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.
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.”
The low threshold used to approve the EUA raises questions that FDA will have to face very soon, among them:
Beyond the policy implications, the EUA raises concerns for patients.
- 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?
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.