Adaptive platform trials using multi-arm, multi-stage protocols: getting fast answers in pandemic settings

Abstract

Global health pandemics, such as coronavirus disease 2019 (COVID-19), require efficient and well-conducted trials to determine effective interventions, such as treatments and vaccinations. Early work focused on rapid sequencing of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), subsequent in-vitro and in-silico work, along with greater understanding of the different clinical phases of the infection, have helped identify a catalogue of potential therapeutic agents requiring assessment. In a pandemic, there is a need to quickly identify efficacious treatments, and reject those that are non-beneficial or even harmful, using randomised clinical trials. Whilst each potential treatment could be investigated across multiple, separate, competing two-arm trials, this is a very inefficient process. Despite the very large numbers of interventional trials for COVID-19, the vast majority have not used efficient trial designs. Well conducted, adaptive platform trials utilising a multi-arm multi-stage (MAMS) approach provide a solution to overcome limitations of traditional designs. The multi-arm element allows multiple different treatments to be investigated simultaneously against a shared, standard-of-care control arm. The multi-stage element uses interim analyses to assess accumulating data from the trial and ensure that only treatments showing promise continue to recruitment during the next stage of the trial. The ability to test many treatments at once and drop insufficiently active interventions significantly speeds up the rate at which answers can be achieved. This article provides an overview of the benefits of MAMS designs and successes of trials, which have used this approach to COVID-19. We also discuss international collaboration between trial teams, including prospective agreement to synthesise trial results, and identify the most effective interventions. We believe that international collaboration will help provide faster answers for patients, clinicians, and health care systems around the world, including for future waves of COVID-19, and enable preparedness for future global health pandemics.

Collaborative Platform Trials to Fight COVID‐19: Methodological and Regulatory Considerations for a Better Societal Outcome

“…Olivier Collignon 1, *, Carl-Fredrik Burman 2 , Martin Posch 3 and Anja Schiel 4 For the development of coronavirus disease 2019 (COVID-19) drugs during the ongoing pandemic, speed is of essence whereas quality of evidence is of paramount importance. Although thousands of COVID-19 trials were rapidly started, many are unlikely to provide robust statistical evidence and meet regulatory standards (e.g., because of lack of randomization or insufficient power).…”

“…However, these efforts were in general not coordinated and this may have led to a suboptimal use of resources, with potentially many trials providing promising evidence of candidate drugs to develop further, but without the robustness needed for regulatory approval. [1][2][3][4][5] Moreover, these trials often do not use comparable design features: for example, end point definitions vary and target populations tend not to be tailored to a specific research question. Assumptions on sample sizes, if given at all, are driven by optimistically large target treatment effects resulting in underpowered trials unable to detect small but potentially clinically meaningful treatment differences.…”

Characteristics, Progression, and Output of Randomized Platform Trials

“…In the literature, the definition of platform trials is inconsistent . Common characteristics of platform trials include the simultaneous assessment of multiple interventions, as well as the ability to drop ineffective interventions or add promising new interventions (arms) .…”

“…discontinuation remained unclear. The number of arms at the start of the platform trial and the total number of arms was typically higher in industry-sponsored trials (median number of arms at start, 4 [IQR, 2-5]; median total number of arms, 6 [IQR,[4][5][6][7][8]) than in non-industry-sponsored trials (median number of arms at start, 3 [IQR,[2][3][4]; median total number of arms, 5 [IQR, 4-7]) (Table3).Overall, 58.3% platform trials (74 of 127) added at least 1 arm, and 62.2% (79 of 127) dropped at least 1 arm during their progression; although planned, 21.3% of platform trials (27 of 127) neither added nor dropped an arm. Of the 85 platform trials that added or dropped an arm during the trial, the corresponding registry entry was not updated for 19 trials (22.4%).…”

Co-designing and pilot testing an infographic to support patients/families through the REMAP-CAP consent process: a mixed-methods study protocol

“…Platform trials have been crucial in the timely identification of optimal treatment interventions for individuals with COVID-19 in the ICU [ 7 , 8 ]; one of these is REMAP-CAP (randomized, embedded, multifactorial, adaptive platform trial for community-acquired pneumonia) [ 9 ]. REMAP-CAP is an international trial with 36 Canadian sites.…”