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 each further wave of COVID-19, and enable preparedness for future global health pandemics.

Keywords: COVID-19; FAME; IPD; MAMS; SARS-CoV-2; adaptive; conduct; efficient; epidemic; meta-analysis; multi-arm; multi-stage; pandemic; platform; trials.