Challenges and Lessons Learned From COVID-19 Trials: Should We Be Doing Clinical Trials Differently?

Abstract

The COVID-19 crisis led to a flurry of clinical trials activity. The COVID-Evidence database shows 2,814 COVID-19 randomized trials registered as of February 16, 2021. Most were small (only 18% have a planned sample size >500) and the rare completed ones have not provided published results promptly (only 283 trial publications as of 2/2021). Small randomized trials and observational, non-randomized analyses have not had a successful track record and have generated misleading expectations. Different large trials on the same intervention have generally been far more efficient in producing timely and consistent evidence. The rapid generation of evidence and accelerated dissemination of results have led to new challenges for systematic reviews and meta-analyses (e.g. rapid, living, and scoping reviews). Pressure to regulatory agencies has also mounted with massive emergency authorizations, but some of them have had to be revoked. Pandemic circumstances have disrupted the way trials are conducted; therefore, new methods have been developed and adopted more widely to facilitate recruitment, consent, and overall trial conduct. Based on the COVID-19 experience and its challenges, planning of several large, efficient trials, and wider use of adaptive designs may change the future of clinical research. Pragmatism, integration in clinical care, efficient administration, promotion of collaborative structures, and enhanced integration of existing data and facilities may be several of the legacies of COVID-19 on future randomized trials.

The impact of the COVID-19 pandemic on scientific research in the life sciences

“…It has been reported [ 19 ] that while the number of clinical trials registered to treat or prevent COVID-19 has surged with 179 new registrations in the second week of April 2020 alone. Only a few of these have led to publishable results in the 12 months since [ 20 ]. On the other hand, we find that clinical trial publications, considering related MeSH (but not COVID-19 directly), have had significant growth from the beginning of the pandemic.…”

Randomized trials on non-pharmaceutical interventions for COVID-19: a scoping review

“…27 Given the unprecedented public health impact worldwide and the wide debates about benefits and harms of NPIs, this number seems disproportionate in light of other interventions that have been the focus of much more randomised trials. 8 For example, over 300 randomised trials included the highly debated hydroxychloroquine in their intervention arm 30 which has been found to be associated with increased mortality in COVID-19 patients. 31 The reasons for such an imbalance remain speculative and require urgent investigation.…”

“…Another barrier may be that as vaccines become more available and accessible, the need for randomised evaluations of NPIs may be perceived to be decreasing 32. The fatal course of the disease, with the dramatic increase in deaths in the early days of the pandemic has probably also shifted the research focus from prevention to treatments for COVID-19 to the detriment of evaluating NPIs 9 30. Overall, the specific role and relevance of these factors is not clear and requires an evidence-based assessment with sound meta-research.…”

The Anti-Coronavirus Therapies (ACT) Trials: Design, Baseline Characteristics, and Challenges

“…Lessons learned from these experiences should inform future planning of clinical trials, especially when faced with a new pandemic disease, with a focus on large, pragmatic, collaborative, efficient trials, with flexible adaptive designs that are integrated into routine clinical care. 29 …”