The shaky study on Remdesivir

From the standpoint of the agency, he said, the study had answered the question it was designed to answer: The median time that hospitalized Covid-19 patients on remdesivir took to stop needing oxygen or exit the hospital was, at 11 days, four days shorter than those who were on placebo. “How many patients would we want to put at risk of dying,” he asked, for that last little bit of proof? Remdesivir, he noted, was not a home run, but is probably better than nothing.

Steven Nissen, a veteran trialist and cardiologist at the Cleveland Clinic, disagreed that giving placebo patients remdesivir was the right call. “I believe it is in society’s best interest to determine whether remdesivir can reduce mortality, and with the release of this information doing a placebo-controlled trial to determine if there is a mortality benefit will be very difficult,” he said. “The question is: Was there a route, or is there a route, to determine if the drug can prevent death?” The decision is “a lost opportunity,” he said.

Peter Bach, the director of the Center for Health Policy and Outcomes at Memorial Sloan Kettering Cancer Center, agreed with Nissen. “The core understanding of clinical research participation and clinical research conduct is we run the trial rigorously to provide the most accurate information about the right treatment,” he said. And that answer, he argued, should ideally have determined whether remdesivir saves lives. 

The reason we have shut our whole society down, Bach said, is not to prevent Covid-19 patients from spending a few more days in the hospital. It is to prevent patients from dying. “Mortality is the right endpoint,” he said.

Most experts contacted by STAT expressed opinions that fell between Nissen and Lane, believing that the decision was a difficult case, with several defending the NIAID. 

“I think it was a really tough call,” said Janet Wittes, a prominent statistician and the president of Statistics Collaborative. 

When the remdesivir results were announced, the NIH said the data came from an “interim” analysis. This means that a study was stopped early because a drug’s benefit was so undeniable that it would be unethical to continue the study. But Lane said this was incorrect. The data come from a preliminary final analysis, a point at which the study would normally end.

With remdesivir, Gilead finds itself at strategic crossroads, with its reputation (and far more) at stake

The ACTT study (short for Adaptive Covid-19 Treatment Trial) began in late February. The first patient dosed in the study was an American repatriated from the Diamond Princess, a British cruise ship where there was an outbreak of more than 800 Covid-19 cases. By the terms of the study, hospitalized patients were randomly assigned to receive either intravenous remdesivir or a placebo. On day 15, the study would score patients on a scale from 1 (dead) to 8 (not hospitalized, with no restrictions on activities). 

As results from other Covid-19 studies conducted in China started to trickle in, Lane and his team began to worry that looking at the outcome on only the 15th day could lead the study to fail even if the drug was effective. On March 22, with only 77 patients enrolled in the study, members of the NIAID team had a conference call on which they decided to change the measure that would be used. Instead of measuring patients on an eight-point scale on one day, the study would measure the time until the patients scored one of the best three outcomes on the scale. This decision was finalized on April 2; it was posted to clinicaltrials.gov, a government registry of clinical trials, on April 16.

Ironically, Lane said, the study would still have been positive if the change had not been made. But the change in the study’s main goal also changed the way the study would be analyzed. Now, the NIAID decided, the analysis would be calculated when 400 patients out of the 1,063 patients the study enrolled had recovered. If remdesivir turned out to be much more effective than expected, “interim” analyses would be conducted at a third and two-thirds that number.

And then there’s this from the American Association of Surgeons and Physicians:

At the Presidential Briefing on Apr 30, Dr. Anthony Fauci announced early results, prior to peer-review, of one clinical trial using remdesivir, an intravenous (IV) experimental antiviral medicine in patients hospitalized with COVID-19. At the “warp speed” currently in vogue for the Fauci-led push to a new vaccine, the very next day the FDA issued an Emergency Use Authorization (EAU) for remdesivir to be used in seriously ill hospitalized patients. To announce the emergency approval, President Trump met with the CEO of the drug’s manufacturer, Gilead Sciences, in the Oval Office.

Such rapid authorization is quite unusual with the FDA. Unlike the experimental remdesivir with no prior FDA approval, hydroxychloroquine (HCQ) required two months from reports of successful use in China and South Korea to get the Mar 28 FDA EUA for use in hospitalized COVID-19 patients. HCQ was approved in 1955 for malaria, and later for lupus and rheumatoid arthritis. Over the last 65 years, hundreds of millions of prescriptions have been written for HCQ worldwide.

The EUA for HCQ did not, however, expand its availability but imposed restrictions to prevent non-hospitalized patients from accessing the government’s stockpile of the drug. Democrat Governors Cuomo (NY), Sisolak (NV), and Whitmer (MI), then imposed restrictive orders on outpatient use, and all but four states have followed their lead.

In decades of widespread use, HCQ has an impressive safety record. Irregular heart rhythm or damage to the retina occur rarely, usually with high doses used long term. FDA shows only 62 cardiac deaths attributed to HCQ out of more than 50 million prescriptions, or 0.000124 percent (1.2 out of each 1 million Rx). Rheumatology guidelines for lupus and rheumatoid arthritis do not even require baseline electrocardiograms before prescribing HCQ, since the risk is minimal.

Approximately $70 million in U.S. taxpayer funding began Gilead’s partnership with the U.S. Army, Centers for Disease Control and Prevention (CDC), and National Institutes of Health (NIH) to develop remdesivir. Initially for treating Ebola, it failed to show benefit and was shelved. If remdesivir is used to treat COVID-19, Gilead shareholders, not the taxpayers, will profit.  

Early results of the first clinical trial of remdesivir against placebo in coronavirus were announced at the White House Apr 30, and showed modest benefits, according to The New York Times. Surviving patients given remdesivir were discharged 4 days sooner than patients given placebo, though no criteria were given for determining improvement. Death rates were not significantly different. About 25 percent of patients receiving remdesivir had potentially severe side effects, including multiple organ dysfunction, septic shock, acute kidney injury, and low blood pressure. Another 23% showed evidence on lab tests of liver damage.

Gilead’s own press release revealed the side effect of acute respiratory failure in 6 percent of patients in the remdesivir 5-day treatment group, and 10.7 percent of patients in the 10-day treatment group, clearly ominous findings with a drug designed to treat respiratory failure caused by COVID-19.

Dr. Steven Nissen, Cleveland Clinic cardiologist who has conducted dozens of clinical trials, explained to The New York Times: “The disclosure of trial results in a political setting, before peer review or publication, is very unusual. Scientists will need to see figures on harms associated with the drug in order to assess its benefits…. This is too important to be handled in such a sloppy fashion.”

Dr. Michele Barry, a global health expert at Stanford University, expressed concern about Dr. Fauci’s overly enthusiastic praise for remdesivir: “It is unusual to call a drug the ‘standard of care’ until peer review of data and publication, and before studies have shown benefit in mortality.”

The leading communicable disease specialist in France, Professor Didier Raoult,  asked about another odd aspect of the remdesivir trial: “Could Anthony Fauci explain why the investigators of the NIAID remdesivir trial did change the primary outcome during the course of the project?” Death as the primary outcome was moved to a secondary outcome, and days to recovery became the primary trial outcome. Changing the primary outcome before trial results are completed is highly unusual and suggests “p-hacking”—manipulating the data to get a statistically significant “p value.”

In contrast, the multi-country compilation of evidence on HCQ and azithromycin in treatment of COVID-19  (updated Apr 27, 2020) has consistently shown that these older medicines prevent infections, significantly reduce severity of illness, reduce viral load and duration of infectivity, reduce number of hospitalizations, reduce ventilator use, and markedly reduce deaths. The data is far beyond “anecodotal,” as Dr. Fauci dismissively called it.

Money appears to be trumping medical wisdom in the recent enthusiasm for remdesivir based on just one study with modest results. One naturally wonders whether this may have anything to do with the fact that the “world’s largest asset manager,” BlackRock, owns the largest share of all Gilead stock at 8.4%. BlackRock’s influence in Washington, D.C., is legendary, and it recently was awarded the financial crown jewel of administering the Federal Reserve’s $4.5 Trillion COVID-19 loan bail-out program.

Is someone stacking the deck in Gilead’s favor? Nineof the experts on the NIH COVID-19 Panel recommending treatment options have disclosed financial support from Gilead. Why did these nine experts not recuse themselves? Did financial conflicts of interest affect the recommendation againstHCQ, the older, safer, cheaper medicine, and for use of remdesivir, the new, expensive experimental medicine, based on weak, not-yet-peer-reviewed evidence?

HCQ has been off patent for decades, is available from a dozen U.S. generic manufacturers, and is also produced in China, India, Israel, and other countries. HCQ costs the patient on average less than $10 (range 37-63 cents per tablet), for the usual 5-7 day course of treatment. Remdesivir costs upwards of $1,000 per dose, plus the added costs of having to be hospitalized to receive it.

In addition to HCQ’s low cost, major pharmaceutical companies (Novartis, Bayer, Teva, and others) have donated nearly 50 million doses to the Strategic National Stockpile. Tragically for Americans sick with COVID-19, most of this medicine still sits in warehouses because state governments are interfering with its use in outpatients when it has greatest effect.

Patients’ lives are being sacrificed on the altar of financial interests and elite D.C. powerbrokers instead of being entrusted to the judgment of patients’ own physicians. We are witnessing the deadly consequences of bureaucrats and governors practicing medicine.

Money over medical wisdom, and politics above patients: two viruses more lethal than COVID-19.

The FDA thinks HCQ is BS for Covid-19. Especially when it is taken as the Trump potjiekos mixed with other drugs, it becomes very dangerous. 

This is a new study. 

The New York State Department of Health, in partnership with the University of Albany, had been conducting a so-called observational study that researchers hoped could shed some insight into the drug’s potential effectiveness.

https://www.cnbc.com/2020/05/11/coronavirus-trump-touted-drug-doesnt-help-patients-but-raises-heart-attack-risk-study-says.html

Yes the observational study was also a shaky test....I’ve read the transcript. That’s the trouble with just googling this stuff when you have no idea what’s happening Shark.....you can’t be sure it’s credible.

It’s not looking great because the test was based on doctors’ assignments from the start, which introduces opportunities for bias....and then the  criteria for success was changed in mid trial.

Remdesivir  may still have a role, but the tests so far are no more credible than the tests for HCQ. It may very well be that we have nothing to treat this disease as yet.

New York has three times more deaths than other state - but the idiot on site quote them as standard bearers.   Does not look like he has any clue as to what is a worldwide usage of certain drugs to combat the virus in the absence if anything specific to the virus being available.   New York does not care about the deaths and that is a fact,