Odd but true: FDA fully approves remdesivir for COVID-19 after negative WHO trial.

The Food and Drug Administration issued a full approval for remdesivir to treat COVID-19 on October 22, 2020. This comes shortly after a negative trial was published on MedRxiv in an interim result (on October 15) by the World Health Organization (WHO), in a trial known as SOLIDARITY.

I posted about this trial yesterday; it showed no mortality advantage for remdesivir, lopinavir, interferon, or hydroxychloroquine (HCQ) in a large number of patients (over 2700 each for remdesivir and placebo) but may be flawed (it has not yet been peer-reviewed.)

Already, commenters on the SOLIDARITY trial (the Disqus thread) have had numerous questions. For example, how early in the course of infection were these drugs given? Detailed information about the age, degree of illness, etc. of the study subjects has not been fully evaluated.

The FDA’s justification for approving remdesivir with “substantial evidence of effectiveness and a demonstration of safety” rests on three randomized, controlled clinical trials which are described in the FDA announcement. Only the first and second trials, with over 500 patients each in drug and placebo arms in the first trial and 200 each in the second trial, shows “statistically significant” clinical improvement with drug over placebo. The third trial shows that the improvement was similar in 5 and 10 day courses of the drug.

The biggest trial was published in the New England Journal of Medicine as a final report on October 8. This was a randomized, double-blind trial done at sixty sites, mostly in the US and Europe, in February through April. It enrolled just over 500 patients each to placebo and remdesivir treatment. 90% of patients wound up in the severe disease category. 80% had a pre-existing condition; the average age was 58, and 64% were male.

The median time to recover was ten days in the remdesivir group and 15 days in the placebo group. Mortality at fifteen days was 6.7% and 11.9%, and at 29 days was 11.4% and 15.2%. Survival to fifteen days was significantly better with remdesivir, but 29 day survival did not quite reach statistical significance.

Remdesivir (trade-named Veklury by Gilead Sciences) was approved under special FDA programs designed to fast-track drugs for emerging infectious disease threats. No mention of the negative WHO trial was made in the FDA news release.

Whether the FDA has considered the WHO trial or taken into account its negative findings is not known. It is possible that the WHO trial was not released until the FDA had already decided on its approval; bureaucracy being what it is, the two publications may have “crossed in the mail.”

I am left with some few concerns about remdesivir, but I am comfortable with its use in COVID-19 for the reason that its mechanism of action is clear and convincing, and that it appears to be relatively safe (unlike HCQ on both counts.)

After further discussion among experts, we may discover that the WHO trial had some flaws that make it less persuasive. Or we may find that remdesivir is not sufficient to really help patients with late, severe COVID-19. The phenomenon often seen in severe cases of the immune system over-reacting to the virus may account for remdesivir’s insufficient efficacy.

It is also possible that many people with severe disease have inherited or acquired defects in their immune systems that have not yet been found or clarified. Several research papers have already been published this year revealing inherited immune defects that were unknown before the pandemic struck.

As has so often occurred in this pandemic, further experience will tell us much more. We are certain to see more cases of severe COVID-19, and more research on patients with the disease.