Information shared by the three stakeholders — NEJM, NIAID and Gilead — on critical issues about whether the drug’s ability to reduce mortality is statistically significant and which category of patients benefit and who don’t stand to gain is both confusing and conflicting.
The results of the much awaited randomised double-blind, placebo-controlled trial using remdesivir anti-viral drug carried out on 1,063 COVID-19 patients in 60 trial sites located in different countries have been published in the New England Journal of Medicine (NEJM).
On April 27, 2020, the data and safety monitoring board reviewed results and the board recommended that the preliminary primary analysis report and mortality data be provided to trial team members from the National Institute of Allergy and Infectious Diseases (NIAID), and patients who were receiving the placebo be given the drug. The results were subsequently made public on April 29. And on May 1, the U.S. Food and Drug Administration gave remdesivir an emergency use authorisation to treat COVID-19 patients.
Is reduction in mortality statistically significant?
While discussing about the drug’s ability to reduce the time to recovery and mortality the researchers led by a team from NIAID says in the NEJM paper: “…Those who received remdesivir had a median recovery time of 11 days as compared with 15 days in those who received placebo. The Kaplan–Meier estimates of mortality by 14 days were 7.1% with remdesivir and 11.9% with placebo.” These are preliminary results from the 1,059 patients (538 assigned to remdesivir and 521 to placebo).
While the time to recovery results were found to be statistically significant, the reduction in mortality was not found to be statistically significant. Elsewhere in the paper, the authors clearly mention this: “Mortality was numerically lower in the remdesivir group than in the placebo group, but the difference was not significant.” A press release from the NIAID also clearly states that the “difference in mortality was not statistically significant”.
But a tweet from NEJM reads surprisingly does not mention that the mortality reduction was not statistically significant. It says: “…A 10-day course of intravenous remdesivir was superior to placebo in shortening the time to recovery. The estimates of mortality at 14 days were 7.1% in the remdesivir group and 11.9% in the placebo group,”
Who benefits from Remidesivir?
The press release from NIAID is misleading to say the least when it comes to informing people who benefits the most from this drug. According to the release: “Health investigators found that remdesivir was most beneficial for hospitalised patients with severe disease who required supplemental oxygen.”
So what does the paper say about who benefits the most from this drug and who doesn’t? The conclusion part in the abstract does not specifically mention which category of patients benefit the most. It simply says: “Remdesivir was superior to placebo in shortening the time to recovery in adults hospitalised with COVID-19 and evidence of lower respiratory tract infection.”
Elsewhere, it clearly spells out the three COVID-19 patient categories who might benefit from the drug. The categories are — First: not hospitalised, no limitations of activities; Second: not hospitalised, limitation of activities, home oxygen requirement, or both; Third: hospitalised, not requiring supplemental oxygen and no longer requiring ongoing medical care (used if hospitalisation was extended for infection-control reasons).
The discussion portion of the paper too explicitly mentions that the “preliminary findings support the use of remdesivir for patients who are hospitalised with COVID-19 and require supplemental oxygen therapy”.
The drug is clearly not for patients who are seriously sick and who do not require noninvasive ventilation or high-flow oxygen devices or for those receiving invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO). These two categories have been listed in the NEJM paper and the drug is not indicated for patients belonging to these two categories.
What FDA, NIAID, Gilead releases say
But the emergency use authorisation by the FDA has approved the drug for treating “suspected or laboratory-confirmed COVID-19 in adults and children hospitalized with severe disease”.
Surprisingly, the NIAID release is not clear in indicating the category of patients who might not benefit from the drug, while the Gilead release is clear. Here, compared the two releases:
“Investigators found that remdesivir was most beneficial for hospitalized patients with severe disease who required supplemental oxygen,” the NIAID release says. And here is what Gilead says in its release: “These findings support the use of remdesivir in this population, with the largest benefit observed among individuals who required oxygen supplementation but were not mechanically ventilated.”
Is remdesivir a magic drug?
The authors caution saying: “Given high mortality despite the use of remdesivir, it is clear that treatment with an antiviral drug alone is not likely to be sufficient. Future strategies should evaluate antiviral agents in combination with other therapeutic approaches or combinations of antiviral agents to continue to improve patient outcomes in COVID-19.”
But one has to wait for the complete trail results to be published before arriving at a verdict.