<p>Antimicrobial development for children remains challenging due to multiple barriers to conducting randomised clinical trials (CTs). There is currently considerable heterogeneity in the design and conduct of paediatric antibiotic studies, hampering comparison and meta-analytic approaches. The board of the European networks for paediatric research at the European Medicines Agency (EMA), in collaboration with the Paediatric European Network for Treatments of AIDS-Infectious Diseases network (www.penta-id.org), recently developed a Working Group on paediatric antibiotic CT design, involving academic, regulatory and industry representatives. The evidence base for any specific criteria for the design and conduct of efficacy and safety antibiotic trials for children is very limited and will evolve over time as further studies are conducted. The suggestions being put forward here are based on the adult EMA guidance, adapted for neonates and children. In particular, this document provides suggested guidance on the general principles of harmonisation between regulatory and strategic trials, including (1) standardised key inclusion/exclusion criteria and widely applicable outcome measures for specific clinical infectious syndromes (CIS) to be used in CTs on efficacy of antibiotic in children; (2) key components of safety that should be reported in paediatric antibiotic CTs; (3) standardised sample sizes for safety studies. Summarising views from a range of key stakeholders, specific criteria for the design and conduct of efficacy and safety antibiotic trials in specific CIS for children have been suggested. The recommended criteria are intended to be applicable to both regulatory and clinical investigator-led strategic trials and could be the basis for harmonisation in the design and conduct of CTs on antibiotics in children. The next step is further discussion internationally with investigators, paediatric CTs networks and regulators.</p>

<p><strong>PURPOSE: </strong>Urinary tract infections (UTIs) are common bacterial infections among children.</p>

<p><strong>OBJECTIVE: </strong>To systematically review the antimicrobials used for febrile UTIs in paediatric clinical trials and meta-analyse the observed cure rates and reasons for treatment failure.</p>

<p><strong>MATERIALS AND METHODS: </strong>We searched Medline, Embase and Cochrane central databases between January 1, 1990, and November 24, 2016, combining MeSH and free-text terms for: "urinary tract infections", AND "therapeutics", AND "clinical trials" in children (age range 0-18&nbsp;years). Two independent reviewers assessed study quality and performed data extraction. The major outcome measures were clinical and microbiological cure rates according to different antibiotics.</p>

<p><strong>RESULTS: </strong>We identified 2762 published studies and included 30 clinical trials investigating 3913 cases of paediatric febrile urinary tract infections. Children with no underlying condition were the main population included in the trials (n = 2602; 66.5%). Cephalosporins were the most frequent antibiotics studied in trials (22/30, 73.3%). Only a few antibiotics active against resistant UTIs have been tested in randomised clinical trials, mainly aminoglycosides. The average point cure rate of all investigational drugs was estimated to 95.3% (95% CI 93.5-96.9%). Among 3002 patients for whom cure and failure rates were reported, only 3.9% (3.9%; 118/3002) were considered clinically to have treatment failure, while 135 (4.5%; 135/3002) had microbiological failure.</p>

<p><strong>CONCLUSIONS: </strong>We observed high treatment cure rates, regardless of the investigational drug chosen, the route of administration, duration and dosing. This suggests that future research should prioritise observational studies and clinical trials on children with multi-drug-resistant infections.</p>

<p><strong>CONTEXT: </strong>Urinary tract infections (UTIs) represent common bacterial infections in children. No guidance on the conduct of pediatric febrile UTI clinical trials (CTs) exist.</p>

<p><strong>OBJECTIVE: </strong>To assess the criteria used for patient selection and the efficacy end points in febrile pediatric UTI CTs.</p>

<p><strong>DATA SOURCES: </strong>Medline, Embase, Cochrane central databases, and clinicaltrials.gov were searched between January 1, 1990, and November 24, 2016.</p>

<p><strong>STUDY SELECTION: </strong>We combined Medical Subject Headings terms and free-text terms for "urinary tract infections" and "therapeutics" and "clinical trials" in children (0-18 years), identifying 3086 articles.</p>

<p><strong>DATA EXTRACTION: </strong>Two independent reviewers assessed study quality and performed data extraction.</p>

<p><strong>RESULTS: </strong>We included 40 CTs in which a total of 4381 cases of pediatric UTIs were investigated. Positive urine culture results and fever were the most common inclusion criteria (93% and 78%, respectively). Urine sampling method, pyuria, and colony thresholds were highly variable. Clinical and microbiological end points were assessed in 88% and 93% of the studies, respectively. Timing for end point assessment was highly variable, and only 3 studies (17%) out of the 18 performed after the Food and Drug Administration 1998 guidance publication assessed primary and secondary end points consistently with this guidance.</p>

<p><strong>LIMITATIONS: </strong>Our limitations included a mixed population of healthy children and children with an underlying condition. In 6 trials, researchers studied a subgroup of patients with afebrile UTI.</p>

<p><strong>CONCLUSIONS: </strong>We observed a wide variability in the microbiological inclusion criteria and the timing for end point assessment. The available guidance for adults appear not to be used by pediatricians and do not seem applicable to the childhood UTI. A harmonized design for pediatric UTIs CT is necessary.</p>

<p>There is no global consensus on the conduct of clinical trials in children and neonates with complicated clinical infection syndromes. No comprehensive regulatory guidance exists for the design of antibiotic clinical trials in neonates and children. We did a systematic review of antibiotic clinical trials in complicated clinical infection syndromes (including bloodstream infections and community-acquired pneumonia) in children and neonates (0-18 years) to assess whether standardised European Medicines Agency (EMA) and US Food and Drug Administration (FDA) guidance for adults was used in paediatrics, and whether paediatric clinical trials applied consistent definitions for eligibility and outcomes. We searched MEDLINE, Cochrane CENTRAL databases, and ClinicalTrials.gov between Jan 1, 2000, and Nov 18, 2015. 82 individual studies met our inclusion criteria. The published studies reported on an average of 66% of CONSORT items. Study design, inclusion and exclusion criteria, and endpoints varied substantially across included studies. The comparison between paediatric clinical trials and adult EMA and FDA guidance highlighted that regulatory definitions are only variably applicable and used at present. Absence of consensus for paediatric antibiotic clinical trials is a major barrier to harmonisation in research and translation into clinical practice. To improve comparison of therapies and strategies, international collaboration among all relevant stakeholders leading to harmonised case definitions and outcome measures is needed.</p>