One of the most wrenching questions in medicine has been playing out to garish effect in White House press conferences.
The question is this: In an emergency, like the exploding pandemic of the coronavirus that causes Covid-19, how much data should doctors require before they use a medicine? President Donald Trump has made clear that he thinks two old malaria drugs, hydroxychloroquine and chloroquine, should be deployed quickly against the coronavirus, SARS-CoV-2. But his own lieutenants, the heads of the Food and Drug Administration and the National Institute of Allergy and Infectious Diseases, have been hesitant.
There’s no question the need for effective treatments is urgent. Cases of Covid-19 are exploding, with more than 24,000 reported nationally and more than 10,000 in New York State alone. Actual numbers may be far higher. Reports say that New York hospitals are full with patients on ventilators who need treatment now.
Hope has emerged around two anti-malaria drugs: chloroquine, discovered in 1934, and a derivative of it called hydroxychloroquine that is thought to have less severe side effects. Both have shown promise in preventing SARS-CoV-2 from infecting cells in the laboratory. And a small and preliminary clinical trial of hydroxychloroquine in France circulated widely and stirred excitement on social media (including from the president) — though its findings were hardly definitive about whether the drug would benefit coronavirus patients. New York Governor Andrew Cuomo said Sunday that a study of the drug will start Tuesday.
The fact that these drugs have already been cleared by the FDA for use against other diseases — they’re prescribed by doctors not just for malaria but also rheumatoid arthritis and lupus — has added momentum to the argument they should be quickly made available for Covid-19; their side effects, which include heart and nerve damage and suicidal thoughts, are well-understood and, given the current circumstances, manageable, supporters argue. Doctors can already prescribe them off-label.
At a Thursday news briefing, Trump trumpeted that chloroquine had shown “very, very encouraging early results” and said “we’re going to be able to make that drug available almost immediately.” Minutes later, FDA Commissioner Stephen Hahn, an oncologist, clarified that the drug would be available “in the setting of a clinical trial — a large, pragmatic clinical trial — to actually gather that information and answer the question that needs to be answered and — asked and answered.”
On Friday, the president said, “It may work, it may not work. I feel good about it. That’s all it is. Just a feeling.” At the same press conference, Anthony Fauci, a physician who heads the NIAID and a veteran of outbreaks going back to HIV, emphasized the need for a methodical clinical trial.
“We’re trying to strike a balance,” Fauci said, “between making something with a potential of an effect to the American people available, at the same time that we do it under the auspices of a protocol that would give us information to determine if it’s truly safe and truly effective.”
On Saturday morning, Trump tweeted: “HYDROXYCHLOROQUINE & AZITHROMYCIN, taken together, have a real chance to be one of the biggest game changers in the history of medicine,” referencing a scientific journal article about the small clinical trial of 36 patients in France. Several other small studies of other antiviral drugs have also shown glimmers of hope. So what should doctors do?
How likely is it that the possible benefits shown in a small study will turn out to be a mirage? One way of understanding this is to look at what happens with medicines in clinical trials. Experimental drugs are usually studied in three stages of progressively larger studies. The first, called Phase 1 trials, are small studies used to get an early read on efficacy and rule out obvious safety issues. These are then refined in larger “Phase 2” studies and then in the large “Phase 3” studies used by the FDA to decide whether to approve a drug.
The study referenced by Trump, and other studies done so far of potential treatments for Covid-19, are small and hastily designed even by the standards of Phase 1 studies. So how often do infectious-disease drugs that enter Phase 2 studies reach the market? An analysis by the Biotechnology Industry Organization says they worked out only 27.5% of the time between 2009 and 2015. That means that three-quarters of the time, medicines against infectious disease that looked promising in small studies either were ineffective or had side effects that made them unusable. Even for medicines that reached Phase 3 trials, just 63% succeeded.
But the issues with these studies go beyond their small size or the fact that early promises, in research, often don’t pan out. It goes to one of the big truths about how doctors, eager to see a new drug succeed, can subconsciously lie to themselves with clinical studies: To be trustworthy, these studies often need to be randomized. This means that not only are some patients assigned to a control group that doesn’t get the promising medicine, but that who gets what treatment is decided, essentially, by a coin flip. (The most rigorous of these randomized trials are also “blinded,” meaning the doctors running the studies don’t know which patients are in which group.)
The use of randomization as the standard way to design a medical study goes back to another deadly infectious disease: tuberculosis. In the early part of the 20th century, it was a scourge, and many doctors turned to gold-based treatments, to try and control it. They turned out to be toxic and ineffective. In 1946, researchers in the United Kingdom’s Medical Research Council decided to conduct a randomized trial of another treatment, the antibiotic streptomycin, in 107 patients. The results were clear: 7% of those who received streptomycin died, compared to 27% of those in the control group.
That study, published in the British Medical Journal in 1948, became the basis for most modern medical research. The sacrifice made by the 52 people in the control group meant that there was no doubt the streptomycin worked _ and that a situation like gold treatment, where many patients get a therapy that harms, instead of helping, wouldn’t repeat itself.
The study Trump and others have touted was anything but randomized. Instead, Covid-19 patients were treated with either hydroxychloroquine or the combination of hydroxychloroquine and azithromycin, an antibiotic also known as Zithromax, at a hospital in Marseille, France. They were compared to coronavirus patients at hospitals in Marseille, Nice, Avignon, and Briançon who didn’t receive these drugs.
The study doesn’t show that patients lived longer or were more likely to recover, but instead shows that the amount of virus in the blood was reduced much faster in the patients who took hydroxychloroquine and even faster in the six patients who took the combination of hydroxychloroquine and azithromycin.
That result is encouraging, but for patients who are not gravely ill, it doesn’t tell how to weigh the side effects of hydroxychloroquine against the potential benefits. That’s the reason for a clinical study like the one starting in New York.
But for doctors on the front lines, particularly in New York City, where hospitals are becoming overwhelmed and where there are many patients on ventilators, the drugs could be an immediate option. As Cuomo put it in a press conference Friday, “where a person is in dire circumstance, [you] try what you can.”
Reports about the potential of hydroxychloroquine as a potential treatment for Covid-19 have been circulating among New York City emergency physicians for more than a week, and some patients are reportedly getting the hydroxychloroquine/azithromycin combination. (Perhaps as a result, there are shortages cropping up for patients with lupus and other diseases who need the drug.) The University of California, San Francisco, and the University of Washington both recommend hydroxycholoroquine for very sick Covid-19 patients.
The qualms about the French study extend to two other studies of antiviral drugs as potential Covid-19 treatments. A study of 80 patients given the Japanese flu drug favipriavir, which is not approved in the U.S., was not randomized; it found a shorter clearance time for the drug. A small randomized trial of HIV medicines, published in the New England Journal of Medicine, found no overall benefit, but hints that it helped some subgroups of coronavirus patients.
Taken together, some stock analysts have forecast that these results could improve the odds that another antiviral drug, Gilead’s remdesivir, could prove effective in two Phase 3 studies in China that are expected to read out in April.
For drug development, getting results so soon is blindingly fast. For doctors on the ground and patients who are struggling to breathe, it is agonizingly slow.