Particularities of IBD Trials in Children

Author(s): Dan Turner*.

Journal Name: Current Pharmaceutical Design

Volume 25 , Issue 1 , 2019


Abstract:

Pediatric inflammatory bowel diseases (IBD) are similar to the adult-onset type in many aspects, including the necessity of high-quality randomized controlled trials. However, recruiting children into clinical trials is conceptually more challenging than in adults. Furthermore, the long delay between adult and pediatric approval of new drugs leads not only to the unbearable extensive use of these drugs as off-label without appropriate dosing and safety data but also to more challenges when eventually the pediatric trial is performed. This review offers possible solutions to age-specific pitfalls in performing trials in pediatric IBD. Many of the challenges could be adequately addressed by accepting full extrapolation of efficacy from adult trials. This is advisable if small pharmacokinetics/ pharmacodynamics (PK/PD) studies show similarity to adult data. Then, pediatric trials can focus on dosing and safety while avoiding the controversial use of placebo. Judicious use of non-invasive activity scores and biomarkers, providing immediate and effective treatment in active disease and ensuring equipoise of treatments both within and outside the trial are the mainstay of a feasible trial in children. The recent trend of including adolescents in adult phase-3 trials addresses some obstacles but introduces others. Acknowledging and addressing these age-specific challenges would facilitate pediatric drug development in IBD.

Keywords: Children, pediatrics, clinical trials, design, placebo, inflammatory bowel diseases, endpoints, biologics.

[1]
Molodecky NA, Soon IS, Rabi DM, et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology 2012; 142: 46-54.
[2]
Benchimol EI, Fortinsky KJ, Gozdyra P, Van den Heuvel M, Van Limbergen J, Griffiths AM. Epidemiology of pediatric inflammatory bowel disease: a systematic review of international trends. Inflamm Bowel Dis 2011; 17(1): 423-39.
[3]
Turner D, Koletzko S, Griffiths AM, et al. Use of Placebo in Pediatric Inflammatory Bowel Diseases: A Position Paper From ESPGHAN, ECCO, PIBDnet, and the Canadian Children IBD Network. J Pediatr Gastroenterol Nutr 2016; 62(1): 183-7.
[4]
Ruemmele FM, Hyams JS, Otley A, et al. Outcome measures for clinical trials in paediatric IBD: an evidence-based, expert-driven practical statement paper of the paediatric ECCO committee. Gut 2015; 64(3): 438-46.
[5]
Mulugeta Y, Barrett JS, Nelson R, et al. Exposure Matching for Extrapolation of Efficacy in Pediatric Drug Development. J Clin Pharmacol 2016; 56(11): 1326-34.
[6]
Sun H, Vesely R, Nelson RM, et al. Steps toward harmonization for clinical development of medicines in pediatric ulcerative colitis-a global scientific discussion, part 2: data extrapolation, trial design, and pharmacokinetics. J Pediatr Gastroenterol Nutr 2014; 58(6): 684-8.
[7]
Hyams JS, Chan D, Adedokun OJ, et al. Subcutaneous Golimumab in Pediatric Ulcerative Colitis: Pharmacokinetics and Clinical Benefit. Inflamm Bowel Dis 2017; 23(12): 2227-37.
[8]
Kelsen JR, Grossman AB, Pauly-Hubbard H, Gupta K, Baldassano RN, Mamula P. Infliximab therapy in pediatric patients 7 years of age and younger. J Pediatr Gastroenterol Nutr 2014; 59(6): 758-62.
[9]
Adedokun OJ, Xu Z, Padgett L, et al. Pharmacokinetics of infliximab in children with moderate-to-severe ulcerative colitis: results from a randomized, multicenter, open-label, phase 3 study. Inflamm Bowel Dis 2013; 19(13): 2753-62.
[10]
Ruemmele FM, Veres G, Kolho KL, et al. Consensus guidelines of ECCO/ESPGHAN on the medical management of pediatric Crohn’s disease. J Crohn’s Colitis 2014; 8(10): 1179-207.
[11]
Feber J, Al-Matrafi J, Farhadi E, Vaillancourt R, Wolfish N. Prednisone dosing per body weight or body surface area in children with nephrotic syndrome: Is it equivalent? Pediatr Nephrol 2009; 24(5): 1027-31.
[12]
Turner D, Muise AM. Very Early Onset IBD: How Very Different ‘on Average’? J Crohn’s Colitis 2017; 11(5): 517-8.
[13]
Kammermeier J, Dziubak R, Pescarin M, et al. Phenotypic and Genotypic Characterisation of Inflammatory Bowel Disease Presenting Before the Age of 2 years. J Crohn’s Colitis 2017; 11(1): 60-9.
[14]
Turner D, Veereman G, Hyams J, et al. Similarity of clinical outcomes and Golimumab pharmacokinetics in adult and pediatric patients with moderate to severe UC. J Pediatr Gastroenterol Nutr 2016; 62: 150.
[15]
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(2): 257-91.
[16]
Turner D, Ruemmele FM, Orlanski-Meyer E, et al. Management of paediatric ulcerative colitis, Part 2: Acute severe colitis-an evidence-based consensus guideline from the european crohn’s and colitis organization and the european society of paediatric gastroenterology, hepatology and nutrition. J Pediatr Gastroenterol Nutr 2018; 67(2): 292-310.
[17]
Ben Shoham A, Cozijnsen MA, Kang B, et al. Development and validation of the “mini index” (mucosal inflammation non-invasively index) for crohn‟s disease on a large prospective pediatric cohort. J Pediatr Gastroenterol Nutr 2017; 65(Suppl. 1): S5.
[18]
Van Limbergen J, Russell RK, Drummond HE, et al. Definition of phenotypic characteristics of childhood-onset inflammatory bowel disease. Gastroenterology 2008; 135(4): 1114-22.
[19]
de Bie CI, Buderus S, Sandhu BK, et al. Diagnostic workup of paediatric patients with inflammatory bowel disease in Europe: results of a 5-year audit of the EUROKIDS registry. J Pediatr Gastroenterol Nutr 2012; 54(3): 374-80.
[20]
Nakar I, Focht G, Church P, et al. The association of mucosal healing (MH), transmural healing (TH) and calprotectin in paediatric Crohn’s disease: A report from the ImageKids study. J Pediatr Gastroenterol Nutr 2017; 16(7): 1089-97.
[21]
Weiss B, Turner D, Griffiths A, et al. The Relation of Simple Endoscopic Score and Magnetic Resonance Enterography in Pediatric Crohn’s Disease : Report from the ImageKids study. ESPGHAN annual meeting 2017.
[22]
Marcovitch L, Nissan A, Mack D, et al. Item Generation and Reduction Toward Developing a Patient-reported Outcome for Pediatric Ulcerative Colitis (TUMMY-UC). J Pediatr Gastroenterol Nutr 2017; 64(3): 373-7.
[23]
Turner D, Levine A, Walters TD, et al. Which PCDAI Version Best Reflects Intestinal Inflammation in Pediatric Crohn Disease? J Pediatr Gastroenterol Nutr 2017; 64(2): 254-60.
[24]
Turner D, Seow CH, Greenberg GR, Griffiths AM, Silverberg MS, Steinhart AH. A systematic prospective comparison of noninvasive disease activity indices in ulcerative colitis. Clin Gastroenterol Hepatol 2009; 7(10): 1081-8.
[25]
Turner D, Otley AR, Mack D, et al. Development, validation, and evaluation of a pediatric ulcerative colitis activity index: a prospective multicenter study. Gastroenterology 2007; 133(2): 423-32.
[26]
Hyams J, Damaraju L, Blank M, et al. Induction and maintenance therapy with infliximab for children with moderate to severe ulcerative colitis. Clin Gastroenterol Hepatol 2012; 10: 391-9.
[27]
Romano C, Famiani A, Comito D, Rossi P, Raffa V, Fries W. Oral beclomethasone dipropionate in pediatric active ulcerative colitis: a comparison trial with mesalazine. J Pediatr Gastroenterol Nutr 2010; 50(4): 385-9.
[28]
Wiernicka A, Szymanska S, Cielecka-Kuszyk J, Dadalski M, Kierkus J. Histological healing after infliximab induction therapy in children with ulcerative colitis. World J Gastroenterol 2015; 21(37): 10654-61.
[29]
Otley A, Smith C, Nicholas D, et al. The IMPACT questionnaire: a valid measure of health-related quality of life in pediatric inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2002; 35(4): 557-63.
[30]
Gasparetto M, Guariso G. Crohn’s disease and growth deficiency in children and adolescents. World J Gastroenterol 2014; 20(37): 13219-33.
[31]
Turner D, Griffiths AM, Walters TD, et al. Appraisal of the pediatric Crohn’s disease activity index on four prospectively collected datasets: recommended cutoff values and clinimetric properties. Am J Gastroenterol 2010; 105(9): 2085-92.
[32]
Oliva S, Thomson M, de Ridder L, et al. Endoscopy in Pediatric Inflammatory Bowel Disease: A Position Paper on Behalf of the Porto IBD Group of the Espghan. J Pediatr Gastroenterol Nutr 2018.
[http://dx.doi.org/10.1097/MPG.0000000000002092]
[33]
Dan Turner, Anne Griffiths, David C Wilson, et al. Designing clinical trials in pediatric inflammatory bowel diseases – a PIBDnet commentary. Gut 2019.
[http://dx.doi.org/10.1136/gutjnl.2018-317987]


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Article Details

VOLUME: 25
ISSUE: 1
Year: 2019
Page: [69 - 72]
Pages: 4
DOI: 10.2174/1381612825666190307125511
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