Drug trials in paediatrics: a reality check

There are fewer children than adults with IBD. The population prevalence of paediatric IBD is such that >90% of patients with IBD are adults [1]. Drug trial recruitment is challenging in all age groups, but relatively fewer adult trial centres are needed to meet recruitment targets. The per-drug industry costs of additional necessary sites for a tandem paediatric trial arm are relatively modest in the context of overall costs and inclusion of a paediatric trial arm would enable more rapid paediatric licencing in positive trials.

Real-world vs trial-world data. Trial homogeneity requirements understandably result in tight inclusion and exclusion criteria. As with adult experiences, paediatric treatment response rates are less favourable in ‘real-world’ populations than in original trials, and even worse among ‘ineligible’ patients [2]. That only 38% of patients meet original trial inclusion criteria highlights the mismatch between trial and real-world patient populations. Prohibitive and potentially unacceptable trial eligibility criteria for children must be addressed in future trial designs.

Placebo-only treatment is an inferior treatment. Subjecting children and young adults to placebo monotherapy in randomised controlled trials (RCTs) is neither acceptable according to the Helsinki Declaration nor required by the European Medicines Agency or the Federal Drug Administration [1, 3]. This contrast with adult trial design should not stand in the way of innovative and creative trial methodologies for younger subjects. External controls, more objective outcome measures such as calprotectin or endoscopic scores and blinded endpoints in paediatric RCTs are among the available options for paediatric studies [4, 5].

Where there are discordant trial outcome measures, let there be harmony. Historic trials were characterised by heterogeneous designs and inconsistent primary outcome measures. A systematic review of the 62 paediatric trials published since 1987 found variable endpoint reporting of clinical, biomarker and endoscopic remission and responses, and limited use of patient-reported outcomes [6]. Despite poor correlation with objective mucosal findings, most paediatric trials to date have used clinical primary endpoints, in contrast to contemporary adult trial outcome measures. That said, the systematic review found 26 distinct definitions of clinical remission and response among the trials. Evidence-based paediatric patient-reported outcomes have been developed and, in keeping with STRIDE-II, outcomes important to patients and families require incorporation [7, 8]. Future paediatric trials can learn and adapt from adult trials, utilising a harmonised core set of primary and secondary trial endpoints with standardised definitions.  

Can we change the status quo of prolonged ‘off-label’ treatments for children?  Paediatric gastroenterologists look enviously at each newly proven medicine for adult patients. Years will pass before the corresponding paediatric trial is undertaken, if this happens at all.  Paediatric anti-TNF trials have lagged long behind adult trials, such that some designs have no longer reflected real-world use in terms of dosing schedules. Advocacy by paediatric clinicians inevitably results in ‘off-label’ medication access for children and young adults. The realpolitik of current industry-led approaches is that the paediatric ‘time-to-trial’ has remained immune to clinical advocacy and, ultimately, to the needs of children with IBD. Regulatory authorities are vested with the power to effect changes in drug approval and trial conduct to better young patients with IBD. Token adolescent enrolment in trials has, ironically, helped to advance drug licencing for adults but not for teenagers themselves. Although there is no evidence for appreciable differences between adults and teenagers regarding drug effectiveness, dosing or safety, authorities refuse extrapolation from adult trial data to this age group. The futility of including patients under 18 years of age in trials could be avoided if they were to be adequately powered with appropriate minimum sample sizes.

Children are no less deserving than adults. An embarrassment of approved medications beyond conventional therapy for adults with IBD contrasts with just two approved medications (in most countries) for children – both anti-TNFα medications. Children and young adults with refractory disease, in particular, deserve more than their current restricted medication choice. Child-centred care is the hallmark of paediatric medicine. With paediatric gastroenterologists now at their best state of IBD drug trial readiness, it falls to the regulatory authorities and industry leadership to put the child with IBD at the centre of their attention also.

References

1. Turner D, Griffiths AM, Wilson D, et al. Designing clinical trials in paediatric inflammatory bowel diseases: a PIBDnet commentary. Gut 2020;69:32–41.
2. Atia O, Pujol-Muncunill G, Navas-López VM, et al. Children included in randomised controlled trials of biologics in inflammatory bowel diseases do not represent the real-world patient mix. Aliment Pharmacol Ther 2022;56:794–801.
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;62:183–7.
4. Schmidli H, Häring DA, Thomas M, Cassidy A, Weber S, Bretz F. Beyond randomized clinical trials: Use of external controls. Clin Pharmacol Ther 2020;107:806–16.
5. Croft NM, Faubion WA, Jr, 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;6:616–27.
6. Crowley E, Griffiths AM, Jairath V. Heterogeneity in efficacy and safety endpoints for pediatric clinical trials in inflammatory bowel disease: A need for harmonization. Gastroenterology 2022;163:1137–44.
7. Turner D, Ricciuto A, Lewis A, et al. STRIDE-II: An update on the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) Initiative of the International Organization for the Study of IBD (IOIBD): Determining therapeutic goals for treat-to-target strategies in IBD. Gastroenterology 2021;160:1570–83.
8. Marcovitch L, Focht G, Carmon N, et al. Development and validation of the TUMMY-UC: A patient-reported outcome for pediatric ulcerative colitis. Gastroenterology 2023;164:610–8.e4.