An adaptive platform trial for evaluating treatments in patients with life‐threatening hemorrhage from traumatic injuries: Rationale and proposal

An adaptive platform trial for evaluating treatments in patients with life‐threatening hemorrhage from traumatic injuries: Ethical and US regulatory considerations

“…While an EFIC trial is required to hold out the prospect of direct benefit, this requirement is not specific to EFIC platform trials. As noted in an accompanying paper, 26 a platform trial “increases the efficiency of learning, with every enrolled subject potentially providing information on the effectiveness of multiple therapies, and avoids the waste associated with the startup and breakdown of individual RCTs before and after addressing each therapeutic question.” Further, response‐adaptive randomization improves the probability of benefit and reduces risk, on average, over time in the trial, while a fixed randomization trial ensures the risks to patients are the same at the end of the trial as they were at the beginning. Thus, it may be that response‐adaptive randomization is more consistent with the requirement for a favorable risk–benefit ratio than a fixed trial design 44 …”

“…While design considerations are considered in more detail in a companion manuscript, 26 the trial design should include: (1) a concurrent standard of care‐based control intervention at all times; (2) randomization of patients to study interventions; (3) pre‐specification of the timing of interim analysis and of all planned adaptations and decision rules (e.g., graduating, stopping, or dropping arms; dropping participant subgroups; changes in randomization proportions); (4) pre‐specification of all final analyses, defining appropriate statistical analysis methods that account for adaptations; and (5) definition of the comparisons for primary analyses, that is, intervention arms compared to control or each other, primary outcomes, and whether the same outcome will be used across different comparisons. There should also be a thorough evaluation of the design's operating characteristics, usually through the use of extensive computer simulations 1,2 .…”

An adaptive platform trial for evaluating treatments in patients with life‐threatening hemorrhage from traumatic injuries: Planning and execution

“…Regardless of the specific analytic methods selected, the planned trial design will need to capture the key event times and appropriately account for the potential time‐dependencies (relative to injury occurrence time) of the initiation of study interventions, completion of the treatment protocol, and occurrence of all study outcomes (including any intermediate endpoints). In US military casualties, over 95% of hemorrhage‐related mortality occurs within the first 24 h after injury 17 . Thus, short‐term mortality will be a competing risk for all non‐mortality outcomes and should therefore always be the primary outcome.…”

“…Adaptive platform trials are an attractive approach for the efficient optimization of life‐saving interventions for patients with traumatic hemorrhage. A companion paper describes why some of the challenges inherent in trauma research are particularly well‐addressed by the flexibility, methodologic rigor, resilience, and sustainability of this approach to clinical trial design 17 . This article proposes a systematic framework for the development and conduct of an adaptive platform trial to reduce preventable death from severe post‐traumatic hemorrhage.…”

“…In US military casualties, over 95% of hemorrhage-related mortality occurs within the first 24 h after injury. 17 Thus, short-term mortality will be a competing risk for all nonmortality outcomes and should therefore always be the primary outcome.…”