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 problem is its an old cheap drug, they can’t gouge the US customer and sell it to the world for pennies like our pharmaceutical companies do with new treatments. Such as gates and fauci’s new drug that costs the Bargain price of just $1000 per pill and of course the fda will approve this.

    • its not about cost. Dexamethasone is very cheap too and has been shown in rigorous study to help those experiencing over-active immune response. Nice try, though. Want to try again? Maybe with some data?

  • “Decisions are based almost entirely on what is known as a randomized controlled trial…”

    It should be noted that within a span of 15-years a total of 74-drugs applications were accepted by the FDA without randomised controlled trials (RCTs): “Regulatory approval of pharmaceuticals without a randomised controlled study: analysis of EMA and FDA approvals 1999–2014.” Quoting from the NIH webpage…

    “The efficacy of pharmaceuticals is usually evaluated for regulatory purposes using randomised controlled trials (RCTs) that, when properly designed and conducted, provide unbiased estimates of treatment effect. However, there are occasions when a therapy is administered to all patients within a trial; this is a frequent step in the development process of pharmaceuticals. While it is not necessarily a preferred approach, the product can be submitted to regulatory agencies for approval following these studies. This can occur with treatments that are new to the market, or for the extension of a licensed treatment to a different patient population, with the argument that clinical equipoise no longer applies. As the treatment is obviously effective, there is no clinical uncertainty, and as such, to withhold the treatment from one group in a trial would be unethical or impractical.”

  • Dear Abbie, Does it bust your TDS bubble to hear that I voted for an opponent of Trump in 2016?

    Seriously, it bothers me that a DRUG has been politicized and articles in respected journals have been published using falsified data to discredit it. What motivated that? It bothers me that doctors are no longer allowed to practice medicine with autonomy and prescribe it if a patient requests it. Google Democratic State Representative, Karen Whitsett. It is anecdotal but there are lots of anecdotal stories of its efficacy. Look up Texas nursing home Dr. Robin Armstrong hydroxychloroquine. He gave it EARLY to 80 nursing home residents and staff and only one died. If I get COVID-19 I’ll take a hard pass on Remdesivir and request the HCQ/zinc/azithromycin combo

    In addition, my SO did drug research on a new drug when a professor at a medical school and the data is massaged and the message is “managed” to make it sound like an improvement. But SO said the old drug was better and cheaper but didn’t yield a very good profit margin. Follow the money.

    Oops, little leak of Remdesivir data before they had the chance to do a good fudging job to make it sound better than it is: https://www.statnews.com/2020/04/23/data-on-gileads-remdesivir-released-by-accident-show-no-benefit-for-coronavirus-patients/

    • sorry but anecdotal observations are strong enough. My 88 year old uncle and a 105 year old were just released from quarantine- they had NO symptoms although they tested positive multiple times. Your Dr Armstrong with his 80 residents could be a blip (maybe his nursing home was filled with my uncles and remarkably resistant 105 year olds). Just because I doubt hydroxy doesn’t mean that I also don’t question Remdesivir benefits…

  • It would be nice if as Mr Harper states above, “doctors can prescribe any drug for any use”. Unfortunately it is false.

    In Minnesota Doctors are reprimanded and threatened with investigation into professional misconduct by the State Board if they prescribe hydroxychloroquine for COVID-19. (google: Doctors Break Down COVID Response and the Demonization of HCQ) and according to JAMA 4/29/2020 “at least 12 states to pass emergency prescribing restrictions.”

    Hydroxychloroquine needs to be studied for EARLY therapy- when a patient first shows up at the doctor’s office with symptoms, not when they are hospitalized in critical condition with multiple organ failure.
    Hydroxychoroquine is cheap, has been used for 60 years, and is safe enough to be prescribed for pregnant women, breastfeeding mothers, elderly, and immunocompromised patients. It has a very long track record. Yes it can prolong QT but that can be monitored.

    Meanwhile brand new drug Remdesivir costs $1200 per dose has not extended lives and is causing liver damage (google Hepatotoxicity Tied to Remdesivir COVID-19 Treatment). Follow the money??

    • hundreds small molecules can act as anti-virals in a dish (at high concentrations). You seem so smart, give me a mechanism by which hydroxychloroquine would act as a anti-VIRAL for SARS-CoV-2 (it currently acts to inhibit a parasite and thanks to Trump our country is well prepared for a malaria pandemic). Why has the Trump cult become obsessed with hydroxychloroquine? They could easily expand their obsession to hundreds of other drugs that can block viral replication in a dish? Really its no mystery: the cult follows its leader that lives in La La Land.

    • Dear Abbie: It sounds like you are limiting your news sources to the U.S. China discovered the usefulness of Hydroxychloroquine, and a French doctor (google Didier Raoult) before Trump even opened his mouth. See also India, and many countries in Africa. I am not American myself, and I do not live in America. But what I see happening in your country and some other western countries, is a shame to your dignity as a nation who is supposed to be leading the world.

    • Anne: those ‘studies’ you seem to believe are also flawed. I get people want a treatment, but just wanting something doesn’t make it true. But I agree that it is shameful that the US is in the boat it now finds itself. No national leadership or co-ordination, fake news, and a pandemic out of control! (Didier Raoult has been completely discredited, btw)

  • Yes, let us stop talking about hydroxychloroquine and focus on the most promising Zelenko protocol (zinc and early intervention on an outpatient basis). This protocol greatly reduces hospitalization, even for high risk patients. Most important to avoid hospital overload.

  • This from the same group that caused panic around a flawed analysis of TZD’s, aka Nissen in diabetes, later proven that the conclusions were not correct. I wonder what the conclusion would be if Trump was anti-hydroxychloroquine?
    So a drug that impairs endocytosis of viruses, is of no value?

  • El mercantilismo encarnado en los políticos pretender opacar la investigación de los científicos de la FDA y OMS, ejemplos que debemos tomar para las elecciones.

  • Dr. Nissen seems to be against investigative products that won’t make anyone millions of dollars. He is an adamant opponent of EDTA for chelation therapy despite an NIH study with positive results. Now against looking a HCQ despite results like this and flawed studies that are retracted (i.e., LANCET). Disappointing for such a respected physician.

  • The whole question with this hydroxychloroquine is whether it is like Tamiflu in that it provides significant benefits when used early but none when used late. Studies in hospitalized patients are designed to fail the early use theory so until we get a good early use study, the question remains unanswered. The FDA and certain “trialists” eager and breathless negative opinion about hydroxychloroquine safety and efficacy makes many physicians susipious of well know bias in medical studies, which seem to be retracted at a high rate when it comes to Covid. There also seems to be a lack of interest in inexpensive existing drugs for Covid in favor of expensive, new, big pharma drugs, however anemic their benefit (remdesivir). The past few years have not been encouraging when it comes to corruption in government agencies and the “establishment”.

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