October was a good month for Gilead Sciences, the giant manufacturer of antivirals headquartered in Foster City, California. On 8 October, the company inked an agreement to supply the European Union with its drug remdesivir as a treatment for COVID-19—a deal potentially worth more than $1 billion. Two weeks later, on 22 October, the U.S. Food and Drug Administration (FDA) approved remdesivir for use against the pandemic coronavirus SARS-CoV-2 in the United States—the first drug to receive that status. The EU and U.S. decisions pave the way for Gilead’s drug into two major markets, both with soaring COVID-19 cases.
But both decisions baffled scientists who have closely watched the clinical trials of remdesivir unfold over the past 6 months—and who have many questions about remdesivir’s worth. At best, one large, well-designed study found remdesivir modestly reduced the time to recover from COVID-19 in hospitalized patients with severe illness. A few smaller studies found no impact of treatment on the disease whatsoever. Then, on 15 October—in this month’s decidedly unfavorable news for Gilead—the fourth and largest controlled study delivered what some believed was a coup de grâce: The World Health Organization’s (WHO’s) Solidarity trial showed that remdesivir does not reduce mortality or the time COVID-19 patients take to recover.
Science has learned that both FDA’s decision and the EU deal came about under unusual circumstances that gave the company important advantages. FDA never consulted a group of outside experts that it has at the ready to weigh in on complicated antiviral drug issues. That group, the Antimicrobial Drugs Advisory Committee (AMDAC), mixes infectious disease clinicians with biostatisticians, pharmacists, and a consumer representative to review all available data on experimental treatments and make recommendations to FDA about drug approvals—yet it has not convened once during the pandemic.
The European Union, meanwhile, decided to settle on the remdesivir pricing exactly 1 week before the disappointing Solidarity trial results came out. It was unaware of those results, although Gilead, having donated remdesivir to the trial, was informed of the data on 23 September and knew the trial was a bust.
“This is a very, very bad look for the FDA, and the dealings between Gilead and EU make it another layer of badness,” says Eric Topol, a cardiologist at the Scripps Research Translational Institute who objected to remdesivir’s FDA approval.
FDA has no obligation to convene outside panels for its decisions, stresses AMDAC member David Hardy, an HIV/AIDS scientist of the University of California, Los Angeles. Yet the agency often does so for tricky drug approvals and Hardy is “amazed” the agency didn’t consult the panel in this case. “This sets the standard for the first COVID-19 antiviral,” he says. “When it comes to the point of giving pharmaceutical companies exclusive marketing rights in this area, that really is something that’s very, very important. And there does need to be more than just governmental input.”
FDA did not respond to Science’s request to discuss why it opted against convening the committee, noting only that it is “at the discretion” of division directors. But FDA’s inaction stands in sharp contrast to its handling of potential COVID-19 vaccines. Last week, the agency convened an advisory group to discuss the mere possibility of such a vaccine passing regulatory muster.
As to the EU agreement, Gilead confirmed to Science that WHO in “late September” provided the company with a manuscript about the study results, but a spokesperson for the European Commission, the EU executive arm, said these weren’t revealed during its negotiations. The company has aggressively called into question the validity of the Solidarity data, in part because the study was carried out in vastly different countries around the world with different health care standards. In a 15 October statement, Gilead went so far as to say “it is unclear if any conclusive findings can be drawn from the study results.”
That criticism has angered investigators in the Solidarity study, including Marie-Paule Kieny, director of research at the French medical research agency INSERM and a former WHO officer. “It’s appalling to see how Gilead tries to badmouth the Solidarity trial,” Kieny says. “Pretending the trial has no value because it is in low-income countries is just prejudice.”
On 10 January, 2 days after SARS-CoV-2 was proved to be the cause of COVID-19, researchers published a study in Nature Communications that showed remdesivir had powerful inhibitory effects in both test tube and mouse studies on the related coronavirus that is responsible for Middle East respiratory syndrome. Two weeks later, doctors treated the first confirmed case of COVID-19 in the United States with the drug and reported that the 35-year-old man improved rapidly.
An interim analysis from a large-scale, placebo-controlled clinical trial carried out by the National Institutes of Health (NIH), announced on 29 April, tempered expectations but also emphasized that remdesivir had promise. The drug reduced the median time that severely ill, hospitalized COVID-19 patients took to recover from 15 days to 11 days. It was a modest gain, but NIH noted in a press release that treated patients “had a 31% faster time to recovery than those who received placebo.” Remdesivir, which must be repeatedly infused intravenously, also seemed to lower the risk of death, but that difference could have arisen by chance. (A peer-reviewed, final report of the study published 8 October in The New England Journal of Medicine reduced the time to recovery for the 531 treated patients to 10 days.)
A second, smaller placebo-controlled study of remdesivir on hospitalized COVID-19 patients in China, published online by The Lancet also on 29 April, found no statistically significant benefit from the treatment—and the antiviral surprisingly had no impact on levels of the coronavirus.
Two days after the results from China and the United States came out, FDA granted remdesivir an emergency use authorization (EUA)—a temporary status that is far from full approval—for use in severe COVID-19 patients. The agency cited the NIH trial data, but not the other study. President Donald Trump praised the EUA in an Oval Office press event with Daniel O’Day, CEO of Gilead.
FULL ARTICLE: www.sciencemag.org