Could mutations of SARS-CoV-2 suppress diagnostic detection?

Abstract

OCEBM levels-of-evidence pyramid for therapies; Fig. 1d)3,4. Newer forms of evidence are also being interrogated. For instance, in a program providing rapid access to compassionate use of the antiviral Veklury, ~60% of patients hospitalized for severe COVID-19 demonstrated improvement, a finding that was quickly disseminated by publication26. These findings also raise the possibility of implementing master observational studies for COVID-19, as has been proposed for cancer with clinical trials such as ROOT that plan large-scale structured data acquisition in an observational setting14,19. In addition, acquisition of real-world data by exploiting digital technology to download medical or insurance records or to mine clinical trial databases has also led to approvals in cancer12,13 and may provide rapid access to important information related to COVID-19 therapeutic effectiveness. It is understood that some of the studies that are ongoing or proposed for COVID-19 are not RCTs and, therefore, while providing proof of concept, may still need to be confirmed by RCTs. Still, it is critical to appreciate how our response to COVID-19 has demonstrated that we do not need to become mired in old or misinterpreted dogma concerning levels-of-evidence rankings to advance a field where there is urgency. It is also important to recognize that levels-of-evidence hierarchies have been extensively updated since their earliest renditions, 30 to 40 years ago1,5. Indeed, in 2009 and 2011, the OCEBM levels-of-evidence pyramid for treatment studies (Fig. 1c,d)3,4 raised several forms of non-RCT with dramatic effects to the top evidence tiers. For these types of observations, therapeutic efficacy may be such that randomization to a control arm may not be ethical30. The key is to balance the risk of authorizing a therapy that may later be disproven versus that of delaying adoption of a life-saving therapy by requiring a RCT that would likely take years to perform30. Indeed, there are quantifiable threshold values above which it is highly likely that effectiveness seen in non-randomized trials will consistently translate to improved survival. In summary, contemporary levels-of-evidence hierarchies have already been broadened to acknowledge the important role played by non-RCTs (Fig. 1). Furthermore, powerful digital and molecular technologies exist today that were inconceivable when the earliest levels of evidence were formulated, over 40 years ago1. Newer types of evidence are being exploited, including real-world data and the use of genomic sequencing and mechanism-based reasoning to select cancer patients for matched geneand immune-targeted treatments. The COVID-19 pandemic has revealed that we can exploit novel types of evidence, including those generated by observational studies (Table 1) and by digital technologies, including downloadable apps. The latter can produce clinically relevant information self-reported by millions of individuals within a few weeks20,21. In all, the COVID-19 pandemic has shown that we must balance scientific rigor, reflected by classic levels of evidence, with the need for urgency. The lessons learned may expedite the discovery of important treatments for other deadly diseases. ❐