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Evaluating the efficiency of platform trials relative to stand-alone trials: a simulation study for the evaluation of
Melissa J Hardy1, Patrick N A Harris1,2, Xiaofang Wang3
1Faculty of Health, Medicine and Behavioural Sciences, Frazer Institute, University of Queensland, Brisbane, Australia.
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.
Insights
Platform trials significantly reduce participant numbers and trial duration for serious Gram-negative bacterial infections compared to traditional stand-alone trials. These efficient designs accelerate the development of new antibacterial treatments for critical pathogens.
Area of Science:
- Clinical trial design
- Infectious disease research
- Antimicrobial resistance
Background:
- Serious Gram-negative bacterial infections, including carbapenem-resistant Acinetobacter baumannii and carbapenem-resistant Enterobacterales, represent a significant global health burden.
- These pathogens are designated as critical priority by the World Health Organization, necessitating efficient development of new treatments.
- Traditional antibacterial registration trials are often stand-alone, two-arm randomized controlled trials, which can be time-consuming and resource-intensive.
Purpose of the Study:
- To evaluate and compare the efficiency of different clinical trial designs for evaluating treatments against serious resistant Gram-negative infections.
- To assess how platform trials, including parallel and staggered designs, perform against traditional stand-alone trials.
- To determine the impact of trial design on key operating characteristics such as duration and sample size.
Main Methods:
- Simulation studies were conducted to compare platform trials (parallel and staggered starts) with multiple stand-alone trials.
- Simulated patient recruitment and randomization were employed to assess trial performance.
- The impact of trial design, control type, and allocation ratio on trial duration, sample size, and operating characteristics was evaluated.
Main Results:
- Parallel or staggered platform trials demonstrated significant reductions in sample size (31-279 participants) and trial duration (7-13 months) compared to stand-alone trials.
- Staggered platform trials with concurrent controls required fewer participants (11.0%-23.4%) and substantially fewer control participants (up to 46.8%) than stand-alone trials.
- Across various designs and scenarios, platform trials maintained nominal levels for type I error and power in treatment-control comparisons.
Conclusions:
- Platform trials offer a more efficient approach to antibacterial drug development compared to traditional stand-alone trials.
- These designs can reduce trial duration and sample size while preserving essential operating characteristics.
- The findings suggest that platform trials, with variations based on control type and allocation, can accelerate the availability of new therapies for critical Gram-negative infections, though operational and regulatory considerations remain.
