Guiding future paediatric drug studies based on existing pharmacokinetic and efficacy data: Cardiovascular drugs as a proof of concept.

Abstract

Off-label drug use in the paediatric population is common, and the lack of high-quality efficacy studies poses patients at risk for failing pharmacotherapy. Next to efficacy studies, pharmacokinetic (PK) studies are increasingly used to inform paediatric dose selection. As resources for paediatric trials are limited, we aimed to summarize existing PK and efficacy studies to identify knowledge gaps in available evidence supporting paediatric dosing recommendations, thereby taking paediatric cardiovascular drugs as proof of concept. For each cardiovascular drug, paediatric indication and prespecified age group, together comprising one record, the authorized state was assessed. Next, for off-label records, the highest level of evidence was scored. High-quality efficacy studies were defined as meta-analysis or randomized controlled trials. Other comparative research, noncomparative research or consensus-based expert opinions were considered low quality. The level of evidence for PK studies was scored per drug and per age group, but regardless of indication. A total of 58 drugs included 417 records, of which 279 (67%) were off-label. Of all off-label records, the majority (81%) were not supported by high-quality efficacy studies, but for 140 of these records (62%) high-quality PK studies were available. We demonstrated that for the majority of off-label cardiovascular drugs, only low-quality efficacy studies were available. However, high-quality PK studies were frequently available. Combining these PK data with extrapolation of efficacy data from adults may help to close the current information gap and prioritize the drugs for which clinical studies and safety data are urgently needed.