Remdesivir’s Sordid Regulatory History Calls Efficacy into Question

Remdesivir’s Sordid Regulatory History Calls Efficacy into Question

On October 28, Science Magazine took a look at the arguably sordid regulatory history of Gilead Sciences’ remdesivir. On October 8, Gilead entered an agreement with the EU to supply remdesivir in a deal worth up to $1 billion or more. Again on October 28, FDA approved it, making it the first drug to gain that status for COVID-19. But scientists who have followed the trials of remdesivir as they proceeded have serious questions about the value of this drug. At its best, it may reduce the time to recovery in severe cases. But smaller studies have shown no benefit. Then the hammer fell: on October 15, WHO’s Solidarity trial, the largest RCT to date on remdesivir, showed no reduction is mortality and no reduction in recovery time for those taking the medicine. Now Science has uncovered that the decisions by FDA and the EU, “came about under unusual circumstances that gave the company important advantages.” TrialSite has pointed out that the first U.S. Emergency Use Authorization (EUA) as well was based on a considerably unorthodox move of changing a major clinical trial endpoint toward the end of the Trial. Due to that move it’s now becoming a blockbuster drug approaching $1 billion in sales. Love them or not, Gilead has proven to be an absolutely shrewd survivor of a company with smart and resourceful business leadership. But a critical dialogue about the process and unfolding situation is important and the part regulators and NIAID plays in how things actually unfolded. And any true change needs to peer into how the drug development apparatus works in a market-based system.

“Very, Very Bad Look for the FDA”

For one thing, the FDA did not consult the Antimicrobial Drugs Advisory Committee, an outside group of experts “at the ready” to opine on complex issues. The group includes infectious disease clinicians, biostatisticians, pharmacists, plus a consumer representative to look at all available data and make approval recommendations. The committee has not convened at all during the pandemic. On the European front, the EU settled on pricing remdesivir one week before the negative Solidarity trial results were released. But Gilead was informed of the data on September 23, so the EU was at a distinct information disadvantage at the time of the October 8 deal. “This is a very, very bad look for the FDA, and the dealings between Gilead and EU make it another layer of badness,” opines Eric Topol, cardiologist at the Scripps Research Translational Institute, and a doctor who objected to remdesivir’s approval. Gilead has attacked the new results based on the widely-ranging nations and care systems, and said, “it is unclear if any conclusive findings can be drawn from the study results.” Solidarity study investigators have been angered at the criticism they have faced. Paule Kieny, a former WHO officer and now director of research at INSERM in France, notes “It’s appalling to see how Gilead tries to badmouth the Solidarity trial,” Kieny indicated. “Pretending the trial has no value because it is in low-income countries is just prejudice.”

“Tell the Truth or Resign”

Back on August 21, a study by Gilead was published in JAMA that looked at COVID-19 patients with pneumonia who got remdesivir for five or ten days compared with those who did not receive the drug. Oddly, while the five-day group “improved more quickly,” the ten-day group did not. The next week, FDA enhanced the drug’s EUA to cover all hospitalized COVID-19 patients. This led Dr. Eric Topol, editor-in-chief of Medscape, to publish a “scathing” open letter to FDA Commissioner Stephen Hahn. Titled, “Tell the Truth or Resign,” Topol looked at the remdesivir decision combined with the EUA’s for HCQ and noted, “These repeated breaches demonstrate your willingness to ignore the lack of scientific evidence, and to be complicit with the Trump Administration’s politicization of America’s healthcare institutions.”

Largest Remdesivir Study Shows Little or No Benefit

The WHO’s Solidarity trial is being run in 405 hospitals in 30 counties. It is three times larger than the other three remdesivir studies combined, and “many scientists expected it to better resolve remdesivir’s worth.” Instead of a placebo, the study compared the drug with three other repurposed drugs and also the standard of care. Solidarity investigators provided some results to FDA on October 10, and posted a preprint on medRxiv five days later. None of the drugs lowered mortality, and remdesivir had no impact on the “duration of hospitalization” or whether patients needed ventilators. This large trial re-ignited debate over the value of smaller remdesivir trials, “and whether FDA should have aired that discussion in pubic instead of weighing data privately.” In the FDA review that approved the drug, they ignored the Solidarity data to focus on other studies.

Gilead’s Chief Medical Officer Merdad Parsey said in a letter posted the same day as FDA’s remdesivir approval that Solidarity, “does not negate other study results—particularly from a trial designed with the strictest of scientific standards, as is the case with” NIH’s study. And Gilead had raised concern over the availability of Solidarity’s data, saying they have requested it but, have not gotten “the underlying data sets or statistical analysis plan” for the study. WHO responds that Gilead will get the full data when the study is complete. Since FDA usually reviews all available data, it should not matter that the data is not yet peer reviewed.

Safety Also an Issue

Also, questions remain about the safety of remdesivir. In late August, WHO, “noted a disproportionately high number of reports of liver and kidney problems in patients receiving remdesivir compared with patients receiving other drugs for COVID-19.” Another key issue is viral load, and the lack of any evidence that remdesivir reduces this. “I’ve been working in antivirals for 30 years. Every time you study an antiviral, you show an effect on the virus and you publish it,” according to Andrew Hill, who is a clinical pharmacologist at the University of Liverpool. “Surely Gilead has done that. Where are the data? It is very, very strange.”

EU Committed to Price, But Not to Purchases

 Turning to Europe, in July the EMA, Europe’s FDA equivalent, gave a conditional approval (similar to an EUA) to remdesivir. And the EU has a “joint procurement agreement” with Gilead for 500,000 treatment courses for $1.2 billion. An EU spokesperson, “confirms to Science it was not informed of the drug’s failure in the Solidarity trial until the day after the new contract was signed on 8 October.” Gilead also claims that while it got a draft of results in late September, they were “heavily redacted,” but WHO says the redactions only related to other drugs. The Gilead-EU deal locks in a $2,400 price tag for a course of treatment, but “it does not oblige any countries to purchase the drug….” Jason Pogue, a researcher at the University of Michigan and president of the Society of Infectious Diseases Pharmacists says the “bottom line” is that there is inadequate evidence that remdesivir works. “There are more questions than answers about the efficacy of remdesivir in hospitalized patients,” he opines.

COVID-19: Big Money, Big States but it’s a System Thing

The reality is that at least in market-oriented systems drug companies are under constant and consistent pressure by shareholder groups to return seriously growing returns.

Generating about $23 billion, Gilead’s current market cap of $73.6 billion leaves it at historical low multiples and share price. The markets (that is myriad institutions, funds, sovereign funds, pension funds, etc.) drive pressure and tension and the management in these companies must continuously “push the envelope” (sometimes in a good way, sometimes not)  to satisfy markets and hence keep up employment levels, etc. Otherwise it gets ugly and with downsize in value comes a downsize in jobs, etc.

TrialSite doesn’t hold out an excuse but spells out how the system really works. For those that want real change, don’t single out the companies alone but work to change the underlying system so that investors favor other key performance indicators.