Evaluating the efficiency of platform trials relative to stand-alone trials: a simulation study for the evaluation of new antibacterials

BACKGROUND: Serious Gram-negative bacterial infections impose significant burden, with carbapenem-resistant Acinetobacter baumannii and carbapenem-resistant Enterobacterales designated as WHO critical priority pathogens. Antibacterial registration trials are traditionally stand-alone two-arm randomized controlled trials evaluating one agent in a site-specific infection. Platform trials have been proposed as an alternative to identify new treatments more efficiently. OBJECTIVES: To evaluate the efficiency of different trial designs for treatments in serious resistant Gram-negative infections. METHODS: We conducted simulation studies comparing platform trials with parallel and staggered starts and multiple stand-alone trials for serious infections caused by critical priority Gram-negative pathogens. Simulated recruitment and randomization were used to assess the impact of trial design, control type and allocation ratio on trial duration, sample size and operating characteristics. RESULTS: In this setting, parallel or staggered platform trials reduced the sample size by 31-279 participants and the trial duration by 7-13 months compared with stand-alone trials. The staggered platform trial with concurrent controls required 11.0%-23.4% fewer participants and up to 46.8% less control participants than stand-alone trials. Across designs and scenarios, type I error and power, were consistently close to the nominal levels for all treatment-control comparisons. CONCLUSIONS: Platform trials can improve efficiency over stand-alone trials, reducing duration and sample size while maintaining operating characteristics. The improvement varies with control type, allocation ratio and staggered entry of agents and could help accelerate antibacterial development. This has implications for funders, sponsors and patients requiring access to new therapies, while recognizing ongoing operational and regulatory challenges.