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The start of a clinical trial to test the drug chloroquine as a treatment for the coronavirus pandemic, announced over the weekend by President Donald Trump, provoked a clamor for the unproven drug, amid reports of shortages.
“There is a significant surge in demand of chloroquine/hydroxychloroquine and we are doing everything possible to work with manufacturers to increase production,” the FDA’s Michael Felberbaum told BuzzFeed News on Monday. “We are working with manufacturers to assess their supplies and are actively evaluating market demand for patients dependent on it for treatment of malaria, lupus and rheumatoid arthritis. But please know this is a fluctuating and dynamic situation we are actively engaged on.”
Chloroquine has been used to treat malaria for decades, with its more recent reformulation of hydroxychloroquine often prescribed for patients with lupus and arthritis. Because it was approved to treat malaria by the FDA in 1949, it can also readily be prescribed “off label” by physicians for COVID-19.
“We're going to have some medications delivered that — we're going to see if they work,” said Trump, who suggested clinical trials of chloroquine might begin on Tuesday (at least six are already registered on the NIH’s website). “They certainly are effective in other ways.” Bayer announced last week it was donating 3 million tablets of chloroquine phosphate for use in clinical trials to the US government, and the FDA said it was coordinating with medical schools and research agencies on such efforts.
Despite the excitement, medical experts including National Institute of Allergy and Infectious Diseases Chief Anthony Fauci raised a host of cautions about widespread prescription of an unproved medication for a brand-new disease. Here are just a few.
The evidence of chloroquine’s effectiveness is very weak
Chloroquine was added to China’s formulary for treating COVID-19 in February, leading to its widespread use there and in South Korea. But Chinese data touting its efficacy is scant, resting on a study of monkey cells in test tubes and a consensus report from doctors in Guangdong province.
More recently, a French study touted by Trump has made waves, comparing 20 patients who took the drug to 16 who didn’t.
Outside experts have heavily criticized the French study, however. Infectious disease geneticist Gaetan Burgio of the Australian National University noted that statistically, weighing national responses to a pandemic on a study of 20 people was unwise, that the French study was not conducted with doctors and patients blind to the treatment, and that only a quarter of the placebo patients had their viral load measured. “This is insane!” he said on Twitter.
Even worse, six patients dropped out of the trial from the group receiving the drug, and three of them ended up in intensive care and one died. These could be viewed as failures of the drug to work against the virus, Alfred Kim of the Washington University Lupus Clinic told Undark magazine.
The drug has side effects
One reason that Trump noted for testing older drugs is that doctors are familiar with their use. “They are safe, from the standpoint,” Trump said.”They're not killing people. We're not going to have that.”
But they do have side effects like most drugs, some severe. The Mayo Clinic lists 14 drugs that shouldn’t be taken with chloroquine, whose side effects can include blurred vision, nausea, vomiting, cramps, headache, and diarrhea. Similar side effects are associated with hydroxychloroquine, another form of the drug, which is also linked to convulsions and “mental changes” by the US National Library of Medicine.
The scientific literature contains a number of case reports of overdoses, some fatal. Nigeria reported two fatal overdoses after Trump’s remarks, and asked people not to take the drug without a doctor’s orders.
"You can’t imagine how wrong this is, it gives me goosebumps, it is so wrong," clinical epidemiologist Peter Jüni of the University of Toronto told BuzzFeed News when asked about politicians encouraging people to try chloroquine or other drugs untested for treating COVID-19.
"If you just have millions of people taking a drug with known toxicities, haphazardly, we are going to see major safety problems.”
On Monday, an Arizona man in his sixties died after self-medicating with chloroquine phosphate, a drug meant to clean aquariums.
There might be shortages for people who need it
Arthritis and lupus patients quickly reported a run on pharmacy stocks of the drug following the president’s comments last week.
“For many people with lupus there are no alternatives to these medications,” the Lupus Foundation of America said in a statement on Monday, warning of “verified” reports of shortages. “Hydroxychloroquine or chloroquine are the only methods of preventing inflammation and disease activity that can lead to pain, disability, organ damage, and other serious illness.”
The drug shopping website GoodRx showed that between March 1 and March 16, there was a 57% surge in demand for hydroxychloroquine and a 90% increase in chloroquine, Bloomberg News reported. And compounding pharmacies, which can quickly manufacture drugs in capsules and typically step in when shortfalls of manufactured tablets hit, have noticed a run on chloroquine as well. One New York compounding pharmacist, Gopesh Patel, told BuzzFeed News that orders went from around 20 a week to more than 200 a week in the last two months.
“We’ve seen demand for the drug increase exponentially,” said Gus Bassani, chief scientific officer of the PCCA compounding pharmacy industry group. “So far, the manufacturers are responding to the needs by ramping up production, and we have material confirmed to be shipped.
“We remain in regular contact with our suppliers around the world and are working to expedite those shipments whenever and however possible. So, supply signals are good.”
Large drug makers like Novartis AG, Teva Pharmaceutical Industries Ltd., and Bayer AG plan to increase production, but some observers worry that a run on the drug will lead to low-quality versions flooding the market.
Patel ended the phone call with BuzzFeed News to prepare doses of chloroquine in liquid form for two children, ages 8 and 10, with coronavirus.
The rush for the drug might interfere with efforts to test it in clinical trials
"It's the trials that will tell us what's going on," said Jüni, adding that it is impossible to understand “based on evidence that is just incomplete and invalid, whether it works or not."
But hordes of people rushing to their doctor to take unproven drugs might interfere with such efforts to test them to find out if they really work or not, Jüni and other experts worry. Why enter a clinical trial, where there is a chance you might not receive an experimental drug if you are in its control arm meant to serve as a comparison with only standard care, when you can just pressure your doctor to give it to you for off-label use?
The University of Minnesota announced the start of a national clinical trial of hydroxychloroquine early last week, for example, seeking up to 1,500 people exposed to COVID-19 disease within the past three days, where half of the volunteers would get the drug while the other half receive an identical-looking sugar pill, a placebo.
And clinical trials aren’t about instant gratification either. The University of Minnesota one has an end date of May 2021. Given the uncertainty of the situation, Jüni was reluctant to give a timeline for the typical trial, but spoke about designs lasting 4 to 6 months that might lead to results in 8 to 10 months.
"There’s no miracles," he said. "We have to actually conduct the trials."
False drug hopes might take the brakes off social distancing too early
The hardest part of “flattening the curve” comes in the weeks ahead in the US, where at current rates of increase, the nation’s count of more than 40,000 cases today will grow to the hundreds of thousands by the end of the month.
That’s because it takes weeks for social distancing to start biting into new case numbers, due to the roughly 14-day infection period of the novel coronavirus. Even after everything shuts down and the economy tanks, people are still developing the disease, heading to the hospital, and adding to case counts.
Meanwhile, President Trump is already itching to remove calls for shutting down business at the end of the “15 Days to Flatten the Curve” campaign announced mid-March (a position supported recently in conservative media) the Washington Post has noted.
That could lead to increased pressure to lean on a “miracle drug” as a key to averting a worse recession. Los Angeles hedge fund Hercules Investments, for example, released a newsletter that told investors on Monday that the French clinical trial was the “most promising reason” to be “optimistic about a short lived contagion followed by a rapid recovery.”
The clash between public health officials and business interests at the White House was already playing out on Monday, with Trump saying, "I'm not looking at months,” when asked how long social distancing will last in the US.
“If you look at the trajectory of the curves of outbreaks and other areas, at least going to be several weeks,” NIAID’s Fauci said last week on NBC’s Today show.
Fauci was not at Monday night’s White House event.