PMID- 29218501 OWN - NLM STAT- MEDLINE DCOM- 20190403 LR - 20220408 IS - 1179-1950 (Electronic) IS - 0012-6667 (Linking) VI - 78 IP - 2 DP - 2018 Feb TI - Evaluating Safety Reporting in Paediatric Antibiotic Trials, 2000-2016: A Systematic Review and Meta-Analysis. PG - 231-244 LID - 10.1007/s40265-017-0850-x [doi] AB - BACKGROUND: 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. OBJECTIVE: 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. DATA SOURCES: We searched the MEDLINE, Cochrane CENTRAL, and ClinicalTrials.gov electronic databases for trials conducted between 2000 and 2016. STUDY SELECTION: 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. RESULTS: 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. FAU - Pansa, Paola AU - Pansa P AD - Paediatric Infectious Disease Research Group, Institute for Infection and Immunity, St George's University of London, Jenner Wing, Level 2, Room 2.215E, Cranmer Terrace, London, SW17 0RE, UK. AD - Department of Pediatrics, Sapienza University of Rome, Policlinico Umberto I, Viale Regina Elena 324, 00161, Rome, Italy. FAU - Hsia, Yingfen AU - Hsia Y AD - Paediatric Infectious Disease Research Group, Institute for Infection and Immunity, St George's University of London, Jenner Wing, Level 2, Room 2.215E, Cranmer Terrace, London, SW17 0RE, UK. FAU - Bielicki, Julia AU - Bielicki J AD - Paediatric Infectious Disease Research Group, Institute for Infection and Immunity, St George's University of London, Jenner Wing, Level 2, Room 2.215E, Cranmer Terrace, London, SW17 0RE, UK. AD - Paediatric Pharmacology, University Children's Hospital Basel, Spitalstrasse 33, 4056, Basel, Switzerland. FAU - Lutsar, Irja AU - Lutsar I AD - Institute of Medical Microbiology, University of Tartu, Ravila 19, 50411, Tartu, Estonia. FAU - Walker, A Sarah AU - Walker AS AD - Nuffield Department of Clinical Medicine, NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, OX1 3PA, UK. FAU - Sharland, Mike AU - Sharland M AD - Paediatric Infectious Disease Research Group, Institute for Infection and Immunity, St George's University of London, Jenner Wing, Level 2, Room 2.215E, Cranmer Terrace, London, SW17 0RE, UK. FAU - Folgori, Laura AU - Folgori L AUID- ORCID: 0000-0002-0680-0450 AD - Paediatric Infectious Disease Research Group, Institute for Infection and Immunity, St George's University of London, Jenner Wing, Level 2, Room 2.215E, Cranmer Terrace, London, SW17 0RE, UK. lfolgori@sgul.ac.uk. LA - eng GR - MC_UU_12023/26/MRC_/Medical Research Council/United Kingdom PT - Journal Article PT - Meta-Analysis PT - Systematic Review PL - New Zealand TA - Drugs JT - Drugs JID - 7600076 RN - 0 (Anti-Bacterial Agents) SB - IM MH - Adolescent MH - Age Factors MH - Anti-Bacterial Agents/administration & dosage/*adverse effects MH - Child MH - Child, Preschool MH - Humans MH - Infant MH - Infant, Newborn MH - Randomized Controlled Trials as Topic MH - Treatment Outcome EDAT- 2017/12/09 06:00 MHDA- 2019/04/04 06:00 CRDT- 2017/12/09 06:00 PHST- 2017/12/09 06:00 [pubmed] PHST- 2019/04/04 06:00 [medline] PHST- 2017/12/09 06:00 [entrez] AID - 10.1007/s40265-017-0850-x [pii] AID - 10.1007/s40265-017-0850-x [doi] PST - ppublish SO - Drugs. 2018 Feb;78(2):231-244. doi: 10.1007/s40265-017-0850-x.