The recent Food and Drug Administration (FDA) emergency use authorization (EUA) for two malaria drugs to treat COVID-19, based on thin evidence of efficacy, has jeopardized research to learn the drugs' real value against the pandemic coronavirus, say former agency executives under President Donald Trump and former President Barack Obama. They also charge that the 28 March EUA for chloroquine phosphate and hydroxychloroquine sulfate undermines FDA's scientific authority because it appeared to be a response not to scientific evidence, but to fervent advocacy of the drugs by Trump and other political figures.
FDA has multiple mechanisms to allow the use of unapproved, experimental drugs for small numbers of desperately ill patients outside of clinical trials. Because chloroquine and hydroxychloroquine are approved for malaria, doctors could prescribe them "off label" for COVID-19 patients even without the EUA. Since Trump first endorsed the drugs on 19 March, however, shortages have been reported, depriving some people with autoimmune disorders such as lupus who also depend on hydroxychloroquine. The EUA will immediately add tens of millions of doses of the drugs for distribution to hospitalized COVID-19 patients through health care centers.
Trump has suggested the EUA was needed because effective clinical trials of the drugs would take too long during the global crisis. At a 5 April news conference, he said: "We don't have time to go and say, 'Gee, let's take a couple of years and test it out, and let's go and test with the test tubes and the laboratories.'"
"I'd love to do that, but we have people dying today," he added.
Scott Gottlieb, FDA commissioner under Trump until last year, has consistently called for more research on the efficacy of hydroxychloroquine, with or without the antibiotic azithromycin. "If the drug combo is working its effect is probably subtle enough that only rigorous and large-scale trials will tease it out," he tweeted on 5 April.
Margaret Hamburg, FDA commissioner during most of Obama's tenure, including the H1N1, Zika, and Ebola crises, says she was "surprised and perturbed" by the EUA. "I understand the desire to find hope, but we need more evidence than is currently available before we encourage widespread use," says Hamburg, who is a past president of AAAS, which publishes ScienceInsider. Valuable clinical trial evidence on the two malaria drugs could be gathered in a few weeks, Hamburg adds—but the EUA could make that more difficult. "Making the drugs available in a more widespread way might actually interfere with the ability to get the data that we need."
Since 2005, FDA has issued EUAs more than 100 times, mostly for diagnostic tests to detect emerging pathogens, including 34 such authorizations for tests for the novel coronavirus that causes COVID-19. (Here's a table of all EUAs.) The recent authorizations for the use of chloroquine and hydroxychloroquine, based on what FDA cited as "limited in-vitro and anecdotal clinical data in case series," and Chinese and South Korean COVID-19 treatment guidelines, fell below earlier standards for therapeutic EUAs, Hamburg and others say. In contrast, the European Medicines Agency called for use of the drugs only in clinical trials or for emergency use as defined by each nation's policies.
The only comparable EUAs—an antibiotic to treat anthrax in 2011 and antiviral drugs to treat the pandemic H1N1 influenza virus in 2009—enjoyed far stronger evidence of safety and efficacy, former FDA officials say. Even then, one of the drugs authorized for use on H1N1 turned out to be ineffective.
EUAs might prove crucial in the new pandemic, but only if credible, says Luciana Borio, a former FDA acting chief scientist who directed medical and biodefense preparedness for Trump's National Security Council. "You want the EUA to be seen by the public as a step the government is taking to facilitate access to a product that they truly believe has benefits that outweigh the risks. Not, 'We're not sure,'" says Borio, who was part of a team set up under Obama to coordinate actions to fight pandemics that was eliminated by the Trump administration during a 2018 reorganization.
Making the drugs available in a more widespread way might actually interfere with the ability to get the data that we need.
- Margaret Hamburg, former FDA commissioner
Although the World Health Organization last month deemed the two malaria drugs worthy of being tested in rapidly organized global COVID-19 treatment trials, the push to use hydroxychloroquine—it's considered a relatively safe form of chloroquine—on a mass scale in the United States came after a tweet from Trump. On 21 March, he said that when taken with azithromycin, the drug has "a real chance to be one of the biggest game changers in the history of medicine." Trump cited a small French trial of 42 COVID-19 patients that has been criticized for lapses widely viewed as rendering its findings unreliable. Even the International Society of Antimicrobial Chemotherapy, publisher of the peer-reviewed journal that released the study, recently said it "does not meet the Society's expected standard."
FDA Commissioner Stephen Hahn initially tried to temper the president's enthusiasm, calling for clinical trials as a first step at a 19 March news conference. Nine days later, with those trials ramping up, the EUA authorized health care centers to draw on the Strategic National Stockpile's massive supply of the drugs for "treatment of COVID-19 when clinical trials are not available, or participation is not feasible." FDA said that in the absence of approved or available alternatives for treating COVID-19, the drugs' "known and potential benefits … outweigh the known and potential risks."
FDA Chief Scientist Denise Hinton, who signed the EAU, did not respond to a request for comment. An FDA spokesperson wrote in an email that the EUA was not a response to Trump's prodding. Instead, the spokesperson said, it was prepared by career staff who consulted with the relevant federal agencies, and was based on "studies in countries including China, Korea, and France." Two small Chinese trials, which many infectious disease researchers and clinicians regard as more scientifically sound than the French study Trump tweeted about, reached opposite conclusions. In one, COVID-19 patients taking hydroxychloroquine had better outcomes, and in the other, those who received a placebo improved more. A second small French trial found hydroxychloroquine plus azithromycin ineffective for severely ill COVID-19 patients.
Borio, now a vice president at In-Q-Tel, a national security–oriented venture capital firm, adds that FDA, in issuing the EUA, also overlooked the drugs' record against other viruses. She cites a "long history of having tried hydroxychloroquine as a treatment for emerging viral infections, and seeing it fail to help patients despite some activity in vitro and even in animal models."
Impeding clinical trials
David Boulware, an infectious disease researcher at the University of Minnesota, Twin Cities, working on COVID-19 trials, suggests the EUA may impede testing of another potential COVID-19 treatment. He says colleagues working on a randomized, placebo-controlled, multisite trial of remdesivir, Gilead Sciences's experimental antiviral drug, have encountered hospitalized COVID-19 patients who ask, "Do I want to get a placebo? I'm really sick and I can get hydroxychloroquine." Some are opting out of the remdesivir study, Boulware says.
People say that the time to do these studies is not during a public health emergency—it's too hard. Actually, that's the best time, because with a crisis unfolding you have the greatest opportunity to learn about these products the quickest way, because of rapid enrollment.
- Luciana Borio, former FDA acting chief scientist
Purposely or not, and despite skepticism from many doctors, FDA might have made hydroxychloroquine the de facto standard of care for COVID-19, he and others suggest. That could also undermine the COVID-19 trials of it and chloroquine. It's too soon to know what the impact might be, researchers organizing those trials told ScienceInsider. But Peter Lurie, a physician and FDA executive under Obama and Trump who now heads the Center for Science in the Public Interest, a Washington, D.C., advocacy group, says the EUA weakens the incentive to sign up for a trial. "Why take a 50% chance of getting a placebo when you can be guaranteed to get a drug you're hoping to get? Then you're left in a situation where a drug is widely used and evidence of its effectiveness for this indication is never generated."
With so many people dying from COVID-19, calling for more data before widespread use of the malaria drugs can be "a hard message," Hamburg concedes. "People want to have a treatment available to them and their loved ones. But until [it's] examined with some rigor, we won't know whether this will work now, and it's also making it hard to get answers for patients tomorrow and the future."
Borio adds that proper trials need not take long. "People say that the time to do these studies is not during a public health emergency—it's too hard. Actually, that's the best time, because with a crisis unfolding you have the greatest opportunity to learn about these products the quickest way, because of rapid enrollment," she says. "If it's a blockbuster, we would know so quickly."
FDA declined to comment specifically about trial enrollment concerns but said it is working with other federal agencies to plan clinical trials of the two drugs.
Risks rise when millions use a drug
Some FDA observers defend the agency by pointing out it has occasionally given full commercial approval to drugs based on relatively scant evidence, including a controversial treatment for Duchenne muscular dystrophy last year. Erika Lietzan of the University of Missouri School of Law, who studies food and drug regulation, cited Ceprotin—a biologic to treat patients with a genetically linked, life-threatening blood clotting problem—approved by FDA in 2007 based on a nonrandomized trial of only 18 subjects.
But the rare diseases addressed by those FDA actions affect few people compared with COVID-19. When FDA endorses a drug with known, life-threatening side effects for use by millions of hospitalized people to treat a poorly understood condition, the potential for harm rises exponentially, Lurie and others warn.
"What is quite certain: When you get large numbers of people exposed to [hydroxychloroquine], there will be important adverse effects," including sometimes-lethal cardiac toxicity, Lurie says. "That can be acceptable in the setting of known benefits, but it's more difficult to accept when there isn't now and might never be evidence of benefit."
"The idea that we have nothing to lose by trying anything with the smallest glimmer of hope is terribly misguided," adds Patricia Zettler, a law professor at Ohio State University, Columbus, and former FDA associate chief counsel under Obama. "As a society, we risk losing the opportunity to understand what actually works, and what doesn't."
Another safety concern emerged on 20 March, when FDA lifted its import restrictions on Ipca Laboratories, a leading Indian maker of the drugs. FDA has repeatedly cited the company for manufacturing lapses, most recently in a scathing inspection report in August 2019. The agency told ScienceInsider the reprieve was only for the malaria drugs, to meet surging U.S. demand. It said the firm "agreed to perform additional quality mitigation steps" for the drugs.
"Ipca had data integrity issues and cascading failures in quality control," says Hamburg, who led FDA when the firm was cited for such problems in 2014. "That signals to me that it's probably not a drug we want from that supplier."
FDA watchers also wonder how the agency will respond to the next remedy supported by anecdotal reports when facing public fears about a growing death toll and presidential pressure. There is no shortage of candidates—including zinc, remdesivir, the Japanese flu drug favipiravir (branded as Avigan), and a stem cell product touted by Trump attorney Rudy Giuliani. FDA said that by law, it "generally cannot confirm, deny, or comment" about such prospects, and "will not speculate" on future EUAs; it has, however, already approved the testing of the stem cell product in a clinical trial of COVID-19 patients.
"When the evidence base for granting the EUA is as flimsy as this, the question becomes, 'Whose EUA will not be granted, especially in the context of an epidemic?'" Lurie says. "What happens when the epidemic is not [historically] bad, when it's just a bad season of the flu?"
And Hamburg says she fears that with its EUA, FDA has taken "a step away from scientific rigor, to a system that is much more subject to all kinds of interference, from wishful thinking to frank political and economic motivations."