UCB, SK, Neurelis, Takeda, GW, Xenon, DSLP (AFT Pharmaceuticals), Janssen, Equilibre, InSightec, Cerebral Therapeutics, and Medtronic. He receives compensation or stock as a member of the board of directors of Acumen Pharmaceuticals and Hexokine Therapeutics.

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