Table 3.

Conventional and Adaptive Trial Designs for Healthcare-Associated Infection Prevention, Treatment of Infections Caused by Antimicrobial-Resistant Bacteria and Antimicrobial Stewardship: Examples, Challenges of Conventional Designs, and Potential Advantages and Limitations of Adaptive Designs

Domain (Possible Research Question)	Conventional trial design		Adaptive trial design
	Example	Common Challenge	Example	Potential Advantage	Limitation
Healthcare-associated infection prevention (What is the effect of a novel screening test to identify patients colonized with MDR GNB on admission on the transmission of these organisms in healthcare facilities?)	Group-level cluster-randomized trial	Inaccurate power calculation due to imprecise estimate of incidence and within- and between-group variance of the control group–level outcome	Sample size recalculation (No. of groups or duration of study) using blinded interim analysis of baseline incidence and within- and between-group variance of the group-level outcome	Adequately powered study; early identification of futility	May be unable to add groups midway through the trial; difficult to estimate the budget for the trial
		Variation in population characteristics among groups likely to affect the response to the intervention	Population enrichment using blinded interim analysis of population characteristics among groups	More likely to detect a positive effect associated with intervention; more precise estimate of effect size in subjects likely to respond	May overestimate the size of the effect in a general population; difficult to estimate the budget for the trial
Treatment of infections caused by antimicrobial- resistant bacteria (What is the effect of a novel antibiotic, used alone or in combination with existing antibiotics, on the MDR GNB BSI-associated mortality rate?)	Separate phase II and III trials for a new drug development	Delay and inefficiency of conducting separate phase II and III trials of a new drug	Multistage seamless phase II/III trial design with interim analysis to choose the optimal dosing regimen to complete trial	Eliminates delay between phases II and III; smaller overall sample size; combines data from both phases for final analysis	Additional planning required to specify the phase II to III transition; operational bias when changes can be used to infer phase II results
	Separate randomized trials of different treatment strategies (eg, different doses, administration regimens, agents, or combinations)	Inefficiency of conducting separate trials of various strategies	Multiarm design to test different treatment strategies vs a common control; interim analysis to choose best-performing strategy to continue the trial	Simultaneous evaluation of multiple treatment strategies allows direct comparison of each; interim analyses allow discontinuation of ineffective treatment strategies or early stopping if one strategy is superior; arms testing new treatment strategies can be added	Careful planning and coordination required for multiarm studies; operational bias when changes in arms infer interim results
Antimicrobial stewardship (What is the effect of different novel rapid tests for detection of resistance genes in MDR GNB on time to initiation of effective antibiotic treatment for MDR GNB BSI?)	Separate randomized trials of new diagnostic tests	Inefficiency of conducting separate trials of new diagnostic tests	Umbrella or platform design to evaluate multiple new diagnostic tests using samples from single subjects (see text)	Simultaneous evaluation of multiple new diagnostic tests allows direct comparison of each; smaller overall sample size compared with separate trials	Careful planning and coordination required

Abbreviations: BSI, bloodstream infection; GNB, gram-negative bacilli; MDR, multidrug-resistant.