ViewPoints: Hydroxychloroquine COVID-19 data will test the balance between speed and rigor

Data supporting various COVID-19 therapeutics are evolving rapidly, which will test the ability of scientists, clinicians and the public to strike an appropriate balance between making sure drugs are safe and effective while also getting them to those in need as fast as possible in the midst of a pandemic. Some – but not all – evidence for hydroxychloroquine has aroused some excitement, but with it has come an added layer of confusion thanks to clumsy statements from political leaders, which makes separating fact from hopeful fiction all the more crucial.

The backstory

A deluge of clinical trials has been launched in hotspots around the globe as the biopharma industry and academic partners have sought to test various theories about whether this or that drug or combination will prove capable of helping to blunt the spread and/or mortality of COVID-19, the respiratory disease caused by SARS-CoV-2.

There has been a lot of attention paid to antiviral agents like remdesivir from Gilead Sciences, which has generated some of the most impressive preclinical data in targeting SARS-CoV-2, as well as Avigan (favirapiravir) from Fujifilm Toyama Chemical, a drug approved in Japan in 2014 that was authorised earlier this month in China for COVID-19 based on some encouraging data from non-randomised studies. (See ViewPoints: Initial glimmers of hope for COVID-19 therapeutics.)

What happened

Last week, researchers reported results from a French trial of hydroxychloroquine, an antimalarial drug approved in 1955, showing that it plus the antibiotic azithromycin achieved a virological cure in 100% of patients with COVID-19. The study enrolled 36 subjects, including 22 with either upper or lower respiratory tract infections and six others who were asymptomatic, while six individuals were lost to follow-up.

In addition, a correspondence published in The Lancet on March 19 mentioned an unpublished open-label, randomised trial in China of the structurally similar analogue chloroquine that generated a "positive preliminary outcome" in COVID-19 patients with mild pneumonia. However, Evercore ISI analyst Umer Raffat tracked down an abstract that suggests it was "far from positive."

Specifically, the results show that virological clearance rate was actually higher for placebo than hydroxychloroquine (93% versus 87%, respectively) in 30 patients. The drug did beat placebo on the proportion of patients who experienced radiologic progression (33% versus 47%), but Raffat noted that this measure is "very hard to interpret" given the tiny sample size of five and seven patients that progressed.

What matters most

Even before the French study, which attracted a lot of media attention, there was already a fair amount of buzz surrounding hydroxychloroquine and chloroquine. This was based largely on a steady stream of anecdotal evidence that had emerged to support their use in fighting COVID-19, which dovetailed nicely with preclinical data indicating that the analogues' antiviral potency is on par with that of remdesivir.

To be sure, there are shortcomings galore with both the French study, which was not randomised and involved a very small number of patients that included none who were severely ill. The more chequered Chinese study also involved a small group of patients, but it at least involved a randomised design.

The bigger picture

If this was a normal situation this sort of evidence would be dismissed out of hand by the clinical community. The speed and lethality of the ever-spreading COVID-19 pandemic means, however, this is far from a typical circumstance.

This explains why Raffat described hydroxychloroquine as potentially the "first meaningful drug for COVID-19" based in large part on the French study. The drug does offer some obvious advantages over a therapy like intravenous remdesivir, notably its oral route of administration and low-cost manufacturability that mean it can be produced in massive quantities very cheaply.

Indeed, generic manufacturers including Mylan, Sandoz and Teva have committed to producing more than 200 million doses of hydroxychloroquine – the slightly safer of the two analogues – while Bayer announced it plans to ship 3 million chloroquine tablets.

What next?

The tricky question is at what point regulatory authorities begin allowing use of hydroxychloroquine (and/or chloroquine) given the intense pressure to make something available as soon as possible. The two analogues have already been recommended for use in treating COVID-19 in South Korea and Italy, which were some of the earliest countries hit by the outbreak.

Regulators at the FDA have mechanisms such as emergency use authorisation that they could use to approve a medicine like hydroxychloroquine based on a less-than-ideal data package, and in fact ensuring access to patients would be especially simple for a drug that has been on the market for decades and is already widely available.

Pressure on the FDA to do so will only increase now that President Donald Trump has promoted use of hydroxychloroquine and described it as a "game-changer." That puts the agency in a difficult position, but there are plenty of reasons for it to hold the line at the moment.

For one thing, hydroxychloroquine's less than stellar performance in the randomised Chinese study should raise important questions about its efficacy profile.

After all, it won't be too long before some much-needed data from a wave of randomised, controlled clinical trials will be made available. A search on clinicaltrials.gov suggests that five large studies of hydroxychloroquine have been launched in the last couple of weeks, including at least one in the US being sponsored by the University of Minnesota.

To read more ViewPoints articles, click here.