Using the general pediatric drug development principles described above, the development of drugs for the treatment of IBD in pediatric patients continues to evolve. In the USA, approvals for IBD products in adults continue to outnumber pediatric approvals. Pediatric approvals lag behind those for adults by a number of years, effectively restricting access to the newest advances in therapies for pediatric patients. Important pediatric IBD drug development program considerations include, but are not limited to, use of extrapolation, adequate dose selection, use of placebo arm, the burden of repeat endoscopies, and measuring outcomes that matter to patients.

A claim of efficacy requires a product demonstrate a meaningful change in a prespecified measurable endpoint. In inflammatory bowel disease, there have been a variety of different indices utilized to measure clinical response to therapy in drug trials. For example, a published review of pediatric trial data submitted to the FDA from 1950 to 2008 of products used to treat patients with ulcerative colitis (UC) identified three disease activity indices utilized as endpoint measures for the three pediatric UC products approved during that time (Colazal, Remicade, and Azulfidine). The Modified Sutherland UC Activity Index (MUCAI) was used for the Colazal pediatric trial (2006) [25]. The Mayo score and the Pediatric UC Activity Index (PUCAI) were used for the Remicade pediatric trial (2011) [26]. It should be noted that Azulfidine was initially approved for UC in 1950 and granted pediatric approval in 2009 based on full extrapolation of efficacy from adult trials; therefore, no pediatric trial was conducted. The results of this review suggest that there exists a lack of consensus on the most appropriate primary endpoint for pediatric UC trials, and the same problem exists in the study of Crohn disease [27]. Considerable debate continues in the field as to the definition of clinical response and/or remission and how best to measure it. Historically, endoscopic appearance of the mucosa was considered the gold standard for evaluating response to therapy in an IBD trial. Others have suggested that mucosal healing, as described on histology specimens (and so requiring biopsy), is the preferred endpoint of interest. Particularly in pediatric patients, where it is necessary to limit the number of endoscopies during a trial, less invasive measures of disease activity are becoming increasingly important. However, from a regulatory standpoint, the use of a noninvasive endpoint, or biomarker, introduces additional complexity. A biomarker must first be clearly demonstrated to correlate well with the outcome of interest, before it can be qualified for use in a trial that will support product labeling [27].

To quantify meaningful changes in signs and symptoms, patient-reported outcome (PRO) and observer-reported outcome (ObsRO) instruments can be used. Changes in symptoms are subjective, however, so standardization of the definitions of the symptoms of interest and carefully designed tools for their measurement are crucial. FDA has recently published guidance for industry on their development and use (“Guidance for Industry: Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims”) [28].

The gold standard of evidence to support a claim of efficacy involves a double-blind, placebo-controlled clinical trial. However, inclusion of a placebo arm in a pediatric trial, particularly for patients who have a serious chronic medical condition such as inflammatory bowel disease, is controversial. Trial design is evolving over time to minimize exposure to placebo and risk from lack of treatment for patients. This may include use of an open-label induction period, followed by randomized withdrawal phase, use of an active comparator instead of placebo, or the use of randomization rates of more than 1:1, to minimize the number of subjects receiving placebo.

Given the lack of consensus across countries and regulatory agencies, international consensus regarding pediatric IBD trial outcome measures would facilitate drug development. In an attempt to develop a consensus statement regarding pediatric UC trial outcome measures, the i-IBD Working Group was convened in 2012 by scientists from the US Food and Drug Administration, European Medicines Agency, Health Canada, and the Pharmaceuticals and Medical Devices Agency of Japan. The i-IBD Working Group “concluded that outcome measurements in pediatric UC trials must account for both endoscopic disease activity of UC and improvement of signs and symptoms.” The group also recommended that assessment of signs and symptoms be used as a co-primary endpoint in pediatric UC trials in conjunction with endoscopic parameters of mucosal appearance to assess disease severity [29]. A similar approach should be taken for Crohns disease.

Studying drugs to treat IBD in children presents a number of challenges, though they are not unique to this disease process. Careful assessment of study design, judicious use of placebo arm, limiting invasive procedures during the trial, consideration of patients’ reported symptoms, and increasing collaboration internationally and across various regulatory agencies are all measures that will contribute toward advancing drug development in the field.