Complexity of paediatric trials restricts effect on clinical practice

Abstract

Inflammatory bowel disease (IBD) has become a major burden of health care, with the number of adult and paediatric patients with this chronic disease increasing globally. It has been estimated that there are close to 10 million patients with IBD worldwide. 1 GBD 2017 Inflammatory Bowel Disease CollaboratorsThe global, regional, and national burden of inflammatory bowel disease in 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Gastroenterol Hepatol. 2020; 5: 17-30 Summary Full Text Full Text PDF PubMed Scopus (343) Google Scholar , 2 Ng SC Shi HY Hamidi N et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies. Lancet. 2017; 390: 2769-2778 Summary Full Text Full Text PDF PubMed Scopus (1672) Google Scholar Paediatric IBD is often more severe and extensive compared with adult IBD, and it might restrict growth. Patients with paediatric IBD need glucocorticoids more often than adult patients, and the need of surgery was more frequent in children, in the era before biologics. 3 Turner D Levine A Escher JC et al. Management of pediatric ulcerative colitis: joint ECCO and ESPGHAN evidence-based consensus guidelines. J Pediatr Gastroenterol Nut. 2012; 55: 340-361 Crossref PubMed Scopus (279) Google Scholar , 4 Turner D Ruemmele FM Orlanski-Meyer E et al. Management of paediatric ulcerative colitis, part 1: ambulatory care-an evidence-based guideline from European Crohn's and Colitis Organization and European Society of Paediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr. 2018; 67: 257-291 Crossref PubMed Scopus (103) Google Scholar , 5 Larsen MD Qvist N Nielsen J et al. Use of anti-TNFalpha agents and time to first-time surgery in paediatric patients with ulcerative colitis and Crohn's disease. J Crohns Colitis. 2016; 10: 650-656 Crossref PubMed Scopus (19) Google Scholar Management of paediatric IBD has shifted towards a more active approach, 3 Turner D Levine A Escher JC et al. Management of pediatric ulcerative colitis: joint ECCO and ESPGHAN evidence-based consensus guidelines. J Pediatr Gastroenterol Nut. 2012; 55: 340-361 Crossref PubMed Scopus (279) Google Scholar , 4 Turner D Ruemmele FM Orlanski-Meyer E et al. Management of paediatric ulcerative colitis, part 1: ambulatory care-an evidence-based guideline from European Crohn's and Colitis Organization and European Society of Paediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr. 2018; 67: 257-291 Crossref PubMed Scopus (103) Google Scholar , 6 Ruemmele F Veres G Kolho KL et al. Consensus guidelines of ECCO/ESPGHAN on the medical management of pediatric Crohn's disease. J Crohns Colitis. 2014; 8: 1179-1207 Summary Full Text Full Text PDF PubMed Scopus (622) Google Scholar , 7 van Rheenen PF Aloi M Assa A et al. The medical management of paediatric crohn's disease: an ECCO-ESPGHAN guideline update. J Crohns Colitis. 2020; (published online Oct 7.)https://doi.org/10.1093/ecco-jcc/jjaa161 PubMed Google Scholar and the use of anti-TNF drugs has increased. Infliximab has been available for paediatric use since 2003, first for Crohn's disease and, since 2011, for ulcerative colitis. The second anti-TNF agent, adalimumab, was only approved by the US Food and Drug Administration in 2021 and European Medicines Agency in 2020 for use in paediatric ulcerative colitis; however, approval for use in Crohn's disease was given in 2014. Why such a delay? The hurdle to getting available drugs licensed for paediatric use is the extreme complexity of drug trials in children. As a result, there are too few paediatric trials, and many children are treated with off-label use of drugs approved for adults. Therefore, the randomised phase 3 trial investigating the use of adalimumab in paediatric ulcerative colitis, by Nicholas Croft and colleagues and published in The Lancet Gastroenterology & Hepatology, 8 Croft NM Faubion Jr, WA Kugathasan S et al. Efficacy and safety of adalimumab in paediatric patients with moderate-to-severe ulcerative colitis (ENVISION I): a randomised, controlled, phase 3 study. Lancet Gastroenterol Hepatol. 2021; (published online June 18.)https://doi.org/10.1016/S2468-1253(21)00142-4 Summary Full Text Full Text PDF PubMed Scopus (2) Google Scholar is more than welcome. Efficacy and safety of adalimumab in paediatric patients with moderate-to-severe ulcerative colitis (ENVISION I): a randomised, controlled, phase 3 studyClinically meaningful rates of remission and response were reported in children who received adalimumab in this study. No new safety signals were observed, suggesting that adalimumab is an efficacious and safe treatment option for children with moderate-to-severe ulcerative colitis. Full-Text PDF