The COVID-19 pandemic has impacted clinical studies in very many ways and is expected to influence our way of planning and executing clinical research in the future. Beyond the overloading of the hospital facilities and the unavoidable delays, our incomplete knowledge of the characteristics of the SARS-CoV-2 virus and of the COVID-19 disease effects and modes of dissemination poses an additional requirement: to identify and characterize the safety signals from documented (tested) and undocumented (untested and/or asymptomatic) COVID-19 patients among study subjects.
As this paper is being written, more than 4.5 million cases of infection by the SARS-CoV-2 virus have been reported worldwide along with 300,000 deaths and 1.6 million cases of recovery1. However, because the fraction of undocumented but infectious COVID-19 cases often goes unrecognized owing to mild, limited, or lack of symptoms2, the total number of infected and recovered individuals, is suspected to be much higher than the official numbers in the total population and current scenarios consider up to twenty times the number of confirmed cases and forty times the number of recovered3. This would account for 90 million infected individuals and 64 million who have recovered. Unavoidably, some of these individuals will be participants in clinical studies for diseases unrelated to COVID-19.
This situation poses a peculiar and previously un-encountered problem: that of symptoms due to undocumented COVID-19 infections flooding the safety database of clinical trials and potentially skewing the results. If, for example an unusual number of subjects in a clinical trial develops fever, one could conclude that the investigational drug is causing fever. But it also may be that many of those subjects have suffered a mild form of the COVID-19 illness and recovered without ever being tested.
Because taken individually, each of the main symptoms of COVID-19 is common and can be attributed to many other causes, including the investigational drugs, only a coordinated review of groups of symptoms by specialized physicians is likely to provide a meaningful result. Indeed, a careful investigation of groups of symptoms known to be associated to SARS-CoV-2 infections by specialists may be able to identify those cases and help describe the impact on the safety profile. For this, ad hoc adjudication processes should be put in place very quickly and the only reasonably fast way for doing so is by using a well-established electronic endpoint adjudication platform capable of receiving the appropriate documentation and conveying the data to a special adjudication committee composed of medical experts familiar with the symptoms of COVID-19.
Epilogue: As the pandemic decreases around the world and the international community gears up to find better ways to face it in the future, fast virus and antibody tests are quickly becoming available to hospitals and other facilities. Very soon, every patient participating in a clinical trial will be able to be tested and the uncertainty will go away. Therefore, our recommendation is to focus on testing and only use electronic adjudication retrospectively in very special cases.
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1https://www.worldometers.info/coronavirus/ accessed: 13May2020
2Ruiyun Li, Sen Pei,Bin Chen et al. Science 01 May 2020:Vol. 368, Issue 6490, pp. 489-493. DOI: 10.1126/science.abb3221
3Anastassopoulou C, Russo L, Tsakris A, Siettos C (2020) Data-based analysis, modelling and forecasting of the COVID-19 outbreak. PLoS ONE 15(3): e0230405. https://doi.org/10.1371/journal.pone.0230405
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