We have read with great interest the FDA's draft for comments, "Guidance for Industry Pediatric Inflammatory Bowel Disease: Developing Drugs for Treatment" (July 2024, https://www.fda.gov/media/180126/download). The Pediatric IBD Porto Group of the European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) appreciates the FDA's efforts to provide comprehensive guidance for the clinical development of drugs targeting pediatric inflammatory bowel disease (PIBD). Given the FDA's global influence on PIBD trials, we feel it is important that we also contribute our input despite our European location. The Porto and Interest groups of ESPGHAN includes all major research-active PIBD centers in Europe from countries of over half a billion population. Leading these centers, 95 international pediatric IBD experts signed this letter following iterative discussions and it is presented in full consensus. We share the concern expressed in the FDA draft regarding the unacceptable long lag between adult and pediatric drug approval in IBD. For instance, it has been over a decade since vedolizumab was approved for adults, yet it remains unapproved for pediatric use. Astonishingly, while there are 13 biologics approved for IBD treatment in adults, only 2 are currently approved for pediatric patients. This disparity leads to poor access to effective drugs for children and, when used off-label, results in unestablished dosing. Overall, children with IBD worldwide are denied optimal therapy leading to harm. There are numerous positive points in the FDA draft, for which we are grateful. Nonetheless, we have concerns regarding other aspects of the draft, particularly the limited implementation of the notion that efficacy can be fully extrapolated from adult trials. This relates to number and type of required pediatric trials, the choice of invasive procedures in the trials, and ensuring effective dosing for all participants in the trials. Efficacy extrapolation: The FDA draft rightly acknowledges extrapolation of efficacy from adult to pediatrics: "In general, the pathophysiology, disease characteristics, and response to treatment of ulcerative colitis (UC) or Crohn's disease (CD) are sufficiently similar between adult and pediatric patients to support extrapolation of efficacy from adequate and well-controlled trials in adult subjects for the same indication." We suggest implementing this notion by focusing on pharmacokinetics (PK) studies for exploring dosing especially in the youngest age group. In turn this also calls into question the requirement for extended invasive procedures, detailed in the next comment. Frequency and type of endoscopic procedures: We urge the FDA to reconsider the relatively new requirement for three invasive procedures in 1 year, particularly those requiring bowel cleanout (i.e., ileocolonoscopies), in both CD and UC. We suggest that after induction, proxy measures, such as the Mucosal Inflammation Noninvasive (MINI) index, fecal calprotectin, and bowel ultrasound, can supplement PCDAI in CD and the PUCAI/partial Mayo score/TUMMY-UC PRO in UC. Regardless, we see no role for full colonoscopy in UC since short sigmoidoscopy is sufficient for assessing endoscopic response and healing. Dosing considerations: Being "half placebo," avoid doses that have shown to be suboptimal in prior adult trials. It is ethically problematic, places children at risk of harm from disease progression and poses feasibility barriers on enrollment since the drugs in pediatric studies are typically available in most Western countries as off-label using the known effective dosing. Efficacy extrapolation: being the most important point, on which other recommendations can be based upon. The draft acknowledges in general the appropriateness of extrapolation of efficacy from adult to pediatrics as quoted above. However, it seems that the full implication of this notion has not been embraced. Early weaning of corticosteroids. Shortening washout periods, even if a previously failed biologic drug still has measurable blood levels. This will reduce risk of complications due to untreated active disease before randomization. Avoiding placebo arms. Embracing Bayesian approaches to analyses. As outlined in the FDA draft, evidence indicates that pediatric patients with IBD exhibit similar responses to treatments as adults and share similar biological etiology. There has been no precedent of an IBD drug being effective in adults but not in children, suggesting that full extrapolation of efficacy is scientifically justified, which is widely endorsed by pediatric gastroenterologists worldwide. Post hoc analyses of several adult studies have shown similar responses regardless of the age of onset of IBD. Full extrapolation of efficacy from adult trials is the pivot from which approval process for pediatric medications can be facilitated. This approach avoids the need for large, yet still underpowered, pediatric efficacy trials. On the other hand, dosing can be extrapolated only to adolescents with similar weight and height as adults. Therefore, pediatric studies could primarily focus on generating robust PK and pharmacodynamics (PD) data, which are crucial for determining appropriate dosing and safety in young children. Children weighing less than 30 kg have different drug metabolisms compared to adolescents and adults and thus simple extrapolation of dosing from adults is inaccurate. Real-world experience suggests that younger children require higher equivalent doses than approved in the label to reach the same drug levels.1, 2 Even within the registration trials themselves, lower drug levels were measured in children <30 kg treated with doses that were modeled from adults, including for adalimumab,3 golimumab,4 etrolizumab,5 and vedolizumab.6, 7 However, no conclusions could be drawn from these differences given the small sample size of the youngest age group. Pediatric trials typically fail to include sufficient numbers of younger children, leading to inadequate data on appropriate dosing and safety for this critical group. This lack of data can result in suboptimal dosing strategies, impacting treatment efficacy and safety. One properly designed Phase 2/3 trial focusing on PK/PD may be sufficient in the setup of full extrapolation for efficacy, ensuing a sufficient sample size of children <40 kg and especially <30 kg. This will facilitate the collection of critical data needed for optimal dosing in children. The study may be open label and not randomized. It will ensure rapid enrollment of sufficient sample sizes, governed by accepting full extrapolation of efficacy from a previously performed well-designed trial in adults. Additionally, large early postmarketing surveillance cohorts should be mandated for supplementing effectiveness, dosing, and safety data. The requirement for three invasive procedures within 1 year, especially when needing bowel cleanouts for ileocolonoscopies, imposes substantial physical and psychological stress on pediatric patients. These procedures require full anesthesia in children (compared with sigmoidoscopy which can be often done with sedation), while increasing the risks of the procedure. Each cleanout involves fasting (24 h of clear fluids only), diarrhea, nausea, fatigue, loss of two school days, and poor sleep, which are particularly distressing for young children and their caregivers. This can intensify the already high reluctance of families to participate in clinical trials. Children with IBD face significant psychosocial challenges, and the additional burden of multiple colonoscopies can further impact their overall well-being. Therefore, these should be performed in the research setting only if the added value is significant compared with less invasive alternatives. Although the clinical trial setup is fundamentally different than clinical practice, any invasive and distressing procedure in children must be clearly justified. However, once extrapolation of efficacy from adults has been accepted and the pediatric trials are anyway underpowered for proving effectiveness, then efficacy endpoints are used mainly for benchmarking the findings from adults. Along these lines, the added benefit of postinduction endoscopic evaluation in addition to the 54-week procedure, and of full colonoscopy over a short sigmoidoscopy in UC, provides little added benefit. In CD, current pediatric guidelines recommend an ileocolonoscopy before initiating biologics and after 6–12 months to allow enough time for maximal effect on endoscopic healing. This practice is designed to minimize the burden on patients while still providing necessary medical oversight. The postinduction ileocolonoscopy is too early for assessing the full extent of effectiveness of the drug on endoscopic healing which will be captured after 54 weeks. Therefore, the risks and significant discomfort of the procedure outweigh its potential benefits. Noninvasive objective measures could supplement the response by the PCDAI in CD, including the MINI index, calprotectin, and bowel ultrasound/magnetic resonance enterography (MRE). The former has been validated in several pediatric studies and is closely associated with endoscopic healing in pediatric CD. In UC, there is currently no evidence to suggest that colonoscopy provides significant added value over sigmoidoscopy in assessing response to treatment in pediatric UC. Moreover, unlike in CD, clinical disease activity indices have a strong correlation with inflammatory degree and endoscopic healing (e.g., ρ ~0.7–0.8 for the PUCAI in several independent studies) and the combination with fecal calprotectin improves the accuracy further. The difference in emotional and psychological burden between sigmoidoscopy and full colonoscopy for the children, is significant. While the former can be completed after 8 h of clear fluids without oral cleanout, and often with light sedation, the latter involves 24 h of clear fluids, laxatives, full anesthesia, and higher risks. Balancing the questionable benefit with the significant increased burden, it is our stance that sigmoidoscopy is sufficient in UC trials, preferably 2- at baseline and Week 54. Subjecting children to invasive procedures for research purposes without strong justification raises ethical concerns since the threshold for a decision to accept extra risk/discomfort by a legal guardian is higher than when adults consent for themselves. The incremental gain from additional postinduction ileocolonoscopy, when adult data could provide analogous insights, is questionable. One at baseline and one at 1 year. Use MINI index, bowel US/MRE, fecal calprotectin, and CRP postinduction to supplement PCDAI response. In UC, utilize sigmoidoscopies (as opposed to full colonoscopy) at baseline and 1 year, with postinduction response assessed by the partial Mayo score, PUCAI and the newly validated TUMMY-UC patient-reported outcome for pediatric UC. We welcome the FDA guidance to avoid placebo in pediatric trials, as another implication of full extrapolation of efficacy. However, the requirement to test two doses in a randomized trial, leads to protocols with "half placebo," meaning testing equivalent doses proven to be suboptimal in prior adult trials. This, because pharma and clinicians are usually reluctant to test doses higher than proven in adults for safety reasons. Since extrapolation of efficacy is obtained from these trials, providing suboptimal dosing again is ethically problematic. Moreover, as outlined above, children <30 kg on average need higher per/kg dosing than adults, as shown for all monoclonal biologics thus far. For ethical and feasibility reasons, sham injections/infusion to maintain blinding in children should be avoided unless a significant merit exists. In pediatric IBD trials, accepting extrapolation means that blinding has minimal benefit since, anyway, the trials are underpowered to show any meaningful differences between the groups. Studies focusing on PK and drug levels do not require blinding. Besides ethical and scientific reasons, the feasibility of a trial with a suboptimal dose arm or with sham injections/infusions is significantly hampered. This is because, in many Western countries, the drugs are available off-label in children once approved in adults. Parents will likely choose treating with accepted dosing outside the trial rather than risking receiving suboptimal dose of the drug. We kindly suggest that the FDA recommends against arms using doses proven to be suboptimal in adult studies. This will prevent exposing children to ineffective treatments and risk of harm from progression of disease. It will ensure ethical and feasible trials as well as that the data collected are meaningful and relevant. If comparing two doses, both should be at least the equivalent dose approved for adults following the adult RCTs. We recommend "early escape" in active children, as early as 1 week, rather than waiting for weeks with active disease as commonly seen in protocols. This will reduce the risk of harm from untreated active disease. Additionally, avoid sham injections/infusions. We urge the FDA to embrace the full implication of extrapolation of efficacy from adult trials by recommending one trial focusing on PK and on younger children with dosing at a minimum proved effective in adults. Based on this focus and accepting extrapolation of efficacy we also suggest reconsidering the requirement for three ileocolonoscopies within a year. By focusing pediatric trials on safety and effective dosing, while reducing the burden of invasive procedures, we can ensure that children with IBD receive timely access to effective treatments while maintaining high ethical and scientific standards. We look forward to continued collaboration with the FDA to refine these guidelines and improve the clinical trial process for pediatric IBD. The authors declare no conflict of interest. ESPGHAN is not responsible for the practices of physicians and provides guidelines and position papers as indicators of best practice only. Diagnosis and treatment are at the discretion of the healthcare provider.

Response to FDA draft guidance on pediatric IBD drug approval trials: A consensus statement from the IBD Porto Group