Challenges in using new drugs in children

Lissy de Ridder, P-ECCO Member

Lissy de Ridder
Lissy de Ridder

Paediatric Inflammatory Bowel Disease (IBD) accounts for 10%15% of all incident cases of IBD, while the incidence in children under 10 years old is rising most rapidly [1, 2]. Children and adolescents present with a more severe phenotype of disease and have both higher and unique risks (e.g. fistulising disease, growth failure, pubertal delay) and a longer disease duration, given that IBD is a lifelong disease. 

Paradoxically, there is a long delay before commencement of paediatric trials of new drugs, even though it is essential that the most vulnerable patient group profits first from promising developments. For young patients suffering from a chronic disease it is vital that optimal treatment is administered and that complications are prevented. This will allow them to pursue and successfully complete an education, which is of crucial importance given that in their future lives they will need to rely more on their brains than on their bodies. In addition, society incurs a huge financial burden if these children drop out of school; hospital attendance and hospitalisations also require parental absence from their own employment. More effective and safe treatment that enables children with IBD to attend school is thus of the utmost importance. While these considerations amply illustrate why more effective and targeted treatments are even more urgently needed in paediatric-onset IBD, MANY fewer studies are performed in paediatric IBD than in adult IBD, in part because many more logistical challenges need to be overcome.

Huge research gap between paediatric and adult IBD

The research gap between paediatric and adult IBD is well illustrated by the long period between the registration of an anti-TNF treatment for use in adult Crohn’s Disease (CD) and its registration for use in paediatric CD. While infliximab (IFX) has been registered for use in adult CD since 1999, paediatric CD patients had to wait until the first prospective (industry-sponsored) trial was performed in 2007, whereafter IFX was finally also registered for use in children [3]. A similar delay occurred for adalimumab, too. More than 10 years later, many questions concerning optimal IFX treatment for children remain, such as dosing of IFX in children. IFX pharmacokinetic data show a consistent trend towards lower mean serum IFX concentrations after a single dose of 5 and 10 mg/kg in paediatric compared to adult CD patients. Recent data suggest decreased sustained IFX efficacy in early-onset IBD patients (<8 years), especially in children 5 years old and younger [4]. Differences in absorption, distribution, metabolism and excretion between children and adults may play a role and illustrate the need for studies in this specific population [5]. The underlying mechanisms of treatment response are currently incompletely understood while inadequate dosing continues to hamper proper use of anti-TNF treatment. It is still essential to explore these mechanisms further in paediatric CD patients.

The same gap between paediatric and adult IBD is seen with respect to registration and also investigator-initiated studies for drugs such as vedolizumab and ustekinumab, let alone “newer kids on the block” such as tofacitinib and etrolizumab.


What are the specific challenges in bringing new drugs to the market for paediatric IBD? First of all, the absolute numbers of paediatric patients are much lower. A child diagnosed with CD at the age of 10 years will be under the care of a paediatric gastroenterologist for approximately 8 years, whereafter he or she will be transferred to adult care. The adult caregiver will follow this patient for several decades. Most paediatric clinics have low hundreds of patients whereas adult clinics have thousands. So, it is far more difficult to recruit a large number of paediatric patients for inclusion in randomised controlled trials, which are usually required to achieve statistically significant results. Because of this much lower number of patients, industry is less interested in bringing drugs to the market for children with IBD as revenues will be far lower.

Second, performing research in children entails extra challenges. It may be more difficult to obtain study approval from the ethical boards and usually consent from both the patient and parents is needed. Study design in paediatric studies can also be problematic, particularly as regards the use of placebo where effectiveness in adult IBD has already been proven, or when there is a need for short-term repeat endoscopies [6].

Third, few centres follow large numbers of children with IBD and also have the facilities and know-how (clinicians with experience in performing clinical and/or translational research and research nurses) to perform high-quality research within this population.


Regulators have united to discuss common approaches to harmonised drug development processes in paediatric IBD [7]. Participation of adolescents in adult trials, e.g. from the age of 16 years, should be considered as this would allow new drugs to be made available to adolescent patients at an earlier stage. This, however, does not represent a solution for our young patients. Partial extrapolation of efficacy from adult studies, allowing for small and underpowered paediatric studies, should be considered where appropriate [6]. Especially for young patients, qualitative translational research will be of added value. Thorough patient characterisation, from bench to bedside, including genetic expression profiling, immunological profiling and pharmacokinetic/pharmacodynamic studies, will substantially improve the targeted and appropriately dosed use of new drugs in paediatric IBD. This will avoid exposure of non-responders to these drugs and improve safety and cost-effectiveness.


The timely performance of well-designed ethically sound clinical trials in paediatric IBD is essential to bring new drugs to the paediatric market and avoid further off-label use in children (currently a very frequent occurrence). Collaboration between all stakeholders, including pharmaceutical industry, regulatory agencies, patient societies and clinicians, will be crucial in achieving this goal.



  1. Benchimol EI, Manuel DG, Guttmann A, et al. Changing age demographics of inflammatory bowel disease in Ontario, Canada: a population-based cohort study of epidemiology trends. Inflamm Bowel Dis. 2014;20:17619.
  2. Benchimol EI, Mack DR, Nguyen GC, et al. Incidence, outcomes, and health services burden of very early onset inflammatory bowel disease. Gastroenterology. 2014;147:80313.
  3. Hyams J, Crandall W, Kugathasan S, et al.; REACH Study Group. Induction and maintenance infliximab therapy for the treatment of moderate-to-severe Crohn's disease in children. Gastroenterology. 2007;132:86373.
  4. 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;59:75862.
  5. Shi R, Derendorf H. Pediatric dosing and body size in biotherapeutics. Pharmaceutics. 2010;2:389418.
  6. 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;62:1837.
  7. Sun H, Papadopoulos EJ, Hyams JS, et al. Well-defined and reliable clinical outcome assessments for pediatric Crohn disease: a critical need for drug development. J Pediatr Gastroenterol Nutr 2015;60:72936.

Posted in ECCO News, Committee News, P-ECCO, Volume 13, Issue 2