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

Abstract

IntroductionOff‐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.MethodsFor 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.ResultsA 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.ConclusionWe 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.

A user-driven framework for dose selection in pregnancy: proof-of-concept for sertraline

“…Data can be extracted from traditional, physiologically-based and population-based pharmacokinetic studies. The quality of pharmacokinetic studies can be graded using the adapted Jadad classification(34), with specific questions in the FDSP for appraising the credibility of available pharmacokinetic models. Furthermore, information should be gained on a therapeutic range, or, in its absence, a routinely observed concentration range, alongside available data on dose-related efficacy and safety.…”

Off-Label Prescribing in Pediatric Population—Literature Review for 2012–2022

“…Likewise, in some studies [ 106 , 108 ], the existence of published scientific evidence was analyzed as well. Smeets et al [ 145 ] described that only 14% of all off-label records ( n = 2718) were supported by high-quality evidence based on randomized clinical trials. This indicates that data should be presented by age-related periods in a child’s development, from neonates to adolescents, rather than overall, as well as those inpatients, ED patients, and outpatients must be considered separately.…”

Off-Label Treatment in Pediatrics – Associations, Latest Recommendations

“…Various studies report different reasons for off-label prescribing. In a study by Smeets et al [15], only 14% of off-label prescriptions for children (n = 2718) were based on high-quality randomised trials. This finding suggests that the presented data should be stratified and evaluated according to age and treatment tactics (outpatients, emergency department, inpatients).…”