Implementation of platform trials in the COVID-19 pandemic: A rapid review

Abstract

Motivation: Platform designs - master protocols that allow for new treatment arms to be added over time - have gained considerable attention in recent years. Between 2001 and 2019, 16 platform trials were initiated globally. The COVID-19 pandemic seems to have provided a new motivation for these designs. We conducted a rapid review to quantify and describe platform trials used in COVID-19.

Methods: We cross-referenced PubMed, ClinicalTrials.gov, and the Cytel COVID-19 Clinical Trials Tracker to identify platform trials, defined by their stated ability to add future arms.

Results: We identified 58 COVID-19 platform trials globally registered between January 2020 and May 2021. According to trial registries, 16 trials have added new therapies (median 3, IQR 4) and 11 have dropped arms (median 3, IQR 2.5). About 50% of trials publicly share their protocol, and 31 trials (53%) intend to share trial data. Forty-nine trials (84%) explicitly report adaptive features, and 21 trials (36%) state Bayesian methods.

Conclusions: During the pandemic, there has been a surge in the number of platform trials compared to historical use. While transparency in statistical methods and clarity of data sharing policies needs improvement, platform trials appear particularly well-suited for rapid evidence generation. Trials secured funding quickly and many succeeded in adding new therapies in a short time period, thus demonstrating the potential for these trial designs to be implemented beyond the pandemic. The evidence gathered here may provide ample insight to further inform operational, statistical, and regulatory aspects of future platform trial conduct.

Keywords: Adaptive design; COVID-19; Drug development; Master protocols; Platform trials.

Fig. 1

PRISMA flowchart for combined search and selection at two time points. We searched ClinicalTrials.gov for master protocols in any indication (October 21, 2020) and COVID-19 (June 22, 2021). We searched PubMed for master protocols in any indication (October 21, 2020 and June 22, 2020). The full Cytel COVID-19 Clinical Trials Tracker dataset was retrieved on November 4th for COVID-19-specific trials of any design. A trial was labeled as platform if it is stated on the trial registration webpage, in a publication, or in the full study protocol that the trial allows for the addition of future arms [3]. A trial was labeled as “potential” platform if the listed sources contained language that suggested but could not confirm the flexibility to add arms, or the trial self-identifies as platform but has no further information.

Fig. 2

COVID-19 platform trial initiation from January 2020 through May 2021. Trial status is shown as classified in ClinicalTrials.gov. A completed trial is one where the final data collection for the primary endpoint has been done for all enrolled participants. None of the four completed trials (ACTT-1, ACTT-2, ACTT-3, and NCT04328961) showed evidence of having added any treatment arms.