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Even with recent substantive improvements in health care in pediatric populations, considerable need remains for additional safe and effective interventions for the prevention and treatment of diseases in children. The approval of prescription drugs and biological products for use in pediatric settings, as in adults, requires demonstration of substantial evidence of effectiveness and favorable benefit-to-risk. For diseases primarily affecting children, such evidence predominantly would be obtained in the pediatric setting. However, for conditions affecting both adults and children, pediatric extrapolation uses scientific evidence in adults to enable more efficiently obtaining a reliable evaluation of an intervention’s effects in pediatric populations. Bridging biomarkers potentially have an integral role in pediatric extrapolation. In a setting where an intervention reliably has been established to be safe and effective in adults, and where there is substantive evidence that disease processes in pediatric and adult settings are biologically similar, a ‘bridging biomarker’ should satisfy three additional criteria: effects on the bridging biomarker should capture effects on the principal causal pathway through which the disease process meaningfully influences ‘feels, functions, survives’ measures; secondly, the experimental intervention should not have important unintended effects on ‘feels, functions, survives’ measures not captured by the bridging biomarker; and thirdly, in statistical analyses in adults, the intervention’s net effect on ‘feels, functions, survives’ measures should be consistent with what would be predicted by its level of effect on the bridging biomarker. A validated bridging biomarker has considerable potential utility, since an intervention’s efficacy could be extrapolated from adult to pediatric populations if evidence in children establishes the intervention not only to be safe but also to have substantive effects on that bridging biomarker. Proper use of bridging biomarkers could increase availability of reliably evaluated therapies approved for use in pediatric settings, enabling children and their caregivers to make informed choices about health care.

Master protocols are innovative clinical trial designs that enable new approaches to analytics and operations, creating value for patients and drug developers. To date, the use of master protocols in pediatric drug development has been limited, focused primarily on pediatric oncology with limited experience in rare and ultra-rare pediatric diseases. This article explores the application of master protocols to pediatric programs required by FDA and EMA based on adult developmental programs. These required programs involve multiple assets developed in limited pediatric populations for registrational purposes. However, these required programs include the possibility for extrapolation of efficacy and safety from the adult population. The use of master protocols is a potential solution to the challenge of conducting clinical trials in small pediatric populations provided that such use would improve enrollment or reduce the required sample size. Toward that end, Janssen and Lilly have been working on a collaborative cross-company pediatric platform trial in pediatric Crohn’s disease using an innovative Bayesian analysis. We describe how two competing companies can work together to design and execute the proposed platform, focusing on selected aspects—the usefulness of a single infrastructure, the regulatory submission process, the choice of control group, and the use of pediatric extrapolation. Master protocols offer the potential for great benefit in pediatrics by streamlining clinical development, with the goal of reducing the delay in pediatric marketing approvals when compared to adults so that children have timelier access to safe and effective medications.

In pediatric Crohn's disease, infliximab trough concentrations after standard weight-based induction therapy are commonly below 7 µg/mL. Clinical treatment outcomes are associated with post-induction infliximab trough concentration. Markers of inflammation are associated with low infliximab concentrations during maintenance dosing. We sought to determine if early markers of disease activity are associated with inadequate post-induction infliximab trough concentrations in pediatric Crohn's disease. We performed a retrospective single-center case-control study of pediatric Crohn's disease patients to assess the association between baseline and week-2 biomarkers (albumin, C-reactive protein, and erythrocyte sedimentation rate) and inadequate post-induction infliximab trough concentration (<7 µg/mL) in patients treated with standard 5 mg/kg dosing. Baseline and week-2 biomarker values were coded as dichotomous variables at clinically useful thresholds. Univariable logistic regression was used to calculate odds ratios of developing an inadequate infliximab trough concentration for each threshold, as well as thresholds in combination. Fifty-five patients were evaluated. Early biomarker thresholds significantly associated with inadequate post-induction infliximab trough concentrations included baseline C-reactive protein >1 mg/dL (odds ratio [OR] 4.58; 95% confidence interval [CI] 1.24--17.01), both baseline C-reactive protein >0.5 mg/dL andalbumin <3.5 g/dL (OR 8.31; 95% CI 1.99--34.63), and week-2 C-reactive protein >0.5 mg/dL or albumin <3.5 mg/dL or erythrocyte sedimentation rate >25 mm/hour (OR 11.08; 95% CI 2.14--57.22). Routine baseline and week-2 markers of disease activity at clinically useful thresholds were associated with inadequate post-induction infliximab trough concentration in pediatric Crohn's disease patients receiving standard weight-based induction dosing.

Environmental enteric dysfunction (EED) is a disease of the small intestine affecting children and adults in low and middle income countries. Arising as a consequence of repeated infections, gut inflammation results in impaired intestinal absorptive and barrier function, leading to poor nutrient uptake and ultimately to stunting and other developmental limitations. Progress towards new biomarkers and interventions for EED is hampered by the practical and ethical difficulties of cross-validation with the gold standard of biopsy and histology. Optical biopsy techniques — which can provide minimally invasive or noninvasive alternatives to biopsy — could offer other routes to validation and could potentially be used as point-of-care tests among the general population. This Consensus Statement identifies and reviews the most promising candidate optical biopsy technologies for applications in EED, critically assesses them against criteria identified for successful deployment in developing world settings, and proposes further lines of enquiry. Importantly, many of the techniques discussed could also be adapted to monitor the impaired intestinal barrier in other settings such as IBD, autoimmune enteropathies, coeliac disease, graft-versus-host disease, small intestinal transplantation or critical care.

Nutrition is a critical part of the management of inflammatory bowel disease (IBD) in children and adults. Malnutrition and micronutrient deficiencies are common at the time of diagnosis and may persist throughout the course of the disease. There are a number of similarities with regards to the nutritional complications and the approach to nutritional management in IBD in both children and adults, but there are also important differences. Growth failure, pubertal delay and the need for corticosteroid-sparing regimens are of higher importance in pediatrics. In the pediatric population, exclusive enteral nutrition may be equivalent to corticosteroids in inducing remission in acute Crohns disease, and may have benefits over corticosteroids in children. Adherence with exclusive enteral nutrition is better in children than in adults. Iron deficiency anemia is an important problem for adults and children with IBD. Intravenous iron administration may be superior to oral iron supplementation. Ensuring adequate bone health is another critical component of nutritional management in IBD, but guidelines for screening and therapeutic interventions for low bone mineral density are lacking in children.

Background. A 17-year-old white male with Crohn's disease who was receiving maintenance infusions of the anti-tumor necrosis factor (TNF) agent, infliximab, presented with a new-onset psoriasiform skin rash. The rash was not responsive to topical or oral corticosteroids and worsened after infliximab infusions and after subsequent administration of a second anti-TNF drug, adalimumab.Investigations. Full medical history and physical examination, including assessment of the morphology of rash and the temporal correlation with administration of anti-TNF agents.Diagnosis. Anti-TNF-agent induced psoriasiform skin rash.Management. Discontinuation of anti-TNF therapy. The patient opted to have his gastrointestinal symptoms treated with oral mesalazine and metronidazole.

Vasopressin (AVP) receptor binding within hypothalamic sites was compared between cycling and lactating female golden hamsters. The density of AVP receptor binding was analyzed by quantitative autoradiography within the ventrolateral hypothalamus and dorsomedial hypothalamic nucleus. Lactation was correlated with a disappearance of AVP receptor binding within the ventrolateral hypothalamus. In contrast, lactation was associated with a two- to three-fold increase in the density of AVP receptor binding within the dorsomedial hypothalamic nucleus. These results suggest that AVP receptor binding within the ventrolateral hypothalamus is responsive to gonadal hormones in female golden hamsters. However, the increase in binding observed within the dorsomedial hypothalamus may be related to other neurobiological changes associated with lactation.