Accelerating clinical drug development for children with tuberculosis

SUMMARY Despite urgent need, the development, approval and availability of child-friendly anti-tuberculosis drugs lag significantly behind that of adults, with children having been ignored in anti-tuberculosis drug development research. This paper outlines possible strategies for accelerating and better integrating the development of drugs and regimens for pediatric tuberculosis (TB) into existing drug development pathways for adults: initiation of pediatric studies of new treatments as soon as promising efficacy data have been generated in adults following successful phase II studies, shifting from the current age de-escalated approach to concomitant enrollment of children from the various age groups in studies, and leveraging the concepts of both the Unified Pathway and regimen development that have helped speed the study and development of novel regimens in adults. KEY WO RDS: trial design; formulation; ethical guidelines; medicines; infectious disease; pediatric; tuberculosis ALTHOUGH IT IS CONSIDERED a productive time in terms of ongoing research in the field of tuberculosis (TB), with new products and regimens being evaluated in adults, pediatric research initiatives are generally following at a slower pace. 1 It is widely accepted that the treatment of pediatric drugsusceptible (DS-TB) and drug-resistant TB (DR-TB) is hampered by factors such as high pill burden, long treatment duration, coexistent toxicities and a lack of child-friendly drug formulations. As such, against a background of historical neglect, the medical need for improved and appropriate pediatric TB treatment remains unmet. The collection of data in children is often delayed compared to adults, and this scarcity of pediatric data has underlined the need to address the numerous knowledge gaps in this population, including pharmacokinetic (PK) and adverse effects profiles of old second-line and new anti-tuberculosis drugs and regimens; optimal duration of treatment and followup; adequate drug combinations and relevant doses for disease manifestations more common in children (e.g., osteoarthritis, meningitis); the optimal duration of anti-tuberculosis treatment in human immunodeficiency virus (HIV) positive children and characterization of drug-drug interactions as well as the optimal duration of treatment for multidrug-resistant TB (MDR-TB) in children with minimal disease (uncomplicated hilar adenopathy). 2,3 These development needs are further emphasized by the increasing number of children with TB globally; 4–6 however, it will be many years before the novel drugs and regimens now being approved and deployed for adults will reach children. Whereas pediatric research needs are increasingly recognized by key documents such as the Stop TB Partnership’s Global Plan to Stop TB, 7 existing funding and incentives available to support these activities remain inadequate. Although children represent about a quarter of the global TB burden, 8 pediatric TB research and development (R&D) accounts for just 2% of total R&D funding. 9