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The FDA’s emergency use authorization of chloroquine and hydroxychloroquine for COVID-19: Dangerous politics, not science

Yesterday, the FDA issued emergency use authorization for hydroxychloroqine and chloroquine to treat COVID-19. Politics, not science, is why.

During my recent absense from this blog, I wasn’t entirely inactive writing about COVID-19. Obviously, I was active (much less frequently) on my not-so-super-secret other blog. During that time, I addressed the topic of the promotion of chloroquine and hydroxychloroquine (the latter sometimes with the antibiotic azithromycin) as treatments for COVID-19. It started with anecdotal reports from China of success repurposing these drugs to treat these patients, which somehow morphed into claims of “great promise” in randomized clinical trials, none of which have yet been published except for one of them, a small negative trial of chloroquine, and a second one, a small reportedly positive trial of hydroxychloroquine, that’s been published as a preprint and has major issues. Overall, the evidence supporting the use of these drugs against COVID-19 is shockingly thin (almost nonexistent), consisting of some in vitro evidence of antiviral activity against SARS-CoV-2, the virus that causes COVID-19, anecdotes, and ; yet they’ve become almost standard of care in many countries. Indeed, the FDA recently granted Emergency Use Authorization (EUA) to use these drugs for COVID-19, leading Steve Usden to express alarm over at Biocentury. He’s basically saying what I’ve been saying on Twitter the last two weeks about the frenzied off-label use of these drugs to treat COVID-19. I’ll comment on his article in a moment. First, since I haven’t written about this yet here, let’s look at some background.

Bad science on hydroxychloroquine

The most famous trial thus far comes from a famous (and maverick) French scientist named Didier Raoult. It was a small study that claimed that the combination of hydroxychloroquine and azithromycin resulted in rapid clearance of SARS-CoV-2 from patients treated with it. It was an abysmally bad study for a number of reasons. The study was not randomized, and the control group was treated entirely at a different hospital than the experimental group. Data were missing from the controls. Some patients in the treatment group who deteriorated were excluded from the analysis; i.e., no intention-to-treat analysis was carried out. There was weirdness and inconsistency about how the virus was measured by PCR. There were no outcome data to show whether the treated group did better than the controls. The list goes on. Indeed, it was so bad that I now suspect more than just incompetence; I suspect scientific fraud. Indeed, more recent data find no difference in viral clearance in COVID-19 patients treated with anti-malaria drugs.

Raoult’s second published trial was only somewhat better, but it was also utterly uninformative because it was single arm (no control group) and the vast majority of patients enrolled had mild disease, with some of them even asymptomatic. Didier Raoult is clearly a man who loves publicity, because he touted his results and became an overnight international celebrity, complete with an appearance on The Dr. Oz Show, while making appearances with French media proclaiming “On sait guérir la maladie” (“We know how to cure this disease”).

The most recent Chinese randomized trial was published online as a preprint (meaning that it hasn’t undergone peer review yet). It’s a larger (but still small) randomized trial of hydroxychloroquine given for five days at a dose of 400 mg/d. They reported that time to clinical recovery, body temperature recovery time, and cough remission time were significantly shortened in the treated group and that the proportion of patients with improved pneumonia was higher in the hydroxychloroquine group (80.6%) compared to controls (54.2%). They also noted that all four patients who progressed to severe illness were in the control group, while two patients in the hydroxychloroquine group experienced minor side effects (one had a rash, the other headache). There are some problems, however. First, this is not placebo-controlled. The authors claim that neither “the research performers nor the patients were aware of the treatment assignments,” but how could that be? The patients could know if they were receiving hydroxychloroquine or not, as could the nurses and the physicians treating them. That could subtly have affected their assessments of the patients, and it could have affected how patients reported their symptoms. (The study relied on patient reports of how severe their coughs were, for instance.) True, body temperature is an objective endpoint, but every other endpoint examined has at least some degree of subjectivity. Worse, the statistics were dodgy on the paper. For instance, I see what looks like Student’s t-test being used on a case of multiple comparisons, and one of the p-values (Table 2) is 0.0476. Let’s just say that whenever a p-value is that close to 0.05 buy still “significant,” my skeptical antennae start twitching wondering if the data underwent some “massaging” to make sure the p-value was significant.

This Tweets also point out some other flaws:

Let’s just say that it looks like there were some…shenanigans…going on with the clinical trial protocol, with design changes and some

Basically, the best you can say about this study is that it is somewhat promising, but so badly flawed that no firm conclusion can be drawn. Rigorous double-blind, randomized, placebo-controlled trials are desperately needed.

Based on this background, Usdin is correct to observe:

FDA’s decision to grant Emergency Use Authorization for hydroxychloroquine and chloroquine to treat COVID-19 was unnecessary and unwise.

The EUA was unnecessary because the drugs are approved in the U.S. to treat malaria and for other uses. Physicians who believe the evidence for safety and efficacy outweighs the risks can prescribe either drug for COVID-19 on an off-label basis.

FDA can – and has – approved clinical trials of the drugs to treat COVID-19.

The main practical effect is that the EUA provides liability protection to physicians who prescribe and hospitals that administer the drugs. More importantly, it will be interpreted as a statement by FDA that the drugs should be used to treat COVID-19.

FDA’s action creates two sets of problems: the potential for harm to patients who will receive one of the two drugs; and damage to trust in the drug approval process that could harm future patients.

The most important sentence above is this one: “More importantly, it will be interpreted as a statement by FDA that the drugs should be used to treat COVID-19.” That is exactly the way the average person and many physicians are interpreting it, and why shouldn’t they? FDA approval has required evidence of efficacy and safety since the Kefauver-Harris Amendment was passed in 1962 in the wake of the thalidomide debacle. We’ve had nearly 60 years in which FDA-approval has meant that rigorous science show safety and efficacy.

Here’s what I fear as a result of all the hype over these drugs and the FDA’s premature EUA. We will now never know for sure if these drugs have activity against COVID-19. Why? This EUA will make it extremely difficult, if not impossible, for researchers to complete the randomized, double-blind, placebo-controlled trials needed because no patients will want to agree to risk being randomized to the placebo control group. Why should they? The FDA declared that hydroxychloroquine and chloroquine are safe and effective! (I know that’s not what the EUA means, but it is how the average layperson will interpret it.) We might never know which patients will most benefit from these drugs (if they work), what the optimal doses are (if they work), or how long treatment should continue (if they work.) Worse, we will be subjecting millions of patients to a known risk of cardiac events from these drugs. The risk is small as a percentage, but the law of large numbers means that if millions of people start taking these drugs there will be many such complications. It’s the same law of big numbers that says that, even if COVID-19 has a case fatality rate of “only” 1%, if 100 million people get it, a million will die.

Usdin further notes:

Prior to issuance of the EUA he exuberantly expressed confidence that they will be “game changers” that will rapidly make the crisis disappear. He asserted that FDA had already “approved” their use for COVID-19 for over a week before the EUA was issued.

Trump has also publicly boasted that he pushed FDA to speed up its review of an EUA for a respirator mask decontamination process and indicated that he is directly communicating orders to FDA Commissioner Stephen Hahn.

At a White House press conference Monday, Trump said “I call up Steve, and Steve says we’ll get it done.” It is difficult to imagine a sentence that more succinctly indicates that FDA’s science-based processes are being subverted.

Exactly. The EUA for chloroquine and hydroxychloroquine resulted from political, not medical science. How did this come about?

The right wing promotion of hydroxychloroquine and chloroquine: Selection bias, confirmation bias, anecdotes and “miracle cure” grift

So how did this start? In China, a group observed that patients with lupus taking one of the chloroquine drugs didn’t get COVID-19. At least that’s their rationale for starting to look at the drugs. Of course, I had to wonder: Wouldn’t those patients be exactly the patients who, being immunosuppressed and chronically ill, would be most fervent about staying home, sheltering in place, and self-quarantining? One also can’t help but wonder if there is a bit of confirmation bias going along with the selection bias. Be that as it may, that reported observation in January in Wuhan was what started all this. There have been several randomized clinical trials registered in China, and the Chinese simply announced at a press conference that they were promising, but we have no published data yet other than what I discussed above. From that, though, the Chinese made a firm recommendation to use chloroquine or hydroxychloroquine, and other countries, trusting the Chinese, started following suit. When the pandemic started to get bad in the US, things got weird.

In the US, what’s really driving the narrative about these drugs are “miracle cure claims,” like this one Tweeted out by President Trump a week ago:

The story is about a man named Rio Giardinieri, a 52-year-old who developed severe COVID-19 disease. He’s been showing up all over the media telling this story of how a single dose of chloroquine saved his life:

After more than a week, doctors told him there was nothing more they could do and, on Friday evening, Giardinieri said goodbye to his wife and three children.

“I was at the point where I was barely able to speak and breathing was very challenging,” Giardinieri said. “I really thought my end was there.”

Then a friend sent him a recent article about hydroxychloroquine, a prescription drug that’s been used to treat malaria for decades and auto-immune diseases like lupus.

If you’ve read testimonials for alternative medicines for cancer or even testimonials for Stanislaw Burzynski, you know what’s coming next. Giardinieri’s testimonial is essentially the same thing:

Giardinieri said he contacted an infectious disease doctor about the drug.

“He gave me all the reasons why I would probably not want to try itbecause there are no trials, there’s no testing, it was not something that was approved,” said Giardinieri.

“And I said, ‘Look, I don’t know if I’m going to make it until the morning,’ because at that point I really thought I was coming to the end because I couldn’t breathe anymore,” Giardinieri continued.

“He agreed and authorized the use of it and 30 minutes later the nurse gave it to me.”

After about an hour after taking the pills, Giardinieri said, it felt like his heart was beating out of his chest and, about two hours later, he had another episode where he couldn’t breathe.

He says he was given Benadryl and some other drugs and that when he woke up around 4:45 a.m., it was “like nothing ever happened.”

He’s since had no fever or pain and can breathe again. Giardinieri said doctors believe the episodes he experienced were not a reaction to the medicine but his body fighting off the virus.

Sounds pretty dramatic, doesn’t it? In actuality, reading this testimonial made me think more than ever that it wasn’t the chloroquine that was responsible for Giardinieri’s remarkable recovery. He had only gotten one dose. Antivirals don’t usually work that fast. This is almost certainly a case of confusing correlation with causation. One also wonders if that “pounding heart” was a cardiac arrhythmia brought on by the drug. There’s no way of knowing for sure, though. In any event, no one’s listening to the caveats and the reasons to doubt these anecdotal stories. They’re only hearing this:

“To me, there was no doubt in mind that I wouldn’t make it until morning,” said Giardinieri. “So to me, the drug saved my life.”

This is the message people are getting. Meanwhile, here in Michigan, in response to the letter warning against hoarding and inappropriate subscribing of chloroquine and hydroxychloroquine, a man named Jim Santilli wrote a Facebook post (now removed but republished here) complaining and describing his own “miracle cure” with hydroxychloroquine and azithromycin. Of note is this passage. Note how similar to Giardinieri’s story Santilli’s story is:

On March 18th, I had a sudden onset of severe respiratory and cardiac issues. I immediately went to the hospital and they did a COVID-19 test. While waiting for the test results in the hospital, my breathing continued to worsen as treatment was received. On the morning of March 21st, I was not doing well and it was a major struggle to breathe. Feeling like I was slowly drowning, I honestly believed I would not live to see midnight. The x-ray that morning also showed my condition was worsening, including some collapsing in the lungs. Luckily, the infectious disease physicians decided to try a non-approved, experimental combination (Hydroxychloroquine and Azithromycin). After my first dose, I had a major improvement. My gasping for air stopped, and I was in tears of happiness due to having hope restored. I finally felt I would beat COVID-19 and it was no longer beating me. On March 22nd, I remained about the same. However, March 23rd brought a significant improvement. I continued to recover and was miraculously able to go home on March 24th to continue the treatment.

These are the narratives being promoted in the press and on social media. Indeed, Santilli’s story is showing up on the local Fox News broadcast, with a slanted report that makes it sound that the drug combination is definitely what saved him. Were hydroxychloroquine and azithromycin responsible for these handful of “miracle recoveries”? We really have no way of knowing without a randomized clinical trial. One thing is for certain. As is the case for alternative cancer cure testimonials, nothing will convince these patients that the “miracle drug” probably wasn’t what resulted in their improvement, and their stories sound convincing to the medically untrained. Worse, I predict that, even if the clinical trials are clearly negative, these sorts of stories will drive conspiracy theories that “they” (e.g., big pharma) covered up the evidence that these drugs work. Maybe the worst possibility of all is that we will never know for sure if these drugs work because the premature hype precludes completing a decent randomized clinical trial of sufficient power to answer the question definitively because no one will agree to be randomized to placebo. That is a distinct possibility, especially now that the FDA has caved to pressure and approved the use of these drugs against COVID-19 despite the extreme paucity of clinical effectiveness.

Enter the grifters and snake oil salesmen

Unsurprisingly, America’s Quack, Dr. Mehmet Oz, has jumped on the chloroquine bandwagon (because of course he has—it’s the sort of thing he does). Here is Mr. Giardinieri being interviewed by Dr. Oz on a segment on The Sean Hannity Show:

Note that Dr. Oz’s take on Raoult’s study is completely credulous, and he says that he interviewed Raoult, because of course he has. He also reported that Raoult now asserts that it’s unethical to withhold hydroxychloroquine and azithromycin from COVID-19 patients, which just goes to show that he has no clue about the concept of clinical equipoise. Even worse, he’s parroting anecdotes while referring to them as “studies.” (None of them, other than Raoult’s studies and the negative Chinese study of chloroquine are published yet.) In fact, it’s profoundly unethical of Dr. Oz to promote this as yet unproven treatment. Looking over Dr. Oz’s website, it exploded yet another of my irony meters to see that his show tomorrow will be “The COVID-19 Pandemic: Beware of Scammers Trying to Take Advantage of Your Fear of the Virus.”

Just look at Dr. Oz’s interview with Prof. Didier Raoult if you don’t believe me. Unsurprisingly, when Dr. Oz asks Prof. Raoult if there were any differences in clinical outcomes in the patients treated with his combination, he dodged the question.

It’s even worse, though. It’s not just hucksters like Dr. Oz and irresponsible doctors like Dr. Zelenko. Now, a shadowy conservative business group founded by a big time political donor to the Republican Party is entering the fray:

A conservative business group founded by a prolific Republican political donor is pressuring the White House to greenlight an unproven COVID-19 treatment, saying in an online petition that the country has plants in the U.S. ready to produce a drug but can’t because of “red tape, regulation, and a dysfunctional healthcare supply chain.”

In recent days, Home Depot co-founder Bernard Marcus’ Job Creators Network has placed Facebook ads and texted supporters to sign a petition urging President Donald Trump to “CUT RED TAPE” and make an anti-malarial drug called hydroxychloroquine available for treating those sickened with the virus, one such message obtained by ProPublica reads.

I’ve been predicting that the same people who foisted the deceptive “right-to-try” law on us in order to weaken the FDA will take full advantage of the COVID-19 pandemic to further weaken the FDA in the name of “speeding up cures” and “cutting red tape.” This brings us to the political pressure, in particular the additional right wing narrative from partisans such as Rush Limbaugh that we are “destroying the economy in the guise of saving lives.”

An emerging narrative about chloroquine, hydroxychloroquine, and azithromycin

Late last week Michigan’s Department of Licensing and Regulatory Affairs issued a warning letter about physicians prescribing hydroxychloroquine and chloroquine to family members with the intent to stockpile, thus creating shortages. The letter, signed by Deb Gagliardi, Director of the Bureau of Professional Licensing, and Forrest Pasanski, Director of the Enforcement Division, warned against prescribing chloroquine or hydroxychloroquine with the intent to stockpile or without better evidence that it works against COVID-19. The letter further reminded pharmacists that they should not fill prescriptions if the pharmacist “believes the prescription will be used for other than legitimate medical purposes or if the prescription could cause harm to a patient” and reminded health care workers that they are “required to report inappropriate prescribing practices.” It was, of course, a reasonable thing to do in order to try to stop some very unethical prescribing that was causing shortages and making it difficult or impossible for lupus patients, for example, to obtain their chloroquine. A followup letter on Friday cited a joint statement by the Michigan State Medical Society and the Michigan Pharmacists Association and a second joint statement by American Medical Association, American Pharmacists Association, and American Society of Health-System Pharmacists.

Unsurprisingly, the conspiracy fever swamps on social media and even on traditional media an emerging narrative was being promoted late last week. It came in the form of articles like this one by a local Pacific Legal Foundation member named Kathy Hoekstra, “Michigan’s doctors fight coronavirus, and governor’s office“. Also unsurprisingly, to Hoekstra, who cited Raoult’s horrible azithromycin/hydroxychloroquine study as evidence that these drugs provide great hope, this action was an unconscionable affront to physician autonomy in prescribing off-label medications and saying that ” if you live in Michigan, and you or a loved one is infected with this potentially lethal disease, you’re out of luck.” She also noted that Henry Ford Hospital and the University of Michigan have protocols that include these drugs, further noting:

With his state now the nation’s pandemic epicenter, and with the blessing and help of the president and FDA, New York Gov. Andrew Cuomo brought in 70,000 doses of hydroxychloroquine, 10,000 doses of Zithromax and 750,000 doses of chloroquine.

The implications of Whitmer and her administration’s knee-jerk scare tactics should terrify all Michigan residents. Not only is our state’s top leader threatening the selfless health care workers who are on the frontline trying to save lives, but she’s denying possible life-saving medications to actual COVID-19 victims.

It was a profoundly dishonest article, given that there really is as yet no good evidence that these drugs impact the course of COVID-19 and, worse, they are not benign drugs. the chloroquine drugs can cause dangerous cardiac arrhythmias. It’s an uncommon side effect, but common enough that most protocols using these drugs against COVID-19 require the patient to be on a cardiac monitor. Moreover, the therapeutic window (the difference between the lowest therapeutic dose and a toxic dose) of the chloroquine derivatives is narrow. In any event, you get the idea. It’s a conspiracy theory fueled by those promoting the drugs as miracle cures for COVID-19 that states that there is a cure for COVID-19 that “they” don’t want you to know about. In that, it’s now different than a lot of cancer cure conspiracy theories. It’s a conspiracy theory that has a political purpose, though.

A straight line from “right-to-try” to COVID-19 miracle cures

I expended a lot of verbiage trying to explain why “right-to-try,” the law that purports to give terminally ill patients a “right to try” experimental medications for their disease, as long as the medication had passed phase I trials. Obviously, those of us who saw right-to-try for what it was, a first step by libertarian-leaning pro-business ideologues who think the FDA kills more people than it saves through its “innovation-suffocating” requirements to weaken the FDA and lower the bar for drug approval (on the way to eliminating the FDA altogether), lost that battle, and right-to-try became the law of the land. (I have yet to find a single convincing case in which the law helped a terminally ill patient.) These are the people who think that the “free market” will take care of making sure that drugs are safe and effective.

It’s long been a strategy of the libertarian, anti-regulation right to use strategies like these to progressively weaken the FDA. They love to latch on to a crisis to push their agenda. They did it, for instance, during the Ebola outbreaks of 2014, with Nick Gillespie and Ronald Bailey arguing over at Reason.com that FDA regulations kill more people than they save and that Ebola should be a good reason to loosen up those pesky FDA requirements because don’t you realize that we don’t have time and people are dying.

I’ve been predicting for weeks now on Twitter that the COVID-19 pandemic would be used as a pretext for the next step in loosening drug approval standards under the guise of “speeding cures to the people” and “loosening red tape.” Hydroxychloroquine and chloroquine were merely the first salvo in that effort, and they were perfect tools to employ in this effort. They’re already FDA-approved for malaria and some autoimmune diseases; it’s trivial for doctors to prescribe them off-label for COVID-19. Get the public to believe that they work, and pressure will build on doctors to use the drugs and the FDA not to interfere. Relentlessly promoting “miracle cure” stories plus the crappy French studies did just that, aided and abetted by right wing think tanks pushing a narrative that the “government” (often states run by Democrats) are “standing in the way of cures” and “letting people die” if they try to intervene to cut down on the hoarding and off-label prescribing off of protocol of hydroxychloroquine and chloroquine.

Sadly, this messaging revealed that many American doctors are quite credulous and not very devoted to evidence-based medicine, not in a pinch. (There are ways to study these drugs quickly in a pandemic.) They started prescribing the drugs willy-nilly. Some of them even started hoarding. President Trump then rode to the rescue by persuading drug companies to make more available. Meanwhile, political pressure was building on the FDA to approve the drugs for COVID-19, which the FDA duly did. It’s no surprise that they did, either. FDA leadership had already been stocked with ideologues who also believed drug approval should be faster and less rigorous. As I mentioned above, as a result, I now fear we will never really know for sure if chloroquine and hydroxychloroquine have clinically meaningful activity against COVID-19 because the RCTs will likely never be completed.

So what’s the next step? Simple. A precedent set, the FDA will now come under increasing pressure to issue EUAs for more and more drugs. It’s already happening in the case of Avigan, a decades-old Japanese influenza drug, pushing the US to accept a donation of Avigan from Japan and issue an immediate EUA, despite this history:

Health officials have repeatedly rejected Avigan in the United States, despite years of advocacy from Japan and Fujifilm. South Korea officials this month also declined to use the drug in that nation’s coronavirus response, warning of insufficient evidence and the risk of “serious side effects.”

This pressure will soon go beyond the off-label use of existing drugs approved for other indications, be it by the FDA or by other countries. “Right-to-try” will be invoked to justify the use of experimental drugs, followed by pressure on the FDA to issue EUAs for them for COVID-19. This will continue, the plan being to pressure the FDA to “super fast track” drugs that aren’t currently approved and approve them for COVID-19 with inadequate testing, as anyone who’s been paying attention could have predicted.

As Usdin writes:

“Anecdotal clinical data in case series” sounds more like a phrase an FDA reviewer would use to denigrate a drug application than a standard for approving one. As the industry commentator Derek Lowe pointed out in his blog, the case series that got Trump excited about chloroquine and hydroxychloroquine doesn’t generate a great deal of confidence.

Trump was right when he said “maybe it’ll work, maybe it won’t – we’ll have to see.”

Also:

The low threshold used to approve the EUA raises questions that FDA will have to face very soon, among them:
  • How will FDA respond when companies request EUAs for compounds that have slightly more convincing data than has been presented for chloroquine or hydroxychloroquine? Will these also get authorized with no controlled clinical trials?
  • Will chloroquine or hydroxychloroquine be considered standard of care for trials of other potential COVID-19 therapies, and if so, how will that affect those trials? For example, will the presence of chloroquine confound trials, or will its availability deter patients from enrolling in trials?
  • If chloroquine or hydroxychloroquine are shown to be ineffective, will this prompt physicians to stop treating an FDA approval as the “gold standard” indicating a drug is safe and effective for its intended use? If so, what will guide their decisions?
  • What role has President Trump’s enthusiasm for the drugs played in the EUA decision? Will endorsement from a president, or perhaps some other VIP, influence future regulatory decisions?
Beyond the policy implications, the EUA raises concerns for patients.

Trump has stated that we know chloroquine and hydroxychloroquine are safe because they have been used for decades.

In fact, we know they are not safe because they have been used for decades.

He was wrong to think that’s a good enough reason to authorize drugs.

That’s why I’m profoundly disappointed in my fellow physicians. From communicating with colleagues, I’ve discovered two things. It’s become in essence standard-of-care at a number of hospitals (perhaps the majority) to administer chloroquine or hydroxychloroquine to moderate to severely ill COVID-19 patients, with some even starting it in the emergency department. I’m also learning that many of them are…underwhelmed by its efficacy:

When this pandemic is over, we will pay for these decisions for a long time. Contrary to the claims of ideologues, the “free market” can’t protect us from dangerous drugs or assure that the drugs sold in our country are safe and effective. If it could, we wouldn’t need the FDA. If it could, we wouldn’t have needed the Kefauver-Harris Amendment. Now that the FDA’s drug approval decisions have become highly politicized, we’re going to have a huge problem to deal with when this pandemic finally abates.

By Orac

Orac is the nom de blog of a humble surgeon/scientist who has an ego just big enough to delude himself that someone, somewhere might actually give a rodent's posterior about his copious verbal meanderings, but just barely small enough to admit to himself that few probably will. That surgeon is otherwise known as David Gorski.

That this particular surgeon has chosen his nom de blog based on a rather cranky and arrogant computer shaped like a clear box of blinking lights that he originally encountered when he became a fan of a 35 year old British SF television show whose special effects were renowned for their BBC/Doctor Who-style low budget look, but whose stories nonetheless resulted in some of the best, most innovative science fiction ever televised, should tell you nearly all that you need to know about Orac. (That, and the length of the preceding sentence.)

DISCLAIMER:: The various written meanderings here are the opinions of Orac and Orac alone, written on his own time. They should never be construed as representing the opinions of any other person or entity, especially Orac's cancer center, department of surgery, medical school, or university. Also note that Orac is nonpartisan; he is more than willing to criticize the statements of anyone, regardless of of political leanings, if that anyone advocates pseudoscience or quackery. Finally, medical commentary is not to be construed in any way as medical advice.

To contact Orac: [email protected]

76 replies on “The FDA’s emergency use authorization of chloroquine and hydroxychloroquine for COVID-19: Dangerous politics, not science”

Having read other reports from people who had COVID-19, it’s worth noting that struggling to breath, coming close to needing a ventilator, and then taking a turn for the better, is not uncommon with no drug intervetion involved.

I dont understand Orac, why a rigorous double blind RCT is needed. Dont vaccines lack them either? In fact dont provaxers argue that it is immoral not to make vaccines mandatory? Thus making it impossible to do rigorous RCTs involving vaccines?

Also id guess we will be fasttracking Covid vaccines in the same way, but actually making them mandatory instead of voluntary. Whats your opinion on that as a provaxxer?

@ Q-ball

Not only are vaccines required for FDA approval to include placebo-controlled randomized clinical trials and much much larger groups than other drugs; the the post-marketing surveillance of vaccines is better than any other post-marketing surveillance of drugs and medical devices. Besides the Vaccine Adverse Events Reporting system (which has teams monitoring for even a very few serious events); but the “real-time” Vaccine Safety Data Link which is connected to the medical records of over 2 million HMO patients, including complete info on vaccine, lot number, date, comorbidities, age, gender, and any medical visits following. And the WHO maintain post-marketing surveillance, and also links to similar programs in several other nations. And if any data show serious adverse events, law allows immediate suspension of sales of vaccines, pending further study. On the other hand, when other drugs, medical devices, or even foods have reported a number of serious events, only a voluntary recalled can be requested. Sometimes taking years to get off market.

In other words, despite what some people believe, vaccines are the safest product on the market by far. Think about it, everyone I know at CDC, FDA, etc. who promotes vaccines has also gotten them and made sure them kids got them.

Because a rigorous study tells you if something actually works. Unlike “Well it works here so it should work there” or “My Aunt Hilda used grass soaked in dog piss and it cleared up her cancer in less than a day”. Which is about the level of science anti-vaxxers work at.

It may take longer but it’s better than feeding people a drug that does more harm than good.

There was also the case of a couple who, having heard Trump tout chloroquine as a cure for COVID-19, took some from the supply of tablets they had on hand to keep their koi pond clean–apparently chloroquine kills algae. It goes without saying that the standards for manufacturing aquarium cleaner tablets are not as strict as the standards for manufacturing pharmaceuticals. Result: the man died, his wife required emergency room treatment. I expect that there will be other cases where people who cannot get pharmaceutical chloroquine due to shortages will try to get it by other means.

I had also heard about Dr. Raoult having been involved in fraud previously, something confirmed at the For Better Science link in the post.

I was hoping you’d address this after reading this first thing this morning:

https://www.nytimes.com/2020/04/01/health/hydroxychloroquine-coronavirus-malaria.html?action=click&module=Top%20Stories&pgtype=Homepage

Some skepticism, but not enough–no mention of the subjectivity of patient-reported “improvement” for example. There was also this:

“It’s going to send a ripple of excitement out through the treating community,” said Dr. William Schaffner, an infectious disease expert at Vanderbilt University.”

Orac needs to take Dr Schaffner to task!

I am again so very grateful for the education you and your minions have given me. Unfortunately, I now suffer from chronic cringe-itis as a result of reading the comments sections that follow these sorts of articles in the NYT. I am further horrified that I once went to one of my docs waving one of their “health” articles and was (typically) offended by his lack of enthusiasm and eyerolling. At least I get it now.

There was also this:

https://www.nytimes.com/2020/04/01/health/coronavirus-cytokine-storm-immune-system.html?action=click&module=Top%20Stories&pgtype=Homepage

Which contained this paragraph:

“Other drugs might also be useful against cytokine storms. For example, a drug called anakinra mutes interleukin-1, another of the wayward proteins. Clinical trials of anakinra for Covid-19 are also underway. A report published this week suggested that hydroxychloroquine, a much-spotlighted malaria drug that also calms an overactive immune response, might also be effective as a treatment for those who are mildly ill from coronavirus.”

I was finding it interesting until that paragraph. Sometimes I wish I had my very own box of blinking lights to feed this stuff to!

I have yet to find a single convincing case in which the law helped a terminally ill patient.

The remdesivir story seems to have taken a number of twists and turns, as well.

Sadly there is always a yearning for miracle cures, its why cranks and quacks get so rich, though I doubt actual Dr’s are immune from such thinking at times like these. Also there is a lot pressure around these drugs being brought to bear.

Chloroquine and Cytokine Storms. Chloroquine and hydroxychloroquine are used with lupus erythematous and rheumatoid arthritis. These are autoimmune diseases where ones own immune system attacks certain cells and/or DNA. However, though this attack involves an increase in certain immune cells, it isn’t even close to a cytokine storm. A poor analogy would be to compare a 20 mph wind to a Category 5 hurricane, 160 mph wind or higher. So, chances are that chloroquine or hydroxychloroquine might dampen the Category 5 to a Category 4, still an acute respiratory distress situation. On the other hand, chloroquine and hydroxychloroquine have a number of minor side-effects and some really serious ones. Given that the vast majority of those dying from COVID-19 are older with comorbidities, often more than one, add in the COVID-19 attack on the body and the risk for serious adverse reactions may well increase substantially. In other words, maybe even increase case fatality rate.

Currently, there are several studies going on. If they find that chloroquine and hydroxychloroquine do reduce case fatalities, I would be overjoyed. While what I wrote above is based on years of training, I have NO problem being wrong if it means saving lives, e.g., being wrong for the right reasons. But until those studies are completed, the risk remains. In addition, if used for COVID-19 we may end up with shortage for those with autoimmune diseases who do benefit from them.

Chloroquine and Cytokine Storms. Chloroquine and hydroxychloroquine are used with lupus erythematous and rheumatoid arthritis. These are autoimmune diseases where ones own immune system attacks certain cells and/or DNA. However, though this attack involves an increase in certain immune cells, it isn’t even close to a cytokine storm. A poor analogy would be to compare a 20 mph wind to a Category 5 hurricane, 160 mph wind or higher. So, chances are that chloroquine or hydroxychloroquine might dampen the Category 5 to a Category 4, still an acute respiratory distress situation. On the other hand, chloroquine and hydroxychloroquine have a number of minor side-effects and some really serious ones. Given that the vast majority of those dying from COVID-19 are older with comorbidities, often more than one, add in the COVID-19 attack on the body and the risk for serious adverse reactions may well increase substantially. In other words, maybe even increase case fatality rate.

Currently, there are several studies going on. If they find that chloroquine and hydroxychloroquine do reduce case fatalities, I would be overjoyed. While what I wrote above is based on years of training, I have NO problem being wrong if it means saving lives, e.g., being wrong for the right reasons. But until those studies are completed, the risk remains. In addition, if used for COVID-19 we may end up with shortage for those with autoimmune diseases who do benefit from them.

Modified for signal-to-noise ratio.

@ Narad

You really are FULL OF SHIT!!!

I guess in your perverted mind that anyone who actually explains clearly some topic is more than you can handle.

You really are FULL OF SHIT!!!

You should really work on expanding your repertoire of scatological responses when presented with something other than fulsome praise.

I found that technical discussion informative and relevant.

And really, of all the places on the internet to complain that peoples’ comments are too long, maybe this isn’t the place?

“A report published this week suggested that hydroxychloroquine, a much-spotlighted malaria drug that also calms an overactive immune response, might also be effective as a treatment for those who are mildly ill from coronavirus.”

Say, NYT, for patients only “mildly ill” from COVID-19, is it really a good idea to be treated with an unproven drug with potentially serious side effects? Wouldn’t supportive care alone be a better idea, especially for patients lacking major disease risk factors?

I’d expect that sort of thing from the Wall St. Journal (which has a gushing editorial on how great the FDA’s EUA announcement is).

@ Narad

Respectful Insolence is sister website to Science-Based Medicine. On both websites, the vast majority of those who post comments do so to enter into a civilized dialogue. We learn from each other. However, for the most part, you seem to post comments, not to dialogue, but just to irritate, get a rise out of people. So, yep, YOU ARE FULL OF SHIT, an accurate description given many of your comments add absolutely NOTHING to the dialogue.

Respectful Insolence is sister website to Science-Based Medicine.

No, it is not, unless you have a novel definition of “sister.”

So, yep, YOU ARE FULL OF SHIT, an accurate description given many of your comments add absolutely NOTHING to the dialogue.

Mirrors are your friends. Repetitive self-aggrandizement, limited vocabulary, and full caps are not. I have certainly been around here for much longer than you have, so spare me future control-freakish lectures. Spell-checking your long-winded comments would also be a mercy to all concerned.

From our clinic pharmacist: “We used to buy hydroxychloroquine for about one cent per pill. Now, there are only 3 sources, with only small amounts available, with the cost $6.36 per pill.” Yeah, you read that right. A 638-fold markup. Capitalism in action! But what do I tell my lupus patients?

@ Bob Curtis

I am really really sorry. I’ve had friends with lupus, unfortunately who passed away. Recently, the DA in my hometown indicted four individuals who bought lots of toilet paper, etc., then offered it online for exorbitant prices. Yep, we indict a few individuals; but not companies/corporations who triple the price of insulin, though it cost no more to manufacture, charge outrageous amounts for masks, testing kits, and as you mentioned, a 638-fold markup on hydroxychloroquine. As far as I’m concerned, the present policy on chloroquine is to make it seem our government is doing something. I doubt researchers at FDA were in on this; but FDA commissioner is a political appointee. And FDA committees include “outsiders.”

Even if it turns out that hydroxychoroquine works, our government should both crack down on price-gouging and ensure that an adequate supply is available for those with autoimmune diseases. I won’t hold my breath.

I agree with you that this decision is highly, highly problematic. It doesn’t even meet the criteria. But I will point out that EUA are emergency authorization, temporary use, and not a substitute to the FDA process, it’s not instead of the need for IND or testing after (though this is a little strange because these are authorized, just not here). That’s not to downplay your concerns, just to sound a caution about the relationship between EUA and testing. Here is a good thread from a professor about the law.

https://twitter.com/hollylynchez/status/1238536549576445958?s=11

@ doritmi

However, our government should NOT allow price-gouging, exploiting our current situation, and ensure an adequate supply is available for those with autoimmune diseases.

According to Isaac Stanley-Becker ( WaPo) because there have been many threats to ( and unwanted admiration for) Dr Fauci security/ agents have been assigned to him. Right wing sites like Gateway Pundit have incited conspiracies about his relation to Hillary Clinton, a prime target of the Right.

Although it is not mentioned, I wonder how much of the venom comes from anti-vaxxers? I’ve seen a great deal of it from the ones I survey such as Kim Rossi, Ginger Taylor and Katie Wright and woo believers because of his support for vaccines. His current visibility and the praise he receives must surely irk them to no end.

Peter Hotez has been on TV a lot, with interviews on CNN or MSNBC. Now that these are all Zoomed in from home, most interviewees are setting up their webcams so their book-cases serves as background. On Hotez’ “set”, the front cover of his book, Vaccines Did Not Cause Rachel’s Autism is clearly visible over his left shoulder. Nice!

I’m always glad to see him on television. Last night, Dr Robert Gallo appeared on MSNBC discussing how much the virus mutates and some possible good news from a virologist ( rather than quote him, it’s easy to find a video ).

Interestingly, I usually hear about these doctors ( and Dr Fauci) from woo-meisters/ anti-vaxers who heap invectives upon them . Perhaps the general public may now understand the value of their contributions.

Its shocking he’s getting death threats simply for telling the truth, or in the minds of some ‘contradicting the dear leader’

Though this is just the latest iteration of the attack on science by the Trump regime and those of the far right and the consequences of it.

We just see this here in Canada, the likes of Dr Bonnie Henry in BC and Dr. Theresa Tam at the federal level are considered rock stars by many here.

It’s an immunosuppressive. Hydroxychloroquine has multiple modes of action, one of which is to affect lysosomal pH. The knock on effect is to reduce TLR signaling and antigen presentation. Widespread inappropriate use is likely to reduce CD4 T responses to SARS-CoV-2, which will adversely affect antibody responses and potentially reduce herd immunity. I understand why compassionate use is an option, given the seriousness of the infection, but can we just wait on clinical trials before it’s used as a cure all.

Ooh, which TLR? (Sorry, I know it’s a tangent, but I used to work with TLR knockout mice and I still have a fondness for TLRs.)

It’s an immunosuppressive.

Cursory research says no; rather, it’s immunomodulatory, although often used with genuine immunosuppressives in, e.g., the management of RA. (I have mediocarpal arthritis, for which it doesn’t seem to be indicated. I think I’d prefer it to the surgery that is. About four years to go for me, even with daily exercises to strengthen the muscles that stabilize the joint.)

Its also called a disease-modifying anti-rheumatic drug (DMARD), an anti-malarial, anti-inflammatory, etc, etc. and you can call it immunomodulatory if you wish. But speaking as an immunologist, immunomodulatory, is a vague and uninformative word because it simply means modulates the immune system, which a huge host of agents do in many, many different ways. So there is a need to be specific. As I noted above, hydroxychloroquine (Plaquenil®) does have several modes of action, and one of those modes of action is to suppress production of inflammatory mediators and antibody responses.

“The HCQ immunomodulatory effects are mediated by its anti-inflammatory, immunosuppressive and photoprotective properties, and interfere with lysosomal degradation.” Ning Liang, et al. Exp Ther Med. 2018 Mar; 15(3): 2436–2442. Immunosuppressive effects of hydroxychloroquine and artemisinin combination therapy via the nuclear factor-κB signaling pathway in lupus nephritis mice.

Dr. Didier Raoult seems like quite the character. I get the impression that he once was a good researcher who is now suffering from early emeritus disease and a bit of narcissism.

Les Crises, A French blog, has some interesting, though not complimentory things to say about his “studies” text.

A follow-up posting is not encouraging Les mensonges de Didier Raoult pour promouvoir la chloroquine et faire oublier le reste. A title that starts with “Didier Raoult’s lies” is not high praise. It looks like Raoult is turning into an evangelist for
chloroquine/hydroxychloroquine a bit like a crusading anti-vaxer.

If I read the last post correctly chloroquine or hydroxychloroquine has been an over-the-counter drug in France and a popular suicide drug.

Les Crises sometimes provides an English translation but I don’t see one at the moment.

@ John Kane

I had a few semesters of French eons ago. Unfortunately, instruction as in German classes, was in English; but did acquire reasonable vocabulary and basic grammar. I own several large French/English dictionaries. So far, made it through first few paragraphs. Beaucoup travail, mais j’ai l’intention d’essayer lire tout l’artikel si je le peut. 😀

Please don’t laugh too hard at my French. My German about the same; however, I am completely fluent in Swedish, a language I have a lot of use for living in San Diego, CA. LOL

@ John Kane

“Dr. Didier Raoult seems like quite the character.”

On another blog I follow, he earned an interesting nickname:

The Druid

And in English, it does sound like someone else… Like an apologist for scientific and philosophical relativism.

(Though in French, the pun isn’t obvious due to pronounciation…)

I was thinking more of something along the lines along Merlin in the TV series Kaamelott.

Glad the movie is supposed to be out anytime soon…

We will now never know for sure if these drugs have activity against COVID-19. Why? This EUA will make it extremely difficult, if not impossible, for researchers to complete the randomized, double-blind, placebo-controlled trials needed because no patients will want to agree to risk being randomized to the placebo control group.

I believe that Australia and China already have RCT trials either in planning or up and running. I doubt that a politically motivated decision by a US agency will badly disrupt them though it may have an effect an Australia because of language. Oh, and the fact that the Australian Prime Minister seems almost as clueless as Trump

Two Australian studies, evidently. The Melbourne trial (HCQ as a prophylactic) is headed by Pelligrini and should be high-quality. The one in Queensland is as dodgy AF, with the investigator saying in advance that HCQ is a miracle cure, and receiving support from a corrupt antivax failed-businessman-turned-politician.

https://www.theguardian.com/world/2020/mar/27/experts-condemn-clive-palmer-funded-ads-claiming-hydroxychloroquine-can-cure-coronavirus

Australian media are dominated by the Murdoch Press, which (like Fox News) is torn between dismissing COVID-19 as a leftie hoax, and promoting HCQ as the surefire cure. So they are all-in with the Queensland trial.
https://www.news.com.au/lifestyle/health/health-problems/coronavirus-australia-queensland-researchers-find-cure-want-drug-trial/news-story/93e7656da0cff4fc4d2c5e51706accb5

Their Minister of Health – a dingbat even by the standards of the current Australian federal govt. – has swallowed the idea that COVID is no big deal because we have a cure. He is determined make it available for everyone, trials are for wimps.
https://9now.nine.com.au/a-current-affair/coronavirus-hydroxychloroquine-supplied-in-australia-to-treat-covid19/dcb776bc-fd9b-429c-ab9c-c2fc229f9089

Oh dear! I thought they were a little better than that, but it seems not. This is the worst news I’ve had all day.

I am no fan of Scott Morison (or the Liberal Party) but, after a dodgy start, including a couple of PR gaffs, he is now following pretty closely, with only a couple of exceptions, the advice of a panel of about 20 medical experts that he expressly set up for that purpose. He is no Donald Trump.

(BTW, John Cain was a highly regarded past Premier in Australia)

I got an email a few weeks ago from the International Society for Cell and Gene Therapy (a major professional organization for stem cell researchers) reminding everyone that the society is against the selling of fake stem cells, and to be on the alert for people pushing fake stem cell treatments for COVID. At the time I thought they were over cautious. Clearly I was wrong.

Also, allogenic NK cells? What could possibly go wrong with that?

If you think that Tony Robbins is bad…

Because I have an excess of free time ** I found videos about COVID-19 on @ High Wire Talk ( Del Bigtree: a new one and last week’s) and on self-empowerment and health on PRN.fm ( Home page especially). Unfortunately, to see Mike Adams’ lunatic videos on NN, you have to sign up ( I refuse to help his numbers in any way)

We all need a laugh these days..

** More seriously, I am trying to replicate Japanese food although sushi is too hard, udon, teriyaki and katsu are not.

@ Terrie:

Thanks . That’s a nice compilation.
One of the benefits of living here is that we can get really authentic ingredients- there is a Japanese mall nearby ( with its own food court), Korean supermarkets and other diverse options. I sometimes buy products which I identify by look alone because I can’t read the labels.

Sushi takes a little finesse, but it isn’t too terribly difficult; one of the most important things is getting the rice right. Maybe I’m just good at finicky stuff like though, in terms of interest and patience and knife skills and so on, hands stuff.

Also, I didn’t use raw fish when I was making it, not that confident; I used strips of lox instead. In the stores around here you can buy prepared raw tuna for poke, that might work, although it would make the cutting a lot more of a pain in the neck.

(I also added stuff like avocado and cucumber.)

I have neither had them nor made them (would definitely eat them if I came across them), but just glancing online, it seems like they wouldn’t be terribly hard to make; they’re basically a big savory pancake with toppings. Sounds like it could be something to do, anyway…

My SO’s cafeteria just had a video up on how to make canned tuna sushi, the kind with the rice on the outside, then the nori, then the canned tuna. I like that kind of sushi, but I was really surprised when SO indicated they’d want some too, given a previously stated hatred of all things canned tuna.

It was quite funny in the video when they open the pouch of tuna and it is easily the size of a copy of Vogue. I guess everything really is bigger in a commercial kitchen.

it seems like they wouldn’t be terribly hard to make; they’re basically a big savory pancake with toppings

Yes indeed, that was part of the appeal. A cheap dinner in the corner restaurant / pub, with the added attraction of a free show while inhaling a beer, in the form of the fry-cook’s legerdemain as he chopped and stirred and folded ingredients on the hotplate behind the bar.
Like so many food styles, Okonomiyaki is quick & cheap street food in its own country and up-market prestige cuisine from a restaurant anywhere else.

Come to think of it, I made my first sushi at a job I had as a teenager at sort of a multi sort of place; small grocery market, also had soups and pastries and whatnot, espresso drinks, also sushi. The older East Asian lady (Japanese maybe?) who taught me to make it was a jovial sort and remarked on how quickly I picked it up. “You catch on quick!”

It was a cool job, lots of different things to do, you didn’t get stuck doing one thing all the time. I stocked shelves sometimes, different stuff, some barista duties, making soup, yadda yadda. I pretty much always had morning shift, though, @ss early in the morning, show up and make the pastries and get everything ready and turn on the open sign and stuff. It was actually nice because I could play my own music on the little stereo thing and just sort of chill (while working.) Also it fit in well with getting a ride to work because my uncle Tim was working on a similar schedule.

Actually there are approved antivirals (against somewhat related RNA viruses) that could work.
Guangdi Li Erik De Clercq
Therapeutic options for the 2019 novel coronavirus (2019-nCoV)
Nature Reviews Drug Discovery 19, 149-150 (2020)
doi: 10.1038/d41573-020-00016
These drugs directly target the virus. An antimalarial drug would work only by accident

Just a question maybe someone round here can answer – asked I can only say from a position of deep ignorance of all these matters.
So this thing about many people having Covid-19 but being asymptomatic – is that a possible thing with say normal flu that we didn’t know about? I mean I’m not aware that there is any particular population sampling going on in flu outbreaks- you feel shit and stay at home, or look shit and we avoid you by and large, but it seems to me we assume that if you’ve got the flu you have the flu symptons (and basically vice versa).Probably the only people who really get tested are confirmations in hospitalisation cases?
How do we know that there aren’t normally lots of people going around with normal flu but showing no symptons?

@ Jools

Yep, people who are asymptomatic can be flu carriers. in fact, some studies estimate as many as 50% of those infected with flu, perhaps more, are asymptomatic carriers. Estimates vary.

Best bet is to get vaccinated. Flu vaccines are not near as effective as other vaccines; but reduce risk of even getting, if get, reduce risk of needing hospitalization or even death. In addition, if vaccinated and still get it asymptomatically, reduce shedding of virus, that is, lowered risk to others. And flu vaccines are about as safe as you can get, even for pregnant women. Studies have even found reduce risk of flu to newborns when mother vaccinated while pregnant.

Thanks. I do get vaccinated – no axes being ground here!
It was purely for information, I was trying to establish in my own mind to what extent the asymptomatic carry thing is a feature of COIVD-19 relative to other common viruses

Though now I look at your answer again I feel my uncertainty hasn’t decreased too much (sorry!).
So ‘people can be asymptomatic flu carriers’ doesn’t take us too far – I assume there are always extremes of the curve given sufficiently large numbers. The ‘how many’ and ‘how do we know that’ bit of the answer seems to suggest that actually we don’t really know (‘estimate’ and ‘up to 50%’). So no-one has really gone out of their way during a flu epidemic to try to get a decent population sample and get a good handle on that?

@ Jools

You write: “So no-one has really gone out of their way during a flu epidemic to try to get a decent population sample and get a good handle on that?”

Not true. There have been many studies that, using different methods, have been conducted to estimate symptomatic vs asymptomatic. First, almost all studies of diseases find ranges, no one exact number. Second, the bottom line is that asymptomatic cases exist, not rare, which answered your question.

Check out one paper, for instance: Luis Furuya-Kanamori, Mitchell Cox, Gabriel J. Milinovich, Ricardo J. Soares Magalhaes, Ian M. Mackay, Laith Yakob (2016 Jun). Heterogeneous and Dynamic Prevalence of Asymptomatic Influenza Virus Infections. Emerging Infectious Diseases; 22(6): 1052 – 1056. Available at:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4880086/pdf/15-1080.pdf

There’s no going back now; two core elements of right-wing ideology are now involved. “I ignored the experts and I was right” has long been a cherished dream of the anti-intellectual far right, and now there’s a chance to pair it with “And Trump personally stepped in and singlehandedly saved the country.” No way he’s letting that opportunity go by; he needs it to be true, so it will be treated as true, regardless of what the evidence shows.

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