Charlotte Simons1, Loes Maton1,2, Maaike van Dartel1, Michiel van den Heuvel1, Ms. Loes den Otter1,3, Dr. Carolien Versantvoort1, Dr. Pieter Colin2, Dr. Jeroen Koomen1,2
1Medicines Evaluation Board (CBG-MEB), 2Department of Anaesthesiology, University of Groningen, University Medical Center Groningen, 3Department of Cognitive Neuropsychiatry and Clinical Neuroscience, Mental Health and Neuroscience Research Institute (MHeNs), Maastricht University
Introduction For new medicines, drug companies obtain regulatory approval on the strategy to generate sufficient evidence to support the benefit/risk assessment of paediatric marketing authorisation applications (PMAAs). Evidence generation in the paediatric population can be supported by extrapolation of evidence obtained in a reference population. Extrapolation of efficacy may be limited to demonstrating similar drug exposure in the target and reference population, when there is sufficient confidence that disease progression, exposure-response and treatment effects are similar.[1,2] This study investigated whether PMAAs supported by extrapolation based on exposure-matching were more successful in terms of approval of the targeted paediatric population and more efficient in terms of duration of the drug development compared to PMAAs not supported by extrapolation. Methods Data was extracted from completed paediatric investigation plans (PIPs), associated drug labels and public assessment reports published on the European Medicines Agency website. Assessment reports were evaluated to assess whether PMAAs were supported by extrapolation based on exposure-matching. Wilcoxon rank-sum tests were used to compare PMAAs supported and not supported by extrapolation based on exposure-matching for outcomes including the duration of drug development completion and restrictions in the use of the medicinal product in the targeted paediatric population in terms of body weight and age limits. Additional subgroup analyses were conducted per therapeutic area, orphan disease status and drug molecular size. Results Exposure-matching supported the benefit/risk assessment of 39.6% of the PMAAs. Exposure-matching to support the benefit/risk assessment has increased over time. Between 2008 and 2010, two (22.2%) exposure-matching studies were conducted, whereas 18 (41.9%) exposure-matching studies were performed between 2020 and 2021. Targeted and approved minimum age of the paediatric population were comparable for PMAAs where extrapolation based on exposure-matching supported the benefit/risk assessment (2.0 vs. 2.0 years, P-value = .72), but not for PMAAs not supported by extrapolation (0.2 years vs. 0.5 years, P-value = .05). Completion of drug development was 5.4 years vs. 4.3 years (P-value = .04) in PMAAs supported by extrapolation based on exposure-matching compared to those not supported by extrapolation, respectively. PIPs were modified more often for marketing authorization applications where the benefit/risk assessment was supported by extrapolation based on exposure-matching compared to those not supported by extrapolation (4.0 vs. 3.0, P-value < .01). Conclusions PMAAs where regulatory decision-making was supported by extrapolation based on exposure-matching were more successful in terms of obtaining marketing approval in the targeted paediatric population compared to those not supported by exposure-matching. However, these paediatric marketing authorization applications are also less efficient as time to complete drug development was prolonged when using extrapolation based on exposure-matching.
[1] European Medicines Agency. Reflection paper on the use of extrapolation in the development of medicines for paediatrics (EMA/189724/2018). [2] International Council for Harmonisation. Guideline E11A Paediatric Extrapolation. https://database.ich.org/sites/default/files/ICH_E11A_Document_Step2_Guideline_2022_0404_0.pdf
Reference: PAGE 33 (2025) Abstr 11567 [www.page-meeting.org/?abstract=11567]
Poster: Clinical Applications