Background:

Adverse events (AEs) are a major cause of morbidity and pose a substantial burden on limited healthcare resources. Drug efficacy and safety data are often extrapolated from adults to children. Children can be more resilient to AEs or more vulnerable.

Objectives:

Our objective was to assess whether the benefit-risk ratio is different between adults and children using evidence from placebo-controlled randomized clinical trials (RCTs).

Methods:

We searched three electronic databases for meta-analyses that included double-blind, placebo-controlled RCTs with separate results for adults and children. For the quantitative synthesis only meta-analyses that had an efficacy primary outcome and at least one safety outcome (adverse events (AEs) and/or withdrawals due to AEs) were retained.
The net efficacy adjusted for risk odds ratio (NEAR-OR) was calculated for adults and children using the expected frequency of patients responding without harms. The best benefit risk profile corresponds to the greatest number of patients to respond favorably without suffering adverse events. The heterogeneity of the benefit risk ratio between adults and children was measured using the ratio of NEAR-ORs.

Results:

Only 20 out of 89 included meta-analyses, evaluating 25 drugs, had data allowing the quantitative synthesis. For two drugs the NEAR-OR changed direction compared to the efficacy OR in children (Figure 1). For example for lamotrigine for drug resistant epilepsy, the OR showed a significant treatment benefit in children but the NEAR-OR showed significantly more harms. For AEs outcomes, two NEAR-RORs were significantly different from 1 (Figure 2). One drug showed a higher treatment benefit without AEs for children and the other showed a higher benefit risk ratio in adults.

Conclusions:

We found a difference in the benefit risk ratio between adults and children for two drugs. The adjustment of the treatment benefit on risks led to a loss of benefit for children for two drugs. The NEAR-OR is a new method which seems useful when assessing the benefit risk ratio of drugs. It needs to be more widely used in order to be validated and to provide robust conclusions.