For the average reader, the conflicting news in regards to Gilead’s remdesivir is rather perplexing. TrialSite News actually has been monitoring data feeds centering on this anti-viral, originally developed for Ebola, since the advent of the crisis. Early on, we discovered that the Wuhan Institute of Virology considering patenting the drug—a bold move for an investigational drug controlled by a major biotechnology company. We have observed several data points where the drug is associated with a successful COVID-19 patient story. This doesn’t mean that the drug is safe or efficacious—rather, these represent snippets of data but there is certainly a considerable accumulation of them. The recent data out of China raised an eyebrow: the data safety monitoring board stopped the study due to a “difficulty recruiting patients after the COVID-19 outbreak in Wuhan.”
A recent study funded by some prominent public sector players—including the Chinese Academy of Medical Sciences Emergency Project of COVID-19, the National Key Research and Development Program of China and the Beijing Science and Technology Project—sought to disclose why an important remdesivir study was cancelled in that country.
In a recent press release, the research authors noted that the study involved 237 adults (18+) from ten hospitals in Wuhan, China. They reported that the data reveals that the antiviral treatment doesn’t speed recovery from COVID-19 when compared with a placebo in hospitalized patients who are critically ill. The study results, published in The Lancet, can be accessed here.
The authors acknowledge that the findings were limited because the study was stopped early after they were unable to recruit enough patients due to the steep decline in cases in China. The authors concluded that more evidence from ongoing clinical trials is needed to better understand whether remdesivir can provide meaningful clinical benefit. Emphasizing these findings, study lead Professor Bin Cao from China-Japan Friendship Hospital and Capital Medical University in China, noted, “Unfortunately, our trial found that while safe and adequately tolerated, remdesivir did not provide significant benefits over placebo.” He continued, “This is not the outcome we hoped for, but we are mindful that we were only able to enroll 237 of the target 453 patients because the COVID-19 outbreak was brought under control in Wuhan. What’s more, restrictions on bed availability resulted in most patients being enrolled later in the disease course, we were unable to adequately assess earlier treatment with remdesivir might have provided clinical benefit.” Professor Cao concluded, “Future studies need to determine whether earlier treatment with remdesivir, higher doses, or combination with other antivirals or SARS-CoV-2 neutralizing antibodies, might be more effective in those severe illness.”
Observational Data Looks Different?
TrialSite News has been monitoring the use of remdesivir, as reported in various press, interviews and other data points, all over America. Although we have mentioned these data points cannot be substituted for randomized controlled trials, there appears to be positive signals for example another of data points from California.
The authors referenced comments, for example, from Professor John Norrie (not involved with the study) from the University of Edinburgh, UK who reminds the reader that “Promising signals from observational data must be rigorously confirmed or refuted in high-quality randomized trials—particularly given that for COVID-19 no proven safe and effective treatments yet exist…That is additionally challenging in a pandemic, and the temptation is to lower the threshold of convincing evidence must be resisted, because adopting ineffective and potentially unsafe interventions risks only harm without worthwhile benefit, while making it even harder to undertake trials to find truly effective and safe interventions.”
Norrie continued: “The study was well designed–a double-blind, placebo-controlled, multicenter randomised trial–and well conducted, with high protocol adherence and no loss-to-follow up…An absence of statistical significance in an underpowered trial means that the findings are inconclusive. The particular challenges of delivering pandemic trials underline the importance of data sharing, allowing rapid curation of relevant datasets for individual patient data meta-analyses. With each individual study at heightened risk of being incomplete, pooling data across possibly several underpowered but high-quality studies looks like it will be our best way to obtain robust insights into what works, safely, and on whom. We eagerly await the ongoing trials.”
A Messy World
The reality is that the world is sort of messy and this is exponentially so in a pandemic. Employing a range of strategies, methods and approaches becomes paramount to not only immediately help people but also collect data in systematic and meaningful ways. Hence, both randomized controlled trials and observational studies are not only important but needed—especially now. Observational studies are swayed and biased, potentially, by co-founders and selection bias—it is possible to mitigate some of the challenges with statistical tools, such as propensity scores and sensitivity analysis which when done in the right way can significantly reduce the bias caused by the lack of randomization.
We have written about the growing use of Real-World Data (RWD) and Real-World Evidence (RWE)-based research and how these methods leverage and capitalize on growing trovers of observational data. A key point—some argue that RWE could replace the randomized controlled study, and of course that is ludicrous. However, the trends point to a growing use of both approaches—they certainly can be complimentary.
And we suggest it is possible to generate contradictory data, especially when factoring in limited data and number of trials. Only time and more results will tell. This author has personally spoken with several people that were given remdesivir while ill with COVID-19 and actively participating in a study only to start feeling better shortly thereafter. This could very well be a coincidence—we cannot confirm its true safety or efficacy till more results from ongoing studies are systematically analyzed.
Professor Bin Cao from China-Japan Friendship Hospital and Capital Medical University