Towards early inclusion of children in tuberculosis drugs trials: a consensus statement

Abstract

Children represent a significant proportion of the global tuberculosis (TB) burden, and may be disproportionately more affected by its most severe clinical manifestations. Currently available treatments for pediatric drug-susceptible (DS) and drug-resistant (DR) TB, albeit generally effective, are hampered by high pill burden, long duration of treatment, coexistent toxicities, and an overall lack of suitable, child-friendly formulations. The complex and burdensome nature of administering the existing regimens to treat DS TB also contributes to the rise of DR TB strains. Despite the availability and use of these therapies for decades, a dearth of dosing evidence in children underscores the importance of sustained efforts for TB drug development to better meet the treatment needs of children with TB. Several new TB drugs and regimens with promising activity against both DS and DR TB strains have recently entered clinical development and are in various phases of clinical evaluation in adults or have received marketing authorization for adults. However, initiation of clinical trials to evaluate these drugs in children is often deferred, pending the availability of complete safety and efficacy data in adults or after drug approval. This document summarizes consensus statements from an international panel of childhood TB opinion leaders which support the initiation of evaluation of new TB drugs and regimens in children at earlier phases of the TB Drug development cycle.

The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis

“…393 For novel tuberculosis drugs, given proof of efficacy from phase 2B or 3 trials in adults, the priority for children is pharmacokinetic and safety studies to establish the optimal and safe doses in children of different ages and weights. In parallel to the opening of adult efficacy trials, paediatric formulations should therefore already be developed to allow for the clinical assessment of these drugs in paediatricappropriate regimens.…”

Challenges in childhood tuberculosis

“…9 The utility of this approach for individualizing treatment with codeine is described by a recent Clinical Pharmacogenetics Implementation Consortium guideline. 10 Incorporation of pharmacogenomic data for polymorphically expressed genes regulating the expression of drug metabolizing enzymes and, potentially, drug transporters, into an allometric approach to assess pharmacokinetics or drug regimen selection in pediatric patients would be expected to increase predictive accuracy of the models.…”

Paediatric study of bedaquiline remains an “open issue”

“…In a consensus statement published in The Lancet, a group of experts convened by the US National Institutes of Health recommended that paediatric investigation of new tuberculosis drugs and regimens begin as soon as efficacy and safety have been established in adults ( phase IIb studies) [4]. Planning for and starting paediatric investigations earlier can help close gaps in access that currently exist between adults, adolescents and children.…”