As that global race to investigate the drug began, though, it hit what looked like speed bumps. In late April, a preprint–no peer review–detailed results for 368 people treated for Covid-19 in Veterans Affairs hospitals with hydroxychloroquine, hydroxychloroquine and azithromycin, or none of the above. The drug didn’t reduce the risk of being put on a ventilator, and it slightly increased the chances people would eventually die of the disease. Suggestive, and not in a good way.
And then the results of a Brazilian trial of chloroquine in people hospitalized with severe Covid-19 seemed to sap even more momentum. A safety committee actually stopped that randomized, double-blind study early. Nearly 40 percent of the people receiving a very high dose of chloroquine had died, and many showed a heart problem called QT interval prolongation, a known side effect of the drug and one potentially made worse when it’s used in combination with azithromycin.
On April 24, the FDA issued a new statement–a Drug Safety Communication–warning that physicians shouldn’t prescribe the drugs to people outside a hospital or trial. The FDA had also received more “adverse event” reports on the drugs, primarily related to heart problems. “While we are unable to offer more specifics on the small number of cases we have reviewed at this time, we will continue to investigate the risks associated with the use of hydroxychloroquine and chloroquine for COVID-19 and will share any additional information or analysis publicly as we’re able,” the statement read.
Sounds bad, right? Except … again, the research wasn’t clear. The VA study was retrospective, and small. That Brazilian study was only of very sick people, exactly the group that big studies like Boulware’s and the international trials planned to exclude on the grounds that they’re probably too sick to help. (Or, perhaps more importantly, it would be too hard for researchers to disaggregate the effects of the drugs from everything else going on in those people’s bodies.) And that high dose of the drug? It was really high–600 mg twice a day for people in the high-dose arm of the trial, and on the low-dose arm 450 mg twice a day on the first day and then once thereafter. That’s compared to a recommended 400 mg twice a day for one day and then once thereafter in US protocols. “What’s being used in the US is much more like the low-dose arm, and there are no issues,” Gellad says. “The high-dose arm had people with other risk factors. It doesn’t tell us much about the way it’s going to be used in the US.”
As for the FDA’s caution? “I think what’s happened is there’s been a lot of promotion of this drug as a cure-all by politicians and by the media. And, parenthetically, at the same time there’s been a lot of unnecessary vilification of the drugs,” Gellad says. “The reality is, there’s a ton of uncertainty … My guess is the FDA wanted to pull back on the idea that the government was promoting the use of this drug, not pushing this therapy but being very responsible, using it in clinical trials.”
The FDA wanted to remind primary care physicians that while they were allowed to prescribe these drugs off-label, they had real side effects–and that some people who don’t have Covid-19 infections really need them for other reasons. “We understand that health care professionals are looking for every possible treatment option for their patients, and we want to ensure we’re providing them with the appropriate information needed for them to make the best medical decisions,” FDA commissioner Stephen Hahn said via press release. “While clinical trials are ongoing to determine the safety and effectiveness of these drugs for Covid-19, there are known side effects of these medications that should be considered.”