Reshaping study design for faster extrapolation-based drug approval in pediatric inflammatory bowel diseases: An ESPGHAN-NASPGHAN position paper.

Children with inflammatory bowel diseases (IBD) have limited access to the available advanced therapies, given the lengthy gap between adult and pediatric approval. We aimed to review key hurdles for pediatric trials and recommend practical solutions. This position paper was developed jointly by the European and North American Societies for Pediatric Gastroenterology Hepatology and Nutrition (ESPGHAN and NASPGHAN), in consultation with patient representatives. A systematic review was performed for identified topics, and two voting rounds with two group meetings led to agreement on 24 statements. The systematic review (reviewing 4366 manuscripts, of which 123 were included in tables of evidence and 213 in support of 23 statements) found similar biologic pathogenesis, and similar or better effectiveness and safety in children older than 2 years compared to adults. Pharmacokinetics were similar in adolescents but dissimilar in younger children. The review also found sufficiently accurate noninvasive endpoints to reflect post-induction treatment response. There was no significant added benefit for ileocolonoscopy over sigmoidoscopy in ulcerative colitis. Drugs should be approved in children >12 years and ≥40 kg based on extrapolation from adult and real-world data. While efficacy may be extrapolated to children <40 kg, pharmacokinetics cannot and thus one open-label single-arm study should be performed to establish a dose that matches adult exposure-response from the adult trial in which adolescents may be enrolled if not exposed to placebo. Full colonoscopies should be minimized in the pediatric dosing trial. Efficacy in patients with infantile IBD cannot be extrapolated from adult data.