Studies in thousands of people on multiple continents now show the malaria drug hydroxychloroquine does not help patients hospitalized with Covid-19 live longer. But on Tuesday the White House, based on a new study that outsiders greeted with deep skepticism, disagreed.

Now the Food and Drug Administration again risks being pulled into an ugly political fracas over whether to permit more patients to be treated with the drug. It is a debate that threatens to undermine the agency’s credibility when it needs it perhaps more than ever.

“The FDA cannot afford another misstep if it wants to maintain credibility with American people, which is going to be so essential when doing a broad vaccine program, should we identify a safe and effective vaccine for Covid,” said Luciana Borio, who served as the FDA’s acting chief scientist from 2017 to 2019.

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At the root of the conflict is the fundamental principle that the FDA uses to evaluate drugs. Decisions are based almost entirely on what is known as a randomized controlled trial, in which patients are randomly assigned to receive a treatment or not. Other types of studies have, again and again, failed to deliver accurate information about medicines’ benefits and risks, and are used sparingly in making medical decisions. Three randomized studies have now shown no benefit for hydroxychloroquine in hospitalized patients.

The study that sparked the latest controversy was anything but randomized. Not only was it not randomized, outside experts noted, but patients who received hydroxychloroquine were also more likely to get steroids, which appear to help very sick patients with Covid-19. That is likely to have influenced the central finding of the Henry Ford study: that death rates were 50% lower among patients in hospitals treated with hydroxychloroquine.

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On Monday, President Trump, who has long been enthusiastic about hydroxychloroquine and even took the drug himself, tweeted about the results, saying that Democrats had politicized the drug and that the FDA should should “Act Now”. The president’s trade adviser, Peter Navarro, told reporters that Henry Ford had asked the FDA to issue a new emergency use authorization for the drug. The agency had previously revoked hydroxychloroquine’s authorization on June 15, based on evidence it was not effective. 

Experts were taken aback by the developments.

“The medical community has come to the inescapable conclusion that hydroxychloroquine is not effective at treating Covid-19 infections,” said Steven Nissen, a cardiologist at the Cleveland Clinic and a longtime clinical trialist. “Peter Navarro is not a scientist, he is the president’s trade representative. He should not be advising the public on matters of health.”

Nissen and Borio say observational studies simply cannot be used to determine whether a medicine is effective. Again and again they have been wrong. In one famous example, estrogen replacement therapy after menopause was thought to have benefits in preventing heart and other problems; large studies showed this was not the case. In another, a knee surgery for arthritis was shown to have no benefits over medical care. 

A paper that showed that hydroxychloroquine was potentially harmful, which was published in The Lancet in May, was met with similar criticism. It was eventually withdrawn over questions about the validity of its data. 

Observational studies are often used to decide what ideas to test in randomized studies, to make sure that results from randomized studies translate to the real world, and to detect side effects. 

But, puzzlingly, Henry Ford has applied for authorization to use hydroxychloroquine “for a clearly defined list of clinical uses, including use in clinical trials,” the system said in a statement.

“We owe it to our patients and our communities to do everything we can to provide safe, effective, affordable treatments, and we will continue to collaborate toward meaningful solutions that address this deadly disease.”

Evidence that hydroxychloroquine does not help hospitalized patients — the use in its original emergency use authorization, which was designed to allow doctors to access a national stockpile of the drug — is mounting.

One study, the RECOVERY study conducted in the U.K., compared 1,542 patients on a particularly high dose of the drug to 3,132 control patients and found no difference in how long patients lived. A second, conducted by the National Institutes of Health, also found no benefit from hydroxychloroquine at higher doses. 

Yet, in his interview with the White House press pool, Navarro argued that the studies so far were based on “bad science” and that the Henry Ford data were evidence enough. He argued that the drug appears to work when given earlier in the disease course than it was in the large randomized studies. He said that rescinding the FDA authorization had “a tremendously negative effect” on two things.

“One is the ability for American people to use this medicine to protect themselves,” Navarro said, “and, two, the ability for hospitals, like the Detroit hospital system, to recruit patients for the kind of randomized blind clinical trials that everybody wants to settle once and for all the questions of efficacy and safety.” 

It is not clear how the FDA’s decision to rescind the emergency authorization for hydroxychloroquine affected either. Doctors can prescribe any drug for any use, and conducting a clinical trial requires a different type of approval from the FDA. It is clear that granting a new emergency use authorization based on an observational study would go against decades of experience by medical researchers and regulators around the globe.

A huge amount of scientific attention has been focused on hydroxychloroquine. An analysis Monday by STAT and AppliedXL, a computational journalism company, found that 1 in 6 clinical trials started for Covid-19 involved hydroxychloroquine or a similar drug, chloroquine.

Said Nissen: “The sooner we stop talking about hydroxychloroquine, the sooner we can focus attention on more promising therapies.”

  • The safest drug known for >70 y with excellent real life data was demonized. Political games, BigPharma, etc. All RTCs either gave it very late in disease or in unusually high/ toxic doses.
    Armchair doctors who are not treating patients are running trials, they don’t even know properties of drug, correct dosing and timing of administration and confusing with sound alike medication (Prof M. Landray, Recovery).
    Drugs with antiviral property will not work when virus already made significant damage, late stage Covid is not a true viral disease but systemic immune response (as seen in rheumatic disease) … if a patient already has one foot in the grave, the best ever treatment may not be efficient…
    Another HCQ target to prevent excessive procytokine formation is also time sensitive.
    Extremely high doses such Recovery and Solidarity used-2400 mg/1st 24 h, 4000 mg/1st 72 h) – these doses are between TD50-LD50. Even a healthy person who accidentally or intentionally took 1800 mg/24 should be immediately hospitalized… Threshold for toxicity is even less for critically ill patients with electrolyte abnormalities, renal failure, etc… There is significant concern among physicians and pharmacist across the world that significant amount of critically ill patients very likely were killed by overdose in Recovery and Solidarity.
    Sorry, but “birth control pills” are not efficient to prevent unwanted pregnancy for already pregnant females. Aspirin, beta blockers are not cardio protective if significantly overdosed and can cause bleeding, heart block, seizures and death.
    Extensive real life experience of real doctors internationally treating real patients just ignored. Real life studies called “A flawed” regardless of similar results across the world but fabricated data (Mehra at al, etc) were immediately published and were on the top of news (till retracted).
    Death of science? Death of medicine? Without honesty, science is unable to accomplish its mission.

  • This writer is dishonest. Note: The agency had previously revoked hydroxychloroquine’s authorization on June 15, based on evidence it was not effective. Not noting the leading reason for pulling this in first place was a study that Lancet pulled from a partisan group.

  • The New York study only gave patients hydroxychloroquine for 5 days. If you look carefully at their graph, patients in the New York study given hydroxychloroquine did much better during that first 5 days than the patients not given hydroxychloroquine. Look closely at the first 5 days of the events graph in the New York study.

  • Your critique of the Ford study is flawed. You site a study comparing a study where patients were given hydroxychloroquine only after patients were hospitalized for several days. In the Ford study, patients were given the drug early 24-48 hours after admission.

  • gee, I wonder if the head (or some other administrator) of the Henry Ford hospital is a Republican. Regardless, this study is so flawed that it is useless. In fact worse than useless cuz it is clearly is meant to help out the WORST POTUS IN HISTORY, not any patients. Trump Undermines R Democracy and Safety (every day finding new ways to soil and endanger our country).

    • This is the level of conversation I am talking about. Tell us about how the data is flawed. Orange man bad. Got you.

  • Part of the trouble was that all the early RCTs involving HCQ were doomed to fail because they did not include zinc, and the drug was given too late in the patients’ disease. A good drug given at the wrong time is bound to fail. This pandemic is not unique in that scientific methodology standards have been all over the shop — but one must ask the question — if you’re feeling ill with Covid, or have contracted any other disease with a 5-10% fatality rate (yes, the way to calculate that is the fraction of RESOLVED cases (not the total) where death is the outcome, rather than recovery) or are desperate, how much risk do you want to take with an RCT where you could get stuck with a placebo? There’s more than one way to conduct a clinical trial.

    The delay in diagnosis is another factor that is not often mentioned. Early on, obtaining a test was about as hard as getting a mortgage application approved, based on all the hoops one had to jump through. Even now, one hears of people waiting six, seven days before they get results. And then they’re told “isolate, stay home” etc. What people need to know is what to do to help themselves NOW, i.e. the moment they feel ill, such as making sure they get enough vitamins, nutrients, water, etc. perhaps nasal washes with saline/povidone/iodine, so that if the diagnosis comes back positive then their chances of dying are reduced. But all we hear from these experts is “wait until there’s a randomized controlled trial proving such and such a therapy or prevention is fully validated.” Ask 3 million people and counting how much they want to wait, or whether they’d like to be helped NOW.

    • I agree. Every study I have read about that says HCQ doesn’t work or causes death has been because they gave it late in the illness, they gave much too high of a dose, and they did not administer zinc in addition to it. That is what caused the drug to not work effectively or killed patients. I’ve never heard of a study where they gave such high doses for any medicine. The politicizing of this drug is the stuff of nightmares. Where does it end? It is truly frightening.

  • I think it’s simply, a whole lot of vitamin C should help, it did in china. Just my opinion….

  • Very disappointing article that clearly has an agenda. Even if an RCT favored hydroxychloroquine, it would be panned by these types of writers. They would find that one tiny thing that denies perfection (because no trial is perfect) and dwell on it. Look, hydroxychloroquine probably helps, I think any right minded CLINICIAN would see that. You know…clinicians – doctors who actually see and take care of patients.

  • Thus far, the only real placebo controlled study to date has shown hdqn has promise and likely decreases mortality rates.

  • HydroxyChloroquine shows a 95% success if used early with zinc and an antbiotic, it shows little benefit if used late in the illness and given to the most ill patient, stop playing politics with human lives.

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