Challenges of designing multicenter trials in pediatric heart failure

Designing clinical trials in pediatric heart failure presents challenges in many aspects of study design and implementation. These stem from the fact that the underlying mechanisms and clinical manifestations of heart failure in children are heterogenous, clinical outcome measures have not been well characterized, and the power to detect clinically important endpoints is limited by the small number of affected patients. The mechanisms of heart failure in children are often radically different than those seen in adults and justifying the study rationale for the use of an adult heart failure medication to children can be challenging. The identification of valid clinical endpoints is limited by a lack of natural history data and the length of time required to reach a clinical outcome can be difficult to incorporate into a clinical trial timeframe. Trial enrollment can be hindered by a lack of equipoise and parental reluctance to agree to study tests. The Federal Drug Administration and European Medicines Authority (EMA) have instituted several measures to encourage the study of new drugs in children with heart failure. These include extending market exclusivity following performance of an approved study in children with heart failure and, in the case of the EMA, requiring approval of a pediatric investigational protocol prior to granting approval for the use of a new medication in the adult population. The challenges of designing clinical trials in pediatric heart failure can only be overcome by a collaborative approach amongst investigators, patients, governmental agencies and pharmaceutical companies.