On 22 October 2020, the FDA approved remdesivir from Gilead Sciences to treat COVID-19. Remdesivir is a broad-spectrum antiviral that has shown some effect in treating the novel coronavirus.
However, does this mean that the FDA approval of the drug is supported by good science? As I’ve written previously regarding rushed approvals of a potential COVID-19 vaccine, we should be concerned that the FDA has become politicized to approve COVID-19 drugs to make Donald Trump look good.
I think there’s evidence that the FDA-approved remdesivir was rushed and that the evidence supporting its use in COVID-19 treatment may be vastly overstated.
FDA approved remdesivir and science
After the FDA approval of remdesivir, scientists were “baffled” by the decision. The evidence supporting the drug’s use in battling SARS-CoV-2, the virus that causes COVID-19, seems to be at best mixed, and more realistically, nonexistent.
Here is some of the research that seems to indicate that the FDA approval of remdesivir was not supported by solid scientific evidence:
- The World Health Organization SOLIDARITY study (see Note 1). The results showed that remdesivir “appeared to have little or no effect on hospitalized COVID-19, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay.” In other words, in this large randomized (but open-label) study, this appears to be a good reason to be skeptical of why FDA approved remdesivir. Predictably, in a 15 October statement, Gilead stated that “it is unclear if any conclusive findings can be drawn from the study results.” Part of Gilead’s criticism is that some of the SOLIDARITY data came from low-income countries, which angered one of the researchers, Marie-Paule Kieny, director of research at the French medical research agency INSERM and a former WHO officer, who stated that “it’s appalling to see how Gilead tries to badmouth the Solidarity trial. Pretending the trial has no value because it is in low-income countries is just prejudice.”
- NIH-sponsored, large-scale, placebo-controlled clinical trial. Remdesivir reduced the median time that severely ill, hospitalized COVID-19 patients took to recover from 15 days to 10 days. And the researchers stated that treated patients “had a 31% faster time to recovery than those who received placebo.” The drug, which must be repeatedly infused intravenously, also seemed to lower the risk of death, but that difference could have arisen by chance. In other words, this study didn’t actually show that remdesivir was a “miracle cure,” but it seemed that this article was critical to why the FDA approved remdesivir.
- A smaller, placebo-controlled study of remdesivir on hospitalized COVID-19 patients in China. The authors concluded that “in this study of adult patients admitted to hospital for severe COVID-19, remdesivir was not associated with statistically significant clinical benefits. However, the numerical reduction in time to clinical improvement in those treated earlier requires confirmation in larger studies.” Moreover, the study showed no impact on SARS-CoV-2 levels in patients.
Despite these decidedly mixed (if not solidly negative results), the FDA issued an emergency use authorization for remdesivir. The Emergency Use Authorization (EUA) is an authority granted to the US Food and Drug Administration (FDA), under various acts of Congress, specifically the Pandemic and All-Hazards Preparedness Reauthorization Act of 2013 (PAHPRA), in response to an emergency. This type of EUA is specific to the USA, but other parts of the world, including Europe, have similar regulations administered by their drug regulatory bodies.
The FDA cited the NIH trial data while ignoring the other data, in issuing the EUA. Of course, Donald Trump was ecstatic about this approval, because it fits his narrative that he’s beating COVID-19 across the world.
Then, the FDA decided to approve remdesivir based on the NIH study and a Gilead-sponsored study, which had decidedly mixed results. It examined patients who received remdesivir for either 5 days or 10 days versus those treated with the standard of care. The 5-day remdesivir group improved more quickly, but, surprisingly, the 10-day group did not. The study only included around 600 patients, small by clinical trial standards. Moreover, the study did not provide any data on the SARS-CoV-2 viral load, which is critical to determining if the drug actually did anything.
Science also reported that:
Martin Landray of the University of Oxford, who is co-leading the world’s largest study of various COVID-19 treatments, says remdesivir “definitely doesn’t work in the sickest patients where the biggest gains would be” but might help people at earlier stages of disease. Further complicating the matter, most people infected with SARS-CoV-2 recover without any intervention. “The argument that the earlier you use it the better is great until you realize what the implications of that are: You won’t save many lives, and you’ll have to treat a lot of patients,” Landray says. “It’s very inconvenient, and it’ll cost you a fortune.”
Questions have also arisen about the potential of remdesivir to do harm. WHO has a regular overview of possible adverse drug events related to COVID-19 treatments. In late August it noted a disproportionately high number of reports of liver and kidney problems in patients receiving remdesivir compared with patients receiving other drugs for COVID-19. The European Medicines Agency (EMA) also announced this month that its safety committee had started a review to assess reports of acute kidney injuries in some patients taking remdesivir.
Summary
We don’t have insight into the FDA’s thinking on approving remdesivir for the treatment of COVID-19. But the studies that they selected to support their approval seems to cherry-pick studies that weakly support the claims from Gilead while ignoring studies that basically reject those claims.
To be fair, there seems to be a lot of criticism of both the nominally positive and negative studies. The problem is that there are no large, pivotal, randomized, double-blinded clinical studies that have been published that allow a reasonable scientist or physician to accept the claims that the FDA approved remdesivir actually works.
This is what concerns many of us with regard to a rushed approval or EUA for a COVID-19 vaccine. Will the FDA actually use powerful evidence that establishes the safety and effectiveness of that vaccine?
Every vaccine on the market today had undergone long and deliberate studies supporting their safety and effectiveness before gaining FDA approval. I remain troubled about how the FDA approved remdesivir, which makes me very troubled about what they might do with a vaccine.
Of course, maybe we’ll have a new President of the United States very soon, who will force the FDA to follow the science, not political expediency. Let’s hope.
Notes
- This is a preprint. There are nearly 10,000 articles on the major preprint servers, Medrxiv and Biorxiv, discussing COVID-19, SARS-CoV-2, and related topics, all awaiting publication. There are good reasons to post preprints during this coronavirus pandemic, but there are good reasons to be very skeptical of them. Mainly, peer-review is missing, an important aspect of vetting everything from the methodology to the statistical analysis. On the hierarchy of biomedical research, preprint research is near the bottom.
Citations
- Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, Kalil AC, Hohmann E, Chu HY, Luetkemeyer A, Kline S, Lopez de Castilla D, Finberg RW, Dierberg K, Tapson V, Hsieh L, Patterson TF, Paredes R, Sweeney DA, Short WR, Touloumi G, Lye DC, Ohmagari N, Oh MD, Ruiz-Palacios GM, Benfield T, Fätkenheuer G, Kortepeter MG, Atmar RL, Creech CB, Lundgren J, Babiker AG, Pett S, Neaton JD, Burgess TH, Bonnett T, Green M, Makowski M, Osinusi A, Nayak S, Lane HC; ACTT-1 Study Group Members. Remdesivir for the Treatment of Covid-19 – Final Report. N Engl J Med. 2020 Oct 8:NEJMoa2007764. doi: 10.1056/NEJMoa2007764. Epub ahead of print. PMID: 32445440; PMCID: PMC7262788.
- Spinner CD, Gottlieb RL, Criner GJ, Arribas López JR, Cattelan AM, Soriano Viladomiu A, Ogbuagu O, Malhotra P, Mullane KM, Castagna A, Chai LYA, Roestenberg M, Tsang OTY, Bernasconi E, Le Turnier P, Chang SC, SenGupta D, Hyland RH, Osinusi AO, Cao H, Blair C, Wang H, Gaggar A, Brainard DM, McPhail MJ, Bhagani S, Ahn MY, Sanyal AJ, Huhn G, Marty FM; GS-US-540-5774 Investigators. Effect of Remdesivir vs Standard Care on Clinical Status at 11 Days in Patients With Moderate COVID-19: A Randomized Clinical Trial. JAMA. 2020 Sep 15;324(11):1048-1057. doi: 10.1001/jama.2020.16349. PMID: 32821939; PMCID: PMC7442954.
- Wang Y, Zhang D, Du G, Du R, Zhao J, Jin Y, Fu S, Gao L, Cheng Z, Lu Q, Hu Y, Luo G, Wang K, Lu Y, Li H, Wang S, Ruan S, Yang C, Mei C, Wang Y, Ding D, Wu F, Tang X, Ye X, Ye Y, Liu B, Yang J, Yin W, Wang A, Fan G, Zhou F, Liu Z, Gu X, Xu J, Shang L, Zhang Y, Cao L, Guo T, Wan Y, Qin H, Jiang Y, Jaki T, Hayden FG, Horby PW, Cao B, Wang C. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. 2020 May 16;395(10236):1569-1578. doi: 10.1016/S0140-6736(20)31022-9. Epub 2020 Apr 29. Erratum in: Lancet. 2020 May 30;395(10238):1694. PMID: 32423584; PMCID: PMC7190303.
- WHO Solidarity trial consortium, Pan H, Peto R, Karim QA, Alejandria M, Henao-Restrepo AM, García CH, Kieny M-P, Malekzadeh R, Murthy S, Preziosi M-P, Reddy S, Periago MR, Sathiyamoorthy V, Røttingen J-A, Swaminathan S, as the members of the Writing Committee, assume responsibility for the content and integrity of this article. Repurposed antiviral drugs for COVID-19 –interim WHO SOLIDARITY trial results. medRxiv 2020.10.15.20209817; doi: 10.1101/2020.10.15.20209817.
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