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FDA authorizes use of unproven drugs to treat coronavirus, saying possible benefit outweighs risk

WASHINGTON -- The Food and Drug Administration has given emergency approval to a Trump administration plan to distribute millions of doses of anti-malarial drugs to hospitals across the country, saying it is worth the risk of trying unproven treatments to slow the progression of the disease in seriously ill coronavirus patients. 

There have only been a few, very small anecdotal studies that show a possible benefit of the drugs, hydroxychloroquine and chloroquine, to relieve the acute respiratory symptoms of COVID-19 and clear the virus from infected patients.

And health experts warn the drugs' well-known side effects could become more commonplace with much wider use. In particular, they say, patients with existing heart problems or taking certain drugs, such as anti-depressants that affect heart rhythm, are at risk of a fatal episode. Experts recommend screening before the drugs are prescribed to prevent drug-related deaths.

"The concern really is if we're talking millions of patients, then this issue of drug-induced sudden cardiac death is absolutely going to rear its ugly head,'' said Michael Ackerman, a pediatric cardiologist and professor at the Mayo Clinic College of Medicine and Science, who last week co-authored a key paper about the risks in response to the surge in drugs' use.

Long-term use of the drugs also is associated with a chance of developing a form of vision loss called retinopathy, but the use of the drugs to fight virus in an infected patient is only for a few days.

The FDA's emergency authorization does not cover longer-term use of the drugs to prevent the coronavirus infection, a practice that has become more commonplace as doctors have prescribed the drugs "off label'' in response to the pandemic.

With no established treatments available, the FDA said in an approval letter dated Saturday that, essentially, trying the anti-malarial drugs was worth a shot. It cited the actions of other countries to adopt the drugs as a coronavirus treatment and the limited laboratory tests and clinical experience that may show benefit.

"It is reasonable to believe that chloroquine phosphate and hydroxychloroquine sulfate may be effective in treating COVID-19,'' the FDA's chief scientist, Denise Hinton, wrote in the letter granting emergency approval.

Hinton's letter did not cite specific studies or evidence the FDA used to support the decision.

A study in France tracking outcomes in 20 patients given hydroxychloroquine, or a combination of hydroxychloroquine and the antibiotic azithromycin, has been widely cited by President Donald Trump and other proponents of prescribing the drugs for coronavirus. Half of the 14 patients receiving hydroxychloroquine alone got better, and all of the six receiving the combination therapy got better. But the tiny sample size and lack of a rigorous trial protocol have been highlighted by those urging caution.

Another study, in China, found that hydroxychloroquine performed no better than standard treatment for coronavirus. Larger, more rigorous clinical trials of the treatments are underway around the world and in the United States.

Novartis and Bayer are contributing millions of doses of the drugs to the federal government, which will distribute them via the Strategic National Stockpile. The extraordinary action came at the request of the Biomedical Advanced Research and Development Authority, a division of the Department of Health and Human Services.

The FDA earlier this month approved a plan to distribute hundreds of thousands of doses of the drugs to hospitals in New York, which has emerged as the epicenter of the pandemic in the United States.

Despite the lack of evidence of a benefit, Trump has repeatedly stated his belief that the drugs will work to treat coronavirus. One of his top advisers on the government response, Anthony S. Fauci, chief of the National Institute of Allergy and Infectious Disease, has stated that the public should view the drugs with caution because of the paucity of evidence.

In a news release Sunday night announcing the unprecedented action, Health and Human Services Secretary Alex Azar hailed Trump for "taking every possible step to protect Americans from the coronavirus and provide them with hope."

Azar cited the president's "bold leadership'' for making possible the donations of pills by Novartis's generic subsidiary, Sandoz, as well as Bayer.

But the speed with which the FDA is moving has raised concerns about the lack of published evidence, even under the looser standards permitted under an "emergency use authorization,'' which is the regulatory mechanism the agency used in this case.

"You need a degree of scientific evidence. It's in the guidance. You can't just bless it,'' said consultant Lewis Schrager, a physician who was a medical reviewer and clinical branch chief at the FDA from 2002 to 2013.

Many hospitals and doctors have already been prescribing the anti-malarial drugs for weeks.

The surge in demand has sapped supplies of hydroxychloroquine, which has been used to treat lupus and rheumatoid arthritis. Patients suffering from those diseases have been unable to get their prescriptions filled in some parts of the country because of the run on the drugs as well as hoarding, according to health experts.

Ackerman said in an interview that identifying at-risk patients for heart problems caused by the drugs will be a crucial mission for front-line health-care providers. About 10 percent of the population has a risk factor that makes them susceptible to a side-effect of prolonging the split-second interval between electrical recharges of the heart, he said. And 1 percent of the population typically is at especially high risk, he said.

If the interval reaches 500 milliseconds, the heart gets close to "getting tripped up and spiraling out of control'' in a dangerous arrhythmia that can lead to sudden heart attack and death, he said. Not only do the anti-malarials cause that interval to lengthen, so does azithromycin, an antibiotic that is being used in combination with hydroxychloroquine to treat coronavirus, said Ackerman.

"If we're treating a hundred people, then this very rare side effect that will never happen,'' he said. "If we're talking 1 million, and 1% are at real risk of this tragic side effect, that is 10,000 people.''

The frenzy surrounding the drugs' potential has created a "wild West atmosphere'' on social media that threatens to eclipse the dangers, he added. Some medical providers are aware of the side effects, while many others are not, he added.

The FDA posted on its website informational fact sheets for providers warning of side effects and dangers to patients with heart disease, low potassium, and other factors. The FDA said hospitals and doctors prescribing the drugs will be required to report negative side effects to the agency.

 

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