Contribute Try STAT+ Today

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.

advertisement

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.

STAT Reports: STAT’s guide to interpreting clinical trial results

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.

advertisement

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.

Support STAT: If you value our coronavirus coverage, please consider making a one-time contribution to support our journalism.

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.

  • One correction: Phase I (so-called “First-in-Man”) trials are conducted on healthy volunteers, not patients with the target condition, and are solely for assessing dosage range and surfacing any toxicity concerns. Efficacy is not assessed until Phases II and III, where the drug is tested, in double-blind fashion, against a placebo control.

  • What the heck does Trump know about medicine? He sounds like an idiot. Let the Medical community resolve the issue not some wanna be surgeon who “didn’t know how much he understood about medicine, he might have chosen medicine as a career instead of politics.” Quack, quack.

  • On a related topic, Bloomberg News has broken a story: “Malaria Drug Chloroquine No Better Than Regular Coronavirus Care, Study Finds” referencing a recent study out of China. You have to read down quite a ways to learn that the “Regular Coronavirus Care” in the control group “includes bed rest, oxgen inhalation, and the use of anti-viral drugs recommended in China’s treatment guidelines like lopinavir and ritonavir, and antibiotics when necessary.” Another account said that the control group got another antiviral not available in the US. So the control group got antivirals too, in which case the cheaper hydroxychloroquine (about $10 for a 20-pill treatment, Good Rx) performed statistically as well (almost everyone recovered in both groups) as the more expensive (about $160/bottle for lopinavir/ritonavir) or unavailable alternatives.

    So this was a good news story for hydroxychloroquine craftily crafted into a bad news story.

  • If we move at the normal glacial speed of science, then the last 3 living scientists can write a very nice, peer reviewed paper; all Ts dotted and Is Crossed entitled, “This Would have worked.”

    The Pres is right on this one, we need to follow the French protocol and give very sick people a chance to live. Whats the good of slashing the FDA red tape if the people leading this effort have so much red tape in their heads that they still want to cling to their old ways; we don’t have the 10 years it takes to walk a drug through the FDA to respond to this crisis.

    • I agree with Thomas laValley. Thomas what’s the explanation for the press pooh pooh-ing hydroxychloroquine+azithromycin? Are they cheerleading for the FDA?

    • Well Richard K,

      Lets look at the number$ for a 10-day treatment (Good Rx or other websites) for the three main Covid-19 cure candidates:
      – (20) 200mg hydroxychloroquine tablets @ $0.50 + $10 Z pac= $20.00
      – (1) 160 ml bottle (80 mg lopinavir/20 mg ritonavir)/ml= $165.00
      – Remdesivir (1) day 200mg @ $1450 + (9) days 100mg @ $950 = $ 10,950.00

      ….so who can afford to promote hydroxychloroquine?

  • The WSJ published a piece on March 23 by Kansas City doctors having success with a regimen of hydroxychloroquine and Z-pal. Because these are given in tablet form and there is a five day regimen hopefully wider usage on positive tested patients providing informed consent will build the case for this regimen as well as remdesivir.

  • “Chloroquine is a potent inhibitor of SARS coronavirus infection and spread” is a paper published in medical journals in August, 2005.

    https://www.ncbi.nlm.nih.gov/pubmed/16115318

    The world/US medical community had a 15-year head start on this…..the first person positively tested for Covid-19 (at least in the US) should have been the first person in the (US) clinical trial to determine the efficacy of chloroquine or it’s safer cousin, hydroxychloroquine, on this particular SARS strain.

    On a more personal note, my wife has been using hydroxychloroquine for 20+ years to manage her connective tissue disease. Forget about the long term risks for Covid patients (like retina damage), they won’t be on the drug nearly long enough. The acute risks (like heart arrythmia) are real and are why the drug should at least initially be dosed in a hospital to evaluate the patient’s tolerance.

    If a person is drowning front of you, would any of you take the time to determine if the flotation device you are about to throw is US Coast Guard approved?

  • I would think there’d be epidemiological information on COVID-19 patients in NY on what percentage were already on hydroxychloroquine, since there are people who take it for inflammatory arthritis. If no patients had that listed on their pre-admission med list, that might give credence to using the medication prophylactically (assuming it wasn’t because of a lower testing rate, or low prevalence of Plaquenil use). If a lower rate of ICU admissions/deaths occurred in this population, that could also indicate efficacy. The hospitals should already have this information. It’s just a matter of sifting it out. Admissions/deaths in patients on the med does not necessarily mean it is ineffective. Could be dose, or additional medical issues such as emphysema.

  • I stopped reading after the first paragraph because you’ve clearly copied and pasted all of your information in the wrong places.

    Go back and get the correct names of the malaria drugs and remember that we are dealing with COVID-19 here, not SARS.

    Very poor editorialship. This does not look professional.

Comments are closed.

Your daily dose of news in health and medicine

Privacy Policy