Antibiotic Clinical Trials: A Review of the Past, Present Challenges, and Potential Solutions

Increasing antimicrobial resistance (AMR) is a global public health concern. Rapid and effective evaluation of interventions for antibiotic-resistant organisms is needed. Randomized controlled trials (RCTs) provide the strongest evidence of causal effects of an intervention. However, conducting antibiotic RCTs has many challenges. We explored antibiotic RCT designs and methodology, to gain an understanding of current approaches and potential solutions for future antibiotic trials.

We conducted a targeted literature review for antibiotic RCTs from 2013 to 2022 published in high impact medical and subspecialty journals. Data extracted included study demographics, characteristics, and trial design features.

The search identified 193 trials. The majority were supported by non-industry sources (72.0%), multicenter (90.7%), 2-arm trials (88.6%) with a parallel design (98.4%) and enrolled adults only (68.4%). Only 52 trials (26.9%) involved sites in low- or middle-income countries (LMICs). The median sample size was 500 (interquartile range [IQR] 253-777) with a significantly larger sample size in industry supported trials. However, non-industry supported trials were of longer duration than industry supported trials (median 36 vs 18 months). All trials utilized a frequentist method.

The most common trials were multicenter, 2-arm trials with parallel traditional RCT designs. Although platform trials are currently ongoing, traditional designs were overwhelmingly used. Study involvement in countries with the highest AMR burden were grossly under-represented. Innovative trial methodologies-such as adaptive, platform, and pathogen-directed designs-should be prioritized to improve efficiency, flexibility, and relevance. Future trials must integrate real-world data, harmonize regulatory requirements, and support equitable global participation.