Remdesivir and Lessons in Pandemic Drug Approvals

September 25, 2021

Call it the result of the Covid pandemic attitude of “Do something, anything!” That’s alongside the lockdowns, exhortations to wear ever more masks at one time, bizarre travel restrictions, and all sorts of goofy alleged remedies like wearing face shields on top of the head, alcohol mats to prevent transmission through shoe soles, and “air purifiers” that somehow through dangling around the neck kill the virus before it can enter olfactory orifices. (The blue LED seems the crucial component.)

Gilead Sciences’ antiviral drug remdesivir (brand name Veklury) is a potent inhibitor of viral RNA replication in the lab. It was originally investigated to treat hepatitis C, then later Ebola and Marburg virus. It failed at all of them; it was a treatment in search of a disease. Finally it has hit paydirt. Having already established that it was safe enough for use, Gilead was able to quickly conduct late-stage clinical studies for Covid, and last October, relying on three such trials, the FDA approved the intravenous drug for treatment of hospitalized Covid-positive patients aged 12 and above. Since then about 50 countries have followed suit.

Dr. Anthony Fauci, head of the National Institute of Allergies and Infectious Diseases, recommended its use to treat Covid-19 patients, saying it’s “proven” that it “can block this virus,” (meaning, but not saying, in the lab) that it appeared to lead to faster recovery, and there were indications the drug led to fewer deaths, while adding that this part of the analysis is still under review.

It remains the only Covid drug with full FDA approval, which has been very good for Gilead. It announced a price of $390 per vial for developed countries, with the expected course of treatment being six vials over five days for a total cost of $2,340. It would be $520 for U.S. private health insurance companies, or $3,120. The minimum production cost is about 93 cents per day so aside from the upfront costs it’s almost pure profit. Even as sales of Gilead’s other drugs are down because people have been avoiding their doctors during the pandemic, remdesivir brought in $2.8 billion in 2020 and the company is forecasting 2021 sales of up to $3 billion for the drug.

All of which would be just swell except for one problem: Studies keep showing the drug doesn’t work. In fact, they were showing that before the FDA approval.

The latest, published in the September 14th issue of The Lancet Infectious Diseases, enrolled people at 48 sites in five European countries who had shown symptoms for seven days and required oxygen. The 429 patients who received remdesivir in addition to standard care fared no better than the 428 patients who received standard care only. This came just a month after a meta-analysis (combination) of studies by the famed Cochrane Library, ubiquitously referred to as “the gold standard” in study reviews. It found “ . . . we are moderately certain that remdesivir probably has little or no effect on all-cause mortality at up to day 28 in hospitalized adults with” Covid infection. “We are uncertain about the effects of remdesivir on clinical improvement and worsening.”

In fact, the World Health Organization (WHO) has never sanctioned use of the drug. A month after the FDA approval, the agency expressed its disapproval saying, “The evidence [from WHO’s Solidarity trial of 5,000-plus patients] suggested no important effect on mortality, need for mechanical ventilation, time to clinical improvement, and other patient-important outcomes.” Gilead’s bold rejoinder was that the study hadn’t been peer-reviewed, but it was, and it was published in America’s most prestigious medical publication, the New England Journal of Medicine.

Relying on the same WHO study, “Remdesivir is now classified as a drug you should not use routinely in Covid-19 patients,” the President of the European Society of Intensive Care Medicine, Jozef Kesecioglu, told Reuters.

Even before FDA approval, a July 2020 review in the British Medical Journal (BMJ) found “The impact of remdesivir on mortality and most other outcomes is uncertain.” But given there was nothing else available, remdesivir is worth prescribing for patients with severe Covid-19, according to a panel of international experts convened by the BMJ. Nevertheless, they said, use of a costly drug like remdesivir may divert funds, time, attention and workforce away from other potentially worthwhile treatments.

Yet people needed hope in what was being portrayed as the worst pandemic of modern times, including people in the market. Earlier in the year the drug was given a boost by TV’s most famous stock guru. “Remdesivir sounds like something that can get people out of hospitals quickly,” Jim Cramer tweeted in April 2020. “That allows our economy to have a fighting chance…. I think that remdesivir would cut the morbidity … which would change how quickly we can open… and what we can do.” If you can’t trust the manic host of Mad Money on disease morbidity, who can you trust?

Point is, we needed something to counter the pandemic. So lots of stuff was thrown at the wall and it was (and is) generally claimed to have stuck regardless of empirical evidence. Not just lockdowns generally, but those of certain rigidity, length, and so on. Not just masking, but masking where and when, with little attention paid to the type of mask. Social distancing varied from one to several meters. Curfews were set and moved, then removed and set again. Sometimes liquor spread Covid; sometimes not. Auckland, New Zealand is currently in the midst of a terribly harsh lockdown in the apparent belief that a highly-contagious human respiratory disease can be eliminated from an island as has been done with rabies.

There’s nothing wrong with the concept of antivirals. In fact a combination of two such has converted HIV from a death sentence to more of a nuisance. Monthly injections can both prevent the disease from progressing to AIDS and prevent the recipient from transmitting the disease. Three different antivirals can reduce the number and severity of herpes outbreaks while reducing risk of transmission. A course of tablets taken for 8-12 weeks can wipe out Hepatitis C in over 90% of patients. By the standards of just a short time ago that’s miraculous. It’s a very exciting field.

But it will be difficult for any antiviral or any drug to show a strong correlation to reduced Covid mortality because despite all the hype (It’s now being claimed it killed more than the “Spanish Flu” in 1918), Covid mortality is already quite low. Even presuming dying with the virus is the same as dying from the virus, almost nobody succumbs who isn’t already near maximum life expectancy (the mean Italian age at death is 79.5) and has several comorbidities. How do you significantly lower such a low death rate?

All of this smacks of another scandal involving earlier antivirals, that of the flu neuraminidase inhibitors Tamiflu (oseltamivir) and Relenza (zanamivir). In 1999 the FDA approved Hoffmann-La Roche’s Tamiflu, while in 2002 the European Medicines Agency (EMA) followed suit. This notwithstanding a host of potentially severe side effects. Four years later, the FDA approved Roche’s Relenza not just for treatment of flu but for prophylaxis. That means you could reasonably expect some people to skip the flu vaccine, counting on Relenza to be there for them if needed.

Many countries amassed huge stockpiles of Tamiflu during the H5N1 avian influenza outbreak  in Southeast Asia in 2005 in preparation for a pandemic that never came. (I exposed it at the time of yet another pandemic with such articles as “Fuss & Feathers.) Nevertheless, the panic caused worldwide shortages that drove up the price of Tamiflu, with Roche reaping almost $3 billion in one year alone, not from use but from stockpiling.

Both Tamiflu and Relenza took advantage of another scare in 2009 with H1N1 (swine flu) that again at the time I exposed as mere panic. H1N1 from the beginning appeared to be much milder than previous strains of influenza yet more contagious, so it actually saved lives. But the WHO used it to change the definition of “influenza pandemic” such that severity was no longer part of the equation. (Interestingly, my article in Forbes about this changing of definitions was selectively deleted during the current pandemic, hence the Wayback Machine link is provided.)

But neither Tamiflu nor Relenza appear to have any significant impact on the course of the flu. From 2010 to 2012, the Cochrane Library requested Roche’s full clinical study reports of their Tamiflu trials. Roche initially refused, only giving in years later and after a freedom of information request to the European Medicines Agency. Finally, Cochrane was able to publish a damning updated review in 2014.

An accompanying 2014 BMJ editorial described a “multisystem failure,” for the series of decisions based on flawed evidence made by the EMA, CDC, and WHO – though the WHO to its credit downgraded the drug’s alleged efficacy, while the CDC has not. These include “the failure to publish all available evidence, to make the data available at the individual patient level, and to recognize the limitations of observational data.”

“It was only once we looked at the whole thing that we found the benefits of Tamiflu were the shortening of the duration of illness by a few hours,” said Tom Jefferson, an epidemiologist and Cochrane reviewer who is currently suing Roche under the U.S. False Claims Act. “There was nothing credible on deaths, transmission, or hospitalization.”

Jefferson’s suit claims Hoffmann-La Roche falsified scientific conclusions and mounted a high-powered marketing and lobbying campaign to deceive the government about the effectiveness of Tamiflu, seeking to recover more than $1.4 billion of taxpayer dollars that the federal government spent on acquiring the drug.

Yet Tamiflu still had its defenders, sometimes with bizarre responses. “Given the possibility that next time things might be worse,” Professor Peter Openshaw, Director of the Center for Respiratory Infection, Imperial College in London said, “we have to ask ourselves: would we prefer to have no reserves of antivirals, when we have nothing else available with which to treat a novel pandemic flu virus?” Well then just approve crystal therapy for flu treatment and you’ll still have your precious reserves, along with a medicine that has no expiration date. And yes, Imperial College is home of “Dr. Lockdown” Neil Ferguson, not exactly renowned for requiring empirical evidence.

So Tamiflu as well as Relenza remain part of the world’s “arsenal,” though with competing generics now that the companies are no longer Scrooge McDuck rolling in his lucre.

As to remdesivir, technically the FDA can withdraw a label either for safety or efficacy reasons. But in reality it does so only for safety. Any withdrawal embarrasses the agency and it doesn’t need that. Besides, as the good Professor Openshaw said of Tamiflu, “There’s nothing else available” in the antiviral arsenal. The public won’t want to hear that.

Further, there’s the law of inertia. Everyone knows remdesivir exists, and the protocols are all in place. Just as doctors long felt pressure to write prescriptions for antibiotics to those who obviously didn’t suffer bacterial infections, there will be continued pressure to prescribe the only FDA-approved antiviral, and indeed the only fully-approved drug at all. Gilead isn’t sweating over this.

At best, this can be a lesson to us all about pandemic drug approvals. But as noted we’ve had those lessons and they didn’t stick. Don’t expect this to have any impact, either.

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