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Last weekend, the Food and Drug Administration granted an emergency use authorization for hydroxychloroquine and chloroquine to treat Covid-19, despite a paucity of data to support their use in the disease.

But some interviewed experts see politics at play in the decision, which followed several public statements by President Donald Trump promoting the drugs as treatments for Covid-19, for which they are also undergoing evaluation in clinical trials.

An FDA spokesperson referred requests for comment to previous statements by the agency. Hydroxychloroquine and chloroquine are closely related drugs used for decades to treat malaria and also used autoimmune diseases like lupus, though neither has FDA approval for Covid-19.

“The issuance of the chloroquine EUA maybe itself wasn’t political, but the big picture was that the drugs themselves and their role in this outbreak were political,” said Joanne Hawana, an attorney specializing in FDA regulations with the firm Mintz, in a phone interview. “It didn’t come from life sciences saying, ‘We have this great idea’ – it came from the White House, which is not the source of medical knowledge. So it was political to begin with.”

Strictly speaking, the EUA is not a blanket license to use hydroxychloroquine or chloroquine in any patient who has Covid-19. And to be sure, people hoarding the drugs in response to early clinical trial data hinting at their efficacy in the disease has made them hard to get for those who desperately need them, such as patients with lupus. Rather, the authorization is a narrow one that distributes supplies of the drugs from the Strategic National Stockpile to local public health authorities so that doctors can prescribe them for hospitalized adolescents and adults with Covid-19 who are unable to take part in ongoing clinical trials. Meanwhile, several companies have donated doses of the drug for use in trials, such as Novartis’ generics division, Sandoz.

Mark Mansour, a Washington-based regulatory affairs attorney with the law firm Locke Lord, said he had been hearing that the agency had made the decision while under significant pressure.

“There is a lot of thinking in the administration at the senior levels that something needs to be done, and this is a way to move the ball forward,” Mansour said in a phone interview. That doesn’t mean the agency was comfortable with the decision, however. “They did push back quite a bit, but it looks like they are losing this battle.”

Trump has drawn criticism for making several statements supporting the drugs in press conferences and on Twitter, along with some right-wing media figures. It was also reported last week that the administration is pushing for an EUA for another unproven drug, Fujifilm’s Avigan (favipiravir).

“HYDROXYCHLOROQUINE & AZITHROMYCIN, taken together, have a real chance to be one of the biggest game changers in the history of medicine,” Trump wrote in a March 21 tweet. The tweet referenced a French study that at the time included data for only 36 patients.

Results may certainly appear impressive at first glance. In the paper Trump referenced, 70% of 20 hydroxychloroquine-treated patients were “virologically cured,” versus 12.5% in the 16-patient control group. In a subsequent paper by the same French researchers that included data on 80 patients receiving hydroxychloroquine and azithromycin, all but two patients showed clinical improvement, with 97.5% negative after five days. Another study, of 62 patients in China, showed that of the 31 randomized to receive hydroxychloroquine on top of standard treatment, 80.6% saw improvement in their pneumonia.

But there’s quite a few caveats. For starters, the French study was small and not randomized. The Chinese study has not undergone peer review, was even smaller and only took place at a single institution. It also doesn’t help that another Chinese study, in 30 patients, showed that patients who received hydroxychloroquine on top of supportive care did no better than those who received supportive care alone.

In other words, although there are hints of efficacy, the data are far too premature to say definitively whether or not hydroxychloroquine or chloroquine is a safe and effective treatment for Covid-19.

Indeed, it’s currently unclear which patients should be treated with the drugs and which ones shouldn’t, as the safety in certain populations and correct dosing remain unknown, said Dr. Ravi Amaravadi, an associate professor of medicine at the University of Pennsylvania who is principal investigator on a 400-patient, randomized and placebo-controlled Phase II clinical trial of hydroxychloroquine in Covid-19. But while there is a need to do clinical trials before handing hydroxychloroquine or chloroquine out broadly to patients with Covid-19, doing so is difficult in the current environment due to issues like restrictions on people’s movement.

“I’m not second guessing the decision to do it because it’s such a terrible pandemic that’s unprecedented,” Amaravadi said in a phone interview, referring to the EUA. “There is this balance of trying to provide any treatment that could be beneficial to large numbers of people, compared to performing clinical trials in the way that they are typically done before expanding use across large populations.”

Others also saw the FDA as acting rationally.

“I think the agency is appropriately trying to do what it can to bring potential therapies to patients while not overexposing on risk,” said Jonathan Havens, an attorney specializing in FDA regulations with the law firm Saul Ewing Arnstein & Lehr, who formerly worked at the agency, in a phone interview.

But the FDA’s counterpart across the Atlantic, the European Medicines Agency, reached a different decision, issuing a guidance Wednesday that stated the drugs are only to be used in clinical trials or through national emergency use programs.

“I think the Europeans have taken the more intelligent approach to this,” Mansour said.

Mansour noted that the drugs can cause serious side effects, with potentially fatal cardiac events being a known issue. While those occur in small numbers, it’s unclear what will happen if the drugs are given to more people.

“We don’t know what will happen on a mass scale if we start administering these drugs to people without understanding what the risks are,” Mansour said.

Moreover, Amaravadi said giving them outside of a clinical trial could make it difficult to collect data on adverse events and report it to the FDA, which can be a time-consuming process that is not reimbursed.

“I’m a little concerned that in the heat of battle, in the middle of treating patients with Covid-19, if you’re not on a research study, I’m not sure how many hospitals are reporting adverse events in the fashion that you would in a clinical trial,” Amaravadi said.

All in all, it does seem the agency is trying to balance what the Trump administration wants with its overall mission, Hawana said. “I don’t think it was the FDA’s fault,” she said. “They tried to take a bad situation that was pushed on them and handle it in a rational way by giving Trump what he wanted without going too far, without making it a blanket order saying everyone can buy this drug.”

The fear that all this risks politicizing the FDA – or creating the appearance thereof – is real, Mansour said. But even if that’s the case, it may taper off after the Covid-19 crisis has passed. “Certainly, there are people at FDA worried about politicization because there’s so much politics wrapped up in this,” he said. “Right now, I think the FDA is just trying to make it through just like everybody else.”

Photo: FDA (free of copyright protection)





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