Why experts are skeptical of studies that seemed to show promising results from using a decades-old malaria drug to treat the coronavirus

Andrew Caballero-Reynolds/AFP via Getty

US president Donald Trump looks on as Director of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health Anthony Fauci (middle) speaks during a news conference on the COVID-19 outbreak at the White House on February 26, 2020.

• Hydroxychloroquine, a generic drug that's used for conditions including malaria, is now being tested as a potential coronavirus treatment option.
• Early results from studies in France and China appeared to show promising signs of the drug working against the coronavirus, but experts and analysts warn against making conclusions from these limited trials.
• We break down the early evidence that has emerged both for and against the drug's use in COVID-19 patients. Higher-quality studies are now ongoing to determine if hydroxychloroquine can help patients.
• Visit Business Insider's homepage for more stories.

In just a few weeks, hydroxychloroquine has transformed from an obscure generic medication to the subject of an intense global debate.

President Donald Trump has talked up the potential benefits of the drug in fighting the novel coronavirus. Doctors are facing larger and larger numbers of infected patients and have no approved treatment options to help them. As Trump has repeatedly argued in his pitch for hydroxychloroquine: "What do you have to lose?"

The underlying data provides a much more complicated picture. Some clinical trials for the pills seem to show amazing results in COVID-19 virus patients. But experts warn these studies are limited by being low quality, often enrolling tiny groups of patients or lacking a control group to compare the results against.

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Here's the latest on where things stand with hydroxychloroquine.

Hydroxychloroquine is not approved for the coronavirus, but prescriptions have spiked anyway

Hydroxychloroquine has not been approved by the US Food and Drug Administration to treat COVID-19.

Regulators have issued an "emergency use authorization" for hydroxychloroquine. This only applies for hospitalized patients who are unable to enroll in a clinical trial. Emergency-use decisions have much more flexibility than full FDA approval.

Adding to the confusion, hydroxychloroquine is already an approved drug. It first gained the FDA's okay in the 1950s to treat malaria, and is now most commonly used by patients with lupus or arthritis (both approved indications).

Read more: Everything we know about remdesivir, hydroxychloroquine, and 4 other drugs being tested against the coronavirus

US physicians have broad authority to prescribe drugs "off-label," or for uses they are not formally approved for. While a debate is raging on the clinical results of the pills in COVID-19, data shows many doctors have already started writing these off-label prescriptions.

Weekly US prescriptions for the drug have skyrocketed to more than double normal levels, according to data cited by Raymond James that's reported with a two-week delay.

The early data is limited, with experts urging for higher-quality studies

One of the main backers of hydroxychloroquine is Dr. Didier Raoult, a prominent infectious disease expert in France. The Financial Times recently described Raoult as "a long-haired, iconoclastic virologist" who has became a "pandemic rock star."

His initial experiment tested the cocktail of hydroxychloroquine and azithromycin in COVID-19 patients. At first look, the results were stunningly good: including a 100% recovery rate among patients receiving this cocktail.

Trump referenced the results in a March 21 tweet that included a citation of the academic journal it was published in by name, the International Journal of Antimicrobial Agents. The president said the two drugs "have a real chance to be one of the biggest game changers in the history of medicine."

But Raoult's study is rife with flaws. Elisabeth Bik, a Ph.D. microbiologist who blogs about scientific integrity, raised many questions about the study in a March 24 post.

First, that 100% recovery rate is misleading.

The study enrolled 42 patients, with 20 receiving just hydroxychloroquine, 6 receiving the cocktail with azithromycin, and 16 serving as a control group.

That group of six all cleared the virus after six days. Not only is this is a tiny sample of patients, but the results appeared to deviate from the study's design with little explanation.

Patients were also not randomly assigned to a treatment group, which can allow for biased results.

Finally, the publication only gave data on 20 of the 26 patients receiving some form of treatment in the study. The six missing patients weren't included in the statistical analysis that Raoult ran. They also didn't fare well, with three being transferred to intensive care and one dying.

Bik was far from alone in her concerns about the study. The medical organization that oversees the International Journal of Antimicrobial Agents stated on April 3 "the article does not meet the Society's expected standard."

Raoult has since released additional data from observing 80 COVID-19 patients taking hydroxychloroquine and azithromycin. These results were in a relatively healthy group of patients with no control group.

"It is difficult to meaningfully interpret the data," RBC Capital Markets biotech analyst Brian Abrahams wrote about that study.

Other small studies show mixed results

Other small studies have been completed in China. One found no statistical benefit for hydroxychloroquine when assigning 30 COVID-19 patients to either receive the pills or placebo. But this study also allowed other experimental treatments to be given to both groups, muddying the results.

A Chinese study of 62 patients is "perhaps the most supportive" evidence yet that hydroxychloroquine could work, Abrahams wrote. This trial randomly assigned patients to either the treatment or control arm and demonstrated the patients taking hydroxychloroquine recovered about a day faster from their coughs and fevers.

But that study also has potential concerns. Evercore ISI biotech analyst Umer Raffat noted this study was supposed to have three arms: a placebo, a low dose, and a high dose. The paper only mentioned the high-dose group and placebo.

Additionally, it made no mention of what was supposed to be the key measure of the study: time to viral nucleic acid going negative, or, how long it took for the virus to be undetectable.

"Clinical improvements look quite good," Raffat wrote on this study. "But again, I was hoping to see other endpoints where it probably wasn't as encouraging - that would complete the picture."

RBC's Abrahams also stated he is "particularly concerned clinical endpoints may have been cherry picked" given the discrepancies between how the study was supposed to be run and the resulting paper.

Taking all the results together, Abrahams argues hydroxychloroquine's efficacy requires data from quality, controlled studies "before any enthusiasm can be justified."

Hydroxychloroquine has some well-known side effects

Hydroxychloroquine has been widely used for decades. The drug's toxicities are well-known but not trivial.

For instance, longtime users of the medicine to control their lupus or arthritis will go to routine eye checks. One of the side effects of prolonged use can be eye damage that can become permanent and serious if a person continues taking the pills.

That's less of a concern in this case, where COVID-19 patients are typically taking treatment regimens for one or two weeks. A bigger worry is heart problems, particularly when taken in combination with azithromycin.

Both drugs can prolong how long the heart relaxes between beats. When it gets too prolonged, patients are at risk of serious arrhythmias that can be life-threatening.

A group of New York-based cardiologists observed 84 COVID-19 patients treated with hydroxychloroquine and azithromycin. They found notable signs of that heart problem, called QT interval prolongation, in 30% of that group, with 11% at high risk for arrythmias.

Why it's important to wait before jumping to conclusions

Derek Lowe spent three decades working on drug discovery in labs. Now, he writes an industry blog called In the Pipeline where he has cautioned people for weeks about prematurely reaching conclusions based on very early reports on COVID-19 drugs.

In an April 6 post, Lowe wrote that often in drug research, early results that look positive end up falling apart with more rigorous study.

"After you've experienced this a few times, you take a lesson to heart that the only way to be sure about these things is to run sufficiently powered controlled trials," Lowe wrote. "No short cuts, no gut feelings - just data."

By sufficiently powered, Lowe said he means enrolling enough patients to notice the effect size of the intervention. That means enrolling hundreds, if not thousands, of patients in a typical drug trial.

Now, there are large high-quality trials underway that will test hydroxychloroquine in a range of uses. These include not just hospitalized COVID-19 patients, but also seeing if it can prevent hospitalizations in early infections or even prevent infections in the first place.

In the meantime, one-off reports about COVID-19 patients taking the drug and recovering are likely to come out, given the sheer number of prescriptions being written and the fact that the vast majority of COVID-19 patients will recover, regardless of treatment.

"If you haven't done this stuff, you can look at a report of people responding to such a treatment and figure that the answer is here - right here, and anyone who doesn't see it must have some ulterior motives in ignoring what's in front of their face," Lowe wrote. "But that's not how it works."

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