There have been some bizarre, troubling developments regarding the purported anti-COVID drug, remdesivir. At the end of April, Anthony Fauci told reporters in the oval office that the NIH’s remdesivir trial showed “a clear-cut, significant positive effect.” From now on, remdesivir “will be the standard of care,” meaning that any new potential drugs to treat COVID-19 must be compared to remdesivir instead of placebo. Remdesivir itself cannot now ethically be compared to be placebo.
To say that there are problems would be an understatement. Dr. Fauci told reporters “the primary endpoint was time to recovery, namely the ability to be discharged.” But that wasn’t the original primary endpoint; it was changed less than two weeks before Fauci’s comments, and the trial was stopped early.
Since NIH remdesivir trial is in the news…
— Walid Gellad, MD MPH (@walidgellad) April 29, 2020
As can be seen in the above screenshot from the clinicaltrials.gov database, the original endpoint was severity of disease measured by an 8-point scale, with 1 being death. On April 16th, the NIH group discarded this entirely and instead selected what was originally the 24th secondary endpoint as their new primary endpoint.
The original primary endpoint was given a savage field demotion, all the way to the 24th secondary endpoint.
In medical research, this is called 'outcome switching'. It can happen for a variety of reasons, not all of them bad.
— James Heathers @email@example.com (@jamesheathers) April 30, 2020
Not only was the primary endpoint switched, it was done so “silently” without being publicly declared. Oxford’s CEBM has an excellent summary of this disturbing situation: “The FDA has authorised remdesivir for use in COVID-19 patients: but there’s no good evidence it reduces mortality.”
“…the CONSORT guidelines on reporting clinical trials state that it is acceptable to switch outcomes during the course of a trial, but that any changes must be declared, and reasons given, when the trial results are reported. The problem comes when outcome switching is not declared by the researchers conducting the study, because this misleads the reader and increases the chances of false-positive results. Unfortunately, this is common; the largest systematic review shows that around a third of primary outcomes are switched. More recently, the COMPare study showed that around a quarter of primary outcomes in major medical journals were switched without any declaration of the change. Ultimately, undeclared outcome switching can lead to patient harm: in 2001, “study 329” reported positive results for the use of paroxetine in adolescents with depression. However, these outcomes had been silently switched, and when the full data were analysed in 2014, paroxetine was found to be ineffective for depression, and associated with significant increases in suicide. This was not discovered until millions of prescriptions had been issued.”
Thread that summarizes my concerns with Remdesivir press realease (not science) as well.
Changing the endpoint midtrial this way is like hosting a race for one destination then declaring wherever you end up after running for an hour is the finish line. https://t.co/XMUXYW3njp
— Mark Hoofnagle (@MarkHoofnagle) April 30, 2020
Worse yet, the very same day of Fauci’s announcement, Lancet published a peer-reviewed study on remdesivir from a group in China that found “remdesivir was not associated with statistically significant clinical benefits.” Without the announcement of the partial results from the NIH study on the same day, the pharmaceutical giant Gilead, which owns remdesivir, would have been left with nothing but a negative result in a prestigious journal…almost certainly manifesting as a big hit on their stock price. From CEBM:
“This brings us on to the most concerning aspect of remdesivir’s rapid authorization: there is still no good evidence that remdesivir reduces the number of people who die from COVID-19. In a recent trial of remdesivir published in the Lancet, remdesivir did not reduce mortality, time to clinical improvement, duration of mechanical ventilation, or viral load. The NIAID stated that their trial of remdesivir showed no significant reduction in mortality (8% vs 11%, P = 0.059). Neither trial was able to reach full completion. This is worrying: rapid widespread dissemination and use of remdesivir to treat patients with COVID-19 will direct funding away from other vital healthcare resources and research efforts, and it may not save a single life.”
In addition to CEBM’s article linked above, there are a number of worthwhile deep-dives into the controversey. Among the best is Dr. David Gorski’s blog post (under his pseudonym Orac), much of which is recapitulated on Science-Based Medicine (note: I’ve donated to SBM in the past). As Gorski points out, Fauci’s announcement means that Gilead stands to make billions from a drug for which there is no clear evidence of benefit.
“…I question whether there really was any benefit at all, particularly in light of the Chinese trial, which found zero difference in viral load in the remdesivir group.
The whole thing looks damned fishy, and we can’t judge the study until it’s actually published. Meanwhile, whatever the true reasons for releasing the study results this way, mission accomplished. The negative effect of the Chinese study on Gilead’s stock price was successfully countered and remdesivir becomes a de facto standard of care for patients hospitalized with COVID-19. Worse, no further trials of remdesivir versus placebo will be possible, because it’s been declared that remdesivir “works” against COVID-19 and is the new standard of care!”
Another reliable science watchdog, Gary Schwitzer of HealthNewsReviews.org, had this to say in his article “What the public didn’t hear about the NIH remdesivir trial“:
“…the setting and the manner of Fauci’s announcement that remdesivir would become the ‘standard of care’ is troubling. Sitting on a couch in the White House, mostly speaking extemporaneously, with the Scientist-in-Chief sitting a few feet away waiting to hear what he wanted to hear from Dr. Fauci – this is far less than the ideal environment for the delivery of what was described as ‘quite good news.’
…For the general public, [switching the primary endpoint] is somewhat akin to the football field being shrunk so that the goal line is not 100 yards away but only 50 yards away – after the game has already begun.
But, of course, this is no game.
To be sure, there can be legitimate reasons for outcome shifting or changing primary endpoints. And in the spirit of this piece, I will not challenge the science. Actually, I can’t on this point because I haven’t seen the reasons for this shift published anywhere.
Instead, I will stick to my analysis of what yesterday’s announcement revealed, what it did not reveal, and how it was communicated.
And for those reasons, I submit that yesterday would be an important case study for lessons in ethical science journalism, science communication, and academic/government research announcements.”
So it’s about two weeks after the announcement. Have the data been released yet? Troublingly, the answer is still “no.”
13 days since partial positive remdesivir results released. Still no further details, no preprint, no data, NOTHING.
This isn't evidence-based medicine. It's hope-based medicine. I've run out of superlatives to describe what a bad idea this is. pic.twitter.com/4i2wXuPY64
— James Heathers @firstname.lastname@example.org (@jamesheathers) May 12, 2020
 Wang Y, Zhang D, Du G, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. The Lancet. April 2020. doi:10.1016/s0140-6736(20)31022-9