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Infectious disease


Does the FDA’s authorization for chloroquine impede clinical trials for COVID-19 drugs?

Despite the hype, support for the use of chloroquine and its relative hydroxychloroquine outside a clinical trial remains mixed

by Jyoti Madhusoodanan, special to C&EN
April 28, 2020


This image shows tablets of hydroxychloroquine arrayed out in the foreground while in the background the prescription label for the drug is visible.
Credit: John Locher/AP
Hydroxychloroquine is approved to treat malaria and immune diseases like lupus. In late March, the US Food and Drug Administration issued an Emergency Use Authorization to make it available for COVID-19 treatment.

When COVID-19 began overwhelming hospitals earlier this year, desperate physicians reached for a pair of decades-old treatments for malaria. Chloroquine and its relative hydroxychloroquine were discovered nearly a century ago and have been used as antimalarials in the US for nearly 60 years. Decades of data have established the drugs’ side effects and safety profile in patients.

This single chemical structure depicts the configurations of chloroquine and sister compound hydroxychloroquine by indicating which groups are swapped out to make one molecule or the other.

After the 2012 outbreak of Middle East respiratory syndrome (MERS), caused by a coronavirus, researchers found chloroquine could inhibit this pathogen in cell studies. Fast-forward to March 20, and researchers led by infectious diseases physician Didier Raoult of France’s IHU Méditerranée Infection published preliminary data suggesting a combination of hydroxychloroquine and the antibiotic azithromycin reduced virus levels in 14 of 20 treated patients within six days (Int. J. Antimicrob. Agents 2020, DOI: 10.1016/j.ijantimicag.2020.105949). Eight days later, the US Food and Drug Administration issued an Emergency Use Authorization (EUA) for treating COVID-19 patients with chloroquine and hydroxychloroquine.

Clinicians in the US were already using both drugs off-label against the novel coronavirus, SARS-CoV-2. But the EUA expands the medications’ availability, enabling authorities to stockpile and distribute them to hospitals, to be used when a clinical trial is not available to patients. An EUA is often confused with an approval for a drug. In a White House press briefing announcing the authorization, President Donald J. Trump said, “The FDA feels good about it . . . As you know, they gave it a rapid approval.”

But researchers and clinicians fear that such hype, coupled with the greater availability of these drugs through the EUA, will hinder the clinical trials needed to find the best treatments for COVID-19. Although several thousand patients have received hydroxychloroquine or other medications during this pandemic, no drug has been approved for COVID-19—and none has proven effective in a clinical study. “The Emergency Use Authorization further distorts the public perception [of hydroxychloroquine], making it inherently harder to do the right studies,” says oncologist Vinay Prasad of Oregon Health Sciences University (OHSU). “It’s a real disservice to patients, because if we had done the proper trials, we could have had answers weeks ago.”

The EUA is likely to hinder studies, not just of chloroquine and hydroxychloroquine, but also for other experimental drugs, Prasad and others say. Clinicians fear that when offered the option to enroll in a randomized clinical trial to test whether chloroquine really works, patients may request an off-label prescription for the government-authorized drug instead. Why risk receiving a placebo or an experimental drug when you have a chance of receiving the drug that’s been touted publicly?

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Some doctors report instances where patients have chosen not to participate in trials for remdesivir, another experimental drug being tested against the novel coronavirus, and requested chloroquine instead. At Emory University hospital, clinicians had been using chloroquine to treat certain COVID-19 patients for a few weeks. One clinician there, Colleen Kelley, is conducting a remdesivir clinical trial led by the US National Institute of Allergy and Infectious Diseases. When Kelley spoke with potential participants for that trial, she would occasionally hear from a patient that they would “rather get the medication they heard about on TV,” Kelley says. “They never called it by name, but they’d say, ‘that other medicine the president is talking about.’ ”

On April 11, one part of a trial in Brazil that was studying chloroquine’s effectiveness against COVID-19 ended because of severe side effects and fatalities in patients who received high doses of the drug. Last week, a preliminary retrospective analysis of 368 COVID-19 patients in US veterans’ hospitals found an increased overall mortality rate in those who received hydroxychloroquine compared with patients who received only standard supportive care (medRxiv 2020, DOI: 10.1101/2020.04.16.20065920). This report was posted on a preprint server and has not yet been peer reviewed for publication. On April 24, the FDA issued a notice cautioning against the use of the drugs outside of a clinical trial or hospital setting because they can cause heart rhythm problems. How this update affects the EUA is unclear.

But the EUA poses risks beyond immediate ones to patients, according to an April 16 viewpoint published by Jesse Goodman of Georgetown University and Luciana Borio, former director of the FDA’s Office of Counterterrorism and Emerging Threats (JAMA 2020, DOI: 10.1001/jama.2020.6434). “The integrity of governmental decision-making is increasingly coming under pressure, risking harm to both patients and to the public confidence needed to respond effectively to this pandemic,” they wrote.

Minimal evidence

The need for speedy decisions because of a pathogenic threat became apparent after the Sept. 11, 2001, terrorist attacks, according to public health researcher Paul Beninger at Tufts University. In the weeks after the attacks, letters carrying anthrax were mailed to several news media offices and two senators, prompting the US government to develop national policies for medical countermeasures.

In the past 20 years, at least eight different acts have been passed to enable rapid responses to nuclear, chemical, or biological threats, including pandemics. The FDA’s authority to issue EUAs was established by the Project BioShield Act in 2004 and has been amended in subsequent regulations. This legislative framework has helped the US respond to outbreaks, including those caused by the H1N1 flu virus, anthrax, and the Ebola and Zika viruses. More than 100 EUAs have been issued so far, mostly for diagnostic tests. To date, more than 40 EUAs have been issued for SARS-CoV-2 diagnostics and one for the drugs chloroquine and hydroxychloroquine to treat COVID-19.

Previous EUAs for drugs have relied on much stronger evidence than the “scant and conflicting supporting evidence” available for hydroxychloroquine and chloroquine’s efficacy against COVID-19, Goodman and Borio wrote in their viewpoint. During the 2009 H1N1 pandemic, for example, when the unapproved antiviral peramivir was authorized as an intravenous therapy, safety and effectiveness data for the drug already existed from earlier clinical trials for seasonal flu that included 2,000 patients.

An EUA isn’t an approval, so therapeutics marked with this type of authorization don’t necessarily need to go through extensive preclinical and clinical tests. The FDA told C&EN by email that authorization through the EUA “rests upon an understanding of the potential effectiveness of the product for treatment of COVID-19,” but precisely what evidence is considered sufficient remains unclear. “It’s very vague language, and the guidelines are really not very specific,” says Sharona Hoffman, a professor of law and bioethics at Case Western Reserve University. “Often you see, as we do here, there’s political pressure and desperation that gives the FDA very broad authority. It’s mostly a way to reassure people.”

Because chloroquine and hydroxychloroquine have been approved by the FDA for treating malaria and autoimmune diseases such as lupus, prior to the EUA, they could already be used off-label by physicians. The EUA has made the drugs even more available. “Some people who might have been willing to be in our trials are now trying to get it directly from their doctor or other sources,” says infectious diseases physician Sarah Lofgren of the University of Minnesota, who is a coinvestigator on a trial to find out whether hydroxychloroquine has preventive effects in health-care workers at high risk of COVID-19 exposure. But Lofgren admits that it’s difficult to know the extent to which this is happening since there’s no record.

To improve the chances of enrolling patients in their trial, critical care physicians Todd Rice of Vanderbilt University and Robert Hyzy of the University of Michigan discussed changing the ratio of COVID-19 patients who would receive hydroxychloroquine versus those who would not receive it. Hyzy suggested a 2:1 rather than 1:1 ratio so patients would have twice the chance of receiving the drug. “When we had this discussion, I said, ‘how am I going to enroll people in a study when physicians are giving the drug to anyone anywhere?’ ” Hyzy recalls.

A clinician has to remain unbiased, has to believe that this is information that’s unknown and needs to be found out.
Robert Hyzy, critical care physician, University of Michigan

Trying times for trials

Promotion of one particular drug by government officials and agencies can also endanger the quality of clinical trial data, Hyzy says, because it can end “equipoise.” This is the balance a clinician must maintain in thinking that both arms of a trial are equivalent until proven otherwise. “A clinician has to remain unbiased, has to believe that this is information that’s unknown and needs to be found out,” Hyzy says.

Some clinicians say the EUA and hype around chloroquine and its sister compound exacerbate an already difficult environment for studying the effectiveness of drugs, particularly because of COVID-19’s infectiousness. Overwhelmed hospitals can lack the resources to collect data, and basic steps like discussing informed consent with patients at the start of a trial—meant to put them at ease—can be challenging when interactions are happening across layers of personal protective equipment. “Our ability to get consent in the usual manner is impeded,” Hyzy explains.

So far, fears of the EUA hindering trial enrollment don’t seem to have come true. But that’s in part because of increasing caution around chloroquine and hydroxychloroquine, Hyzy and other experts say. Mixed evidence of the drugs’ benefits and reports of severe cardiac side effects and deaths have led many hospitals to update their guidance to clinicians. Hyzy’s hospital stopped using the drugs outside clinical trials shortly after the EUA was issued. On April 21, the US National Institutes of Health issued treatment guidelines that stated the drugs should not be used outside a clinical trial. Three days later, the FDA issued its own caution. Kelley expects that her hospital, like many others, will likely update its treatment recommendations shortly.

“Everyone got on the bandwagon about this drug a month ago,” Hyzy says. “But there’s been a lot more circumspection since then. People are asking, what do we really know? And the answer is: Not much.”

Jyoti Madhusoodanan is a freelance science writer based in Portland, Oregon.


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