> The ‘very, very bad look’ of remdesivir, the first FDA-approved COVID-19 > drug > > By Jon Cohen <https://www.sciencemag.org/author/jon-cohen>, Kai > Kupferschmidt <https://www.sciencemag.org/author/kai-kupferschmidt>. > https://www.sciencemag.org/news/2020/10/very-very-bad-look-remdesivir-first-fda-approved-covid-19-drug > > > SCIENCE. Oct. 28, 2020 > > > 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 (ADAC), 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, as the trial’s sponsor, > began to review the WHO 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 ADAC 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 > <https://www.sciencemag.org/news/2020/10/there-s-only-one-chance-do-right-fda-panel-wrestles-covid-19-vaccine-issues> > 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 > <https://www.gilead.com/news-and-press/company-statements/gilead-sciences-statement-on-the-solidarity-trial>, > 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.” > Disappointing trials > > 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 > <https://www.nejm.org/doi/full/10.1056/NEJMoa2001191>. > > An interim analysis from a large-scale, placebo-controlled clinical trial > carried out by the National Institutes of Health (NIH), announced on 29 > April > <https://www.c-span.org/video/?c4872715/nihs-fauci-touts-positive-results-remdesivir-drug-trial>, > 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 <https://www.nejm.org/doi/full/10.1056/NEJMoa2007764> 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 > <https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31022-9/fulltext>, > 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 > <https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-issues-emergency-use-authorization-potential-covid-19-treatment>, > but not the other study. President Donald Trump praised the EUA > <https://www.youtube.com/watch?v=sZq7xk7E1a0&ab_channel=NBCNews> in an > Oval Office press event with Daniel O’Day, CEO of Gilead. > > On 21 August, a Gilead-sponsored study published online in JAMA > <https://jamanetwork.com/journals/jama/fullarticle/2769871> 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 > <https://www.gilead.com/news-and-press/press-room/press-releases/2020/8/gileads-investigational-antiviral-veklury-remdesivir-receives-us-food-and-drug-administration-emergency-use-authorization-for-the-treatment-of-p> > 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 > <https://www.sciencemag.org/news/2020/10/remdesivir-and-interferon-fall-flat-who-s-megastudy-covid-19-treatments>. > 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 > <https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/214787Orig1s000Sumr.pdf>, > 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 > <https://www.gilead.com/news-and-press/company-statements/gilead-sciences-statement-on-the-solidarity-trial> > . > > Gilead Chief Medical Officer Merdad Parsey wrote in an open letter > <https://stories.gilead.com/articles/open-letter-from-merdad-parsey> 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. > > 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.” > > 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 > <https://www.who.int/medicines/regulation/medicines-safety/COVID19-PV-update11.pdf> > 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 > <https://www.ema.europa.eu/en/medicines/human/EPAR/veklury> in some > patients taking remdesivir. > > 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?’” > > 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” > <https://www.ema.europa.eu/en/medicines/human/EPAR/veklury> 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” > <https://ec.europa.eu/commission/presscorner/detail/en/ip_20_1416> 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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