{"doi":"10.1002/bcp.70393","title":"Paediatric developmental safety and the ICH E11A extrapolation of safety","abstract":"Safety assessment remains a fundamental component of paediatric drug development and could not be extrapolated to paediatric patients from another patient population until ICH E11A.1 The concept of a safety evaluation in a paediatric patient is more complex than in adults because of the developmental process, which remains a continuous concern throughout all ages of paediatric patients. Drug effects on developmental systems are very much dependent on the stage of development at the time of exposure, so the evaluation process must consider multiple systems that may be affected at different periods of development. Adult surveillance of adverse effects should not solely dictate surveillance in paediatrics. Previously, extrapolating safety data from reference populations (patient populations that data are being taken from) to paediatric target populations (paediatric population data are being extrapolated to) was deemed inappropriate due to concerns about potential population-specific differences in drug safety profiles. The complexity of assessing the safety of drugs in paediatric patients led to important limitations regarding the extrapolation of safety information from the adult population to paediatric patients. The original inclusion of paediatric extrapolation of efficacy information in the 1994 final US FDA regulation on paediatric labelling stated that, when needed, additional paediatric safety information is necessary.2 Our scientific understanding and experience with paediatric drug development trials has since advanced considerably, enabling the development of a more advanced framework for paediatric extrapolation and including extrapolation of both efficacy and safety. The ICH E11A Paediatric Extrapolation Guidance for Industry1 sets forth a comprehensive framework that outlines key considerations for developing paediatric safety extrapolation strategies. Paediatric efficacy extrapolation operates along a continuum that reflects the degree of certainty regarding disease similarity, drug pharmacology and expected treatment response across populations. The extrapolation of safety should be considered separately as part of a Safety Extrapolation Plan (Section 4.1.7 in the ICH E11A Guidance). The on- and off-target effects of a new drug that are relevant to paediatric development cannot always be discerned from the adult population. Even when extrapolating efficacy and safety from an older paediatric reference patient population to a younger paediatric population, the developmental effects of a drug could be considerably different depending on the maturational stage of the organ system affected. Juvenile animal studies are triggered when there is a safety concern, and a weight-of-evidence approach is outlined in the ICH S11 Nonclinical Safety Testing in Support of Development of Pediatric Pharmaceuticals Draft Guidance for Industry.3 Juvenile animal studies may not reflect human development, and less than 10% of these studies result in changes in the clinical development programmes.4 Additionally, the pharmaceutical industry routinely screens for on and off-target effects during drug development using a panel of secondary pharmacology screening programmes,5 and some screened targets are associated with developmental toxicities.6 The positive links between off-target activity and a potential relationship with a paediatric developmental toxicity should be adjudicated in relation to the age group being treated, the benefit–risk assessment for drug use in that paediatric population, and the quantitative assessment of risk for this developmental toxicity. The incidence of adverse effects in the paediatric population is particularly important where safety findings of special importance have been observed in the reference population. For example, if an adverse effect is frequent in the paediatric population and could have an important developmental effect, such as on learning or the development of motor skills, then a more compl","journal":"British Journal of Clinical Pharmacology","year":2025,"id":583605,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9548,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":749847,"name":"Susan M. Abdel‐Rahman","orcid":"0000-0002-5815-2029","position":1,"is_corresponding":false},{"id":506108,"name":"Gelareh Abulwerdi","orcid":"0000-0002-1036-6378","position":2,"is_corresponding":false},{"id":28714,"name":"Rebecca Racz","orcid":"0000-0002-5487-5692","position":3,"is_corresponding":false},{"id":1073814,"name":"Sherbet Samuels","orcid":"0009-0001-1569-6157","position":4,"is_corresponding":false},{"id":743963,"name":"Dionna J. Green","orcid":null,"position":5,"is_corresponding":false},{"id":378481,"name":"Lynne Yao","orcid":"0009-0004-7611-217X","position":6,"is_corresponding":false},{"id":378479,"name":"Gilbert J. Burckart","orcid":"0000-0003-2005-9301","position":0,"is_corresponding":true}],"reference_count":6,"raw_metadata":null,"created_at":"2026-07-19T02:59:07.970345Z","pmid":"41316913","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}