Evaluating Safety Reporting in Paediatric Antibiotic Trials, 2000–2016: A Systematic Review and Meta-Analysis
There are very few options to treat multidrug-resistant bacterial infections in children. A major barrier is the duration and complexity of regulatory trials of new antibiotics. Extrapolation of safety data from adult trials could facilitate drug development for children.
We performed a systematic review on the safety of antibiotic clinical trials (CTs) in children (0–18 years) to evaluate the overall quality of safety trials conducted in children and to determine if age-specific adverse events (AEs) could be identified for specific antibiotic classes.
We searched the MEDLINE, Cochrane CENTRAL, and ClinicalTrials.gov electronic databases for trials conducted between 2000 and 2016.
All trials in which safety was declared a primary or secondary endpoint were included. Exclusion criteria were (1) topical or inhalational route of administration; (2) non-infectious conditions; (3) administration for prophylaxis rather than treatment; (4) selected population (i.e. cystic fibrosis, malignancies, HIV and tuberculosis); and (5) design other than randomized controlled trials. Trials reporting data on both adults and children were included only if paediatric results were reported separately.
Data Extraction and Synthesis
Two authors independently extracted the data. To assess the quality of published trials, the Extension for harms for Consolidated Standards of Reporting Trials (CONSORT) Statement 2004 was used.
Main Outcome and Measure
In order to quantitatively assess the rate of developing AEs by drug class, the numbers of overall and body-system-specific AEs were collected for each study arm, and then calculated per single drug class as median and interquartile range (IQR) of the proportions across CTs. The AEs most frequently reported were compared in the meta-analysis by selecting the CTs on the most represented drug classes.
Eighty-three CTs were included, accounting for 27,693 children. Overall, 69.7% of CONSORT items were fully reported. The median proportion of children with any AE was 22.5%, but did not exceed 8% in any single body system. Serious drug-related AEs and drug-related discontinuations were very rare (median 0.3 and 0.9%, respectively). Limitations included the inability to stratify by age group, particularly neonates.
Conclusions and Relevance
Overall, AEs in paediatric antibiotic CTs were predictable and class-specific, and no unexpected (age-specific) side effects were identified. Smaller, open-label, dose-finding, high-quality, single-arm pharmacokinetic trials seem potentially sufficient for certain common antibiotic classes, extrapolating well-established safety profiles determined from large adult efficacy trials. This approach could reduce duration and enhance subsequent registration of urgently needed new antibiotics. This will need to be combined with enhanced methods of pharmacovigilance for monitoring of emerging AEs in routine clinical practice.
MS and LF contributed to the concept and design of the study. MS, LF and PP designed the search strategy and selection criteria. PP and LF collected the data. All authors contributed to the interpretation of the data. PP, LF and MS wrote the first draft of the manuscript. All authors reviewed and contributed to subsequent drafts and approved the final version for publication. All authors agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The corresponding author confirms that he had full access to all the data in the study and had final responsibility for the decision to submit the manuscript for publication.
Compliance with Ethical Standards
Conflict of interest
Mike Sharland reported grants from GSK, Pfizer, and DNDi outside the submitted work. Paola Pansa, Yingfen Hsia, Julia Bielicki, Irja Lutsar, A. Sarah Walker, and Laura Folgori had no conflicts of interest to disclose.
This study did not receive any direct funding.
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