- Scientists have questioned FDA’s emergency authorization of GiLead’s Remdesivir overlooking critical data and evidence.
- Many have questioned how the company has undermined WHO’s Solidarity trial.
- The absence of viral load data in FDA’s approval evidence is a critical concern.
- Scientists say an outside expert panel debate was necessary before the approval
- Many are comparing this to the authorization of hydroxychloroquine use.
Within a month of publishing clinical trials data showing the effect of remdesivir, GiLead got FDA approval and clinched a coveted EU deal. This fast remdesivir authorization overlooking critical data and evidence has made scientist question the move, reports Science
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.
It’s appalling to see how Gilead tries to badmouth the Solidarity trial. Pretending the trial has no value because it is in low-income countries is just prejudice.
On 21 August, a Gilead-sponsored study published online in JAMA compared hospitalized COVID-19 patients with moderate pneumonia who received remdesivir for 5 days or 10 days versus those treated with the standard of care. The 5-day remdesivir group improved more quickly, but, oddly, the 10-day group did not. (An earlier published study sponsored by Gilead found no difference between the two treatment courses.)
The next week, FDA expanded remdesivir’s EUA to include all hospitalized COVID-19 patients. That led Topol to publish a scathing open letter to FDA Commissioner Stephen Hahn on Medscape, a popular medical website of which Topol is editor-in-chief. Under the headline “Tell the Truth or Resign,” Topol lumped the decision together with heavily criticized EUAs issued earlier for the malaria drug hydroxychloroquine—which the agency later rescinded—and antibody-rich “convalescent” plasma obtained from the blood of recovered COVID-19 patients.
“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,” Topol wrote.
Debating the evidence
WHO’s Solidarity trial, conducted in 405 hospitals in 30 countries, is about three times as large as the other three trials together and many scientists expected it to better resolve remdesivir’s worth. Solidarity did not use a placebo, but instead compared remdesivir and three other repurposed drugs with each other and the standard of care. The Solidarity trial investigators described the study results to FDA representatives on 10 October and posted a preprint on them on medRxiv 5 days later. Solidarity mainly aimed to determine whether the drugs lowered mortality among hospitalized COVID-19 patients, which none of them did. The researchers also noted that remdesivir did not affect “the duration of hospitalization” or whether COVID-19 patients required ventilators, which are only used when people advance to very serious disease.
The release of the Solidarity data has triggered a fresh debate about the relative value of each remdesivir trial—and whether FDA should have aired that discussion in public instead of weighing the data privately.
In its review that recommended remdesivir’s approval, the agency only included data from three trials: the NIH study and two Gilead-sponsored trials, ignoring the Solidarity data as well as the findings from the other placebo-controlled trial in China.
That infuriated the Solidarity team. “The mantra I’ve always heard as a joke about the FDA is that they say ‘In God we trust, everyone else has to provide data,’” Kieny says. “So look at all the data.”
As far as Gilead is concerned, the Solidarity data should not play an important role. “We are concerned that the data from this open-label global trial have not undergone the rigorous review required to allow for constructive scientific discussion, particularly given the limitations of the trial design,” the company wrote in its statement.
The argument that the earlier you use it, the better is great until you realize what the implications of that are: You won’t save many lives, and you’ll have to treat a lot of patients. It’s very inconvenient, and it’ll cost you a fortune.
Gilead Chief Medical Officer Merdad Parsey wrote in an open letter posted the day of 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. Gilead has also raised questions about the availability of Solidarity’s data, telling Science it has requested from WHO, but has yet to receive, “the underlying data sets or statistical analysis plan” for the trial.
Disparity in National Healthcare Systems in Solidarity Trial
WHO counters that Gilead knew the statistical analysis plan before joining the trial and will receive the full data set once the study is complete. It does not matter that the data have not yet been peer reviewed, WHO scientists say, because FDA traditionally reviews all available data, including unpublished findings. As to the disparity in health systems that Gilead cites as a confounding factor in Solidarity’s findings, WHO’s chief scientist, Soumya Swaminathan, notes that 50% of the 2750 patients who received remdesivir in the trial were from Canada and Europe, places recognized for high-quality health care. And she stresses that the other participating countries do not necessarily have substandard care.
Clifford Lane of the National Institute of Allergy and Infectious Diseases, who helped run the NIH study, says its main difference with Solidarity is “the degree of granularity” of the analyses of subgroups that may have benefited.
“I think the Solidarity data are fine,” Lane says. “It’s a very large study and it has a very robust endpoint.”
Martin Landray of the University of Oxford, who is co-leading the world’s largest study of various COVID-19 treatments, says remdesivir “definitely doesn’t work in the sickest patients where the biggest gains would be” but might help people at earlier stages of disease. Further complicating the matter, most people infected with SARS-CoV-2 recover without any intervention. “The argument that the earlier you use it the better is great until you realize what the implications of that are: You won’t save many lives, and you’ll have to treat a lot of patients,” Landray says. “It’s very inconvenient, and it’ll cost you a fortune.”
Remdesivir Can Cause Harm?
Questions have also arisen about the potential of remdesivir to do harm. WHO has a regular overview of possible adverse drug events related to COVID-19 treatments. In late August it 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. The European Medicines Agency (EMA) also announced this month that its safety committee had started a review to assess reports of acute kidney injuries in some patients taking remdesivir.
Gilead Sciences’s remdesivir has become part of the standard of care for many COVID-19 patients in the United States and the company has been increasing production of the antiviral to meet increasing demand.
Crucial Data Missing in FDA Authorization
Many researchers point out that another crucial piece of data is missing entirely from FDA’s statement on remdesivir’s approval: evidence the drug reduces the amount of SARS-CoV-2 in the body, the viral load.
“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,” says Andrew Hill, a clinical pharmacologist at the University of Liverpool. “Surely Gilead has done that. Where are the data? It is very, very strange.”
Richard Peto, an Oxford statistician and epidemiologist who helped design Solidarity and analyze the data, stresses that the WHO trial cannot prove whether remdesivir has zero benefit for COVID-19. “Trials produce confidence intervals, not just point estimates and this is actually the difficulty in trying to discuss this,” Peto says. “Gilead and the FDA have sort of maneuvered us into a position where we’re being asked to try and prove remdesivir does nothing rather than asking the usual way round, which is, ‘Can the manufacturers prove it does something?’”
Scientists Say Debate Needed Before Approval
To many scientists, such complexities underscore that FDA should have consulted ADAC, its panel of outside experts, for a vigorous debate. It could have “elevated the discussion,” says ADAC Chair Lindsey Baden, an infectious disease specialist at Brigham and Women’s Hospital. “Hydroxychloroquine, convalescent plasma, remdesivir—these are complicated decisions given the imperfect nature of the data upon which the decisions are being made, and the urgency of the clinical use gives all the more reasons to have an open discussion,” says Baden, whose group last met in October 2019.
“This was not a straightforward approval and this is not an ordinary time,” adds Luciana Borio, a former acting chief scientist at FDA who now works at a not-for-profit venture capital firm. “It would have been helpful to have a public discussion on the matter.”
Georgetown University’s Jesse Goodman, a former chief scientist at FDA, notes that it is complicated to organize advisory committee meetings, but adds that the agency obviously just arranged one for COVID-19 vaccines. “Although it’s a pandemic and everybody is super busy, it’s something … you can do virtually,” he says. “It would have been an opportunity to make clear publicly the rationale and their risk-benefit assessment.”
European Commission in the dark
EMA, Europe’s FDA counterpart, in July gave “conditional approval” to remdesivir—which is similar to an EUA—but it has yet to give its full blessing. The European Union nevertheless has negotiated a “joint procurement agreement” with Gilead that offers 500,000 treatment courses over the next 6 months for $1.2 billion. A spokesperson of the Commission 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.
“The Commission became aware of the results of the Solidarity trial on 9 October from the reporting of [EMA] at the COVID task force meeting on the same day,” the spokesperson says.
“There was no discussion with WHO about the ongoing study prior to signing the contract with Gilead.”
When Science asked Gilead why it didn’t disclose the Solidarity data during its negotiations with the Commission, the company acknowledged it received a draft manuscript from WHO in late September but said it was “heavily redacted.” WHO says the only information blacked out was results relating to the other drugs used in the trial because of confidentiality agreements with their manufacturers.
Although the agreement with Gilead locks EU members into a price of about $2400 for a full course of remdesivir, it does not obligate any countries to purchase the drug, the Commission spokesperson tells Science. “The EU needs to publish the deal with Gilead,” says Yannis Natsis of the nonprofit European Public Health Alliance. “It should at least renegotiate the volume of the doses and the price per treatment.” Gilead says it doesn’t plan to adjust its negotiated price in the wake of the Solidarity data.
Kieny says it’s an “enormous” waste for EU countries to invest in remdesivir based on the idea that it might help a small subset of patients. “You can always say, ‘OK, now, if I disaggregate the population and if I take only those who have a blue eye and a wooden leg, maybe this is very effective,’” she says.
Indeed, some advocates of remdesivir point to analyses of Solidarity patient subgroups that suggest a mortality benefit in those who received supplemental oxygen but were not on ventilators. But accepting that would also mean accepting that remdesivir harmed those who were on ventilators, Hill says. “You can’t do a subgroup analysis and only believe half the story.”
The bottom line from the trials so far is there simply isn’t enough evidence that remdesivir works, says Jason Pogue, a University of Michigan, Ann Arbor, researcher who is president of the Society of Infectious Diseases Pharmacists. Pogue believes FDA made a mistake and, unless more data emerge, EMA should not give the drug full approval.
“There are more questions than answers about the efficacy of remdesivir in hospitalized patients,” he says.
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Source: Science
