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I have been discussing the premature—and, from my perspective, bizarre—fixation with using the antimalarial drugs chloroquine and hydroxychloroquine to treat COVID-19 and the abandonment of critical thinking and science-based medicine ever since a French “brave maverick doctor” named Didier Raoult first published a truly execrable and possibly fraudulent study last month claiming that the combination of hydroxychloroquine plus azithromycin could eliminate SARS-CoV-2, the coronavirus that causes COVID-19. Since then, Raoult published a second study, an uncontrolled case series made up primarily of patients with very mild or even asymptomatic COVID-19 and an update on the case series that suffered from all the same flaws that made the first case series singularly uninformative. Meanwhile, as I discussed a couple of weeks ago, studies from any source other than Raoult’s group were piling up and strongly suggesting that neither hydroxychloroquine nor the hydroxychloroquine + azithromycin combination demonstrate detectable activity against COVID-19 but do cause toxicity. As I’ve pointed out before, the entire saga shows that, when push comes to shove and a crisis hits, physicians’ dedication to science- and evidence-based medicine is disturbingly weak. (If you don’t believe me, look at the comments after this video, which consist mostly of doctors questioning why the doctor in the video was not enthusiastic about using the drug and touting their anecdotal experience to argue that the drug works.) So it came as no surprise (to me, at least) when the FDA issued a warning on Friday about chloroquine and hydroxychloroquine:

The Food and Drug Administration warned consumers Friday against taking malaria drugs chloroquine and hydroxychloroquine to treat Covid-19 outside a hospital or formal clinical trial setting after deaths and poisonings were reported. The agency said patients taking the drugs for approved reasons, including malaria or to treat autoimmune conditions like lupus, should continue taking their medicine as prescribed. The agency also said it became aware of reports of “serious heart rhythm problems” in patients with the virus who were treated with the malaria drugs, often in combination with antibiotic azithromycin, commonly known as a Z-Pak. It also warned physicians against prescribing the drugs to treat the coronavirus outside of a hospital.

The full text of the FDA warning can be found here. Given this warning, I thought that an update on the hydroxychloroquine story was in order, as a lot of things have happened just in the last two weeks that demonstrate that, even in a pandemic, it’s almost never a good idea to bypass science- and evidence-based medicine. Certainly, in the case of hydroxychloroquine, it wasn’t.

First, though, it’s been said that the FDA’s issuance of an emergency use authorization (EUA) for these drugs to treat COVID-19 was one of the most irresponsible things the FDA has ever done, far more based on politics than science, and the FDA’s having to issue this warning demonstrates one reason why. The public and, sadly, many doctors don’t know the difference between an EUA and FDA approval, tending to view them as basically equivalent. The restrictions on the use of these drugs in the EUA, such as the statement that they “should be used for COVID-19 only when patients can be appropriately monitored in the hospital as required by the EUA or are enrolled in a clinical trial with appropriate screening and monitoring” tended to get lost in the hype for these drugs. This hype was epic and pervasive, too, coming from President Trump and his supporters at Fox News (such as Laura Ingraham and Sean Hannity), Didier Raoult and the cult of personality that’s sprung up around him since he published his first study, America’s quack Dr. Mehmet Oz, and a wide variety of fame-seeking “brave maverick doctors” touting uncontrolled, incompetently done, and unethical “case series” of COVID-19 patients whom they’ve treated with hydroxychloroquine and various other drugs.

Meanwhile, the drumbeat of negative studies has continued since last I wrote about this

The negative evidence continues to accumulate

The FDA warning capped off weeks during which a drip-drip-drip-drip of negative studies had been appearing on preprint servers and, to a lesser degree, in the peer-reviewed medical literature. For example, last Friday JAMA Network Open Access published a randomized controlled trial from Brazil that had previously been available on a preprint server. It appears to be the same study I discussed two weeks ago. This was a parallel, double-blinded, randomized, phase IIb clinical trial that studied 81 COVID-19 patients. There were two groups, patients receiving high dose (600 mg twice a day over ten days) versus low dose (450 mg twice a day on the first day, once a day thereafter for the next four) chloroquine plus ceftriaxone, a cephalosporin antibiotic. There was no placebo control because Brazil had mandated chloroquine or hydroxychloroquine for COVID-19 patients. The study reports that the high dose patients showed more severe QT prolongation and that there was a trend towards higher mortality compared to the low dose. Specifically, by day 13, 6 of the 40 patients in the low-dose group had died, while 16 of the 41 patients in the high-dose group had died. When adjusted for age, the result was not statistically significant, but nonetheless concerned the doctors enough during an interim analysis that the study was halted. One weakness of this study is that it was not able to independently assess the toxicity of chloroquine because all patients also received azithromycin, according to the hospital protocol.

This study joined another study published on a preprint server earlier in the week. This was a retrospective cohort study of 368 hospitalized veterans at US Veterans Health Administration medical centers until April 11, 2020, some of whom were treated with hydroxychloroquine (hydroxychloroquine, n=97; hydroxychloroquine + azithromycin, n=113; no hydroxychloroquine, n=158). The findings:

Rates of death in the HC, HC+AZ, and no HC groups were 27.8%, 22.1%, 11.4%, respectively. Rates of ventilation in the HC, HC+AZ, and no HC groups were 13.3%, 6.9%, 14.1%, respectively. Compared to the no HC group, the risk of death from any cause was higher in the HC group (adjusted hazard ratio, 2.61; 95% CI, 1.10 to 6.17; P=0.03) but not in the HC+AZ group (adjusted hazard ratio, 1.14; 95% CI, 0.56 to 2.32; P=0.72). The risk of ventilation was similar in the HC group (adjusted hazard ratio, 1.43; 95% CI, 0.53 to 3.79; P=0.48) and in the HC+AZ group (adjusted hazard ratio, 0.43; 95% CI, 0.16 to 1.12; P=0.09), compared to the no HC group.

The authors concluded:

Specifically, hydroxychloroquine use with or without co-administration of azithromycin did not improve mortality or reduce the need for mechanical ventilation in hospitalized patients. On the contrary, hydroxychloroquine use alone was associated with an increased risk of mortality compared to standard care alone. Baseline demographic and comorbidity characteristics were comparable across the three treatment groups. However, hydroxychloroquine, with or without azithromycin, was more likely to be prescribed to patients with more severe disease, as assessed by baseline ventilatory status and metabolic and hematologic parameters. Thus, as expected, increased mortality was observed in patients treated with hydroxychloroquine, both with and without azithromycin. Nevertheless, the increased risk of overall mortality in the hydroxychloroquine-only group persisted after adjusting for the propensity of being treated with the drug. That there was no increased risk of ventilation in the hydroxychloroquine-only group suggests that mortality in this group might be attributable to drug effects on or dysfunction in non-respiratory vital organ systems.

The obvious weakness of this study is that it was retrospective. One can always question whether the authors adequately controlled for confounders and whether there was some form of undetected selection bias going on. On the plus side, I note that in this study the authors did attempt to control for a wide variety of potential confounders, including comorbidities, medications, and clinical and laboratory abnormalities. One can also ask how applicable these results are to the general population, given that the cohorts studied consisted only of men whose median age was 65 years and the majority of whom were African-American. Even so, this study at the very least failed to discover even a hint of activity of hydroxychloroquine against COVID-19. If hydroxychloroquine were the “game changer” described by President Trump and Didier Raoult, one would expect to find some indication of that in a study like this.

A few days after my last post on the subject of hydroxychloroquine for COVID-19, another negative study, this time from investigators in France, was posted on a preprint server. This was a study of 181 patients with pneumonia due to SARS-CoV-2 requiring supplemental oxygen support treated in four French hospitals. The authors collected data from the routine care of all adults in these hospitals with documented COVID-19 requiring oxygen to emulate a target trial aimed at assessing the effectiveness of hydroxychloroquine administered at a dose of 600 mg/day. The composite primary endpoint was transfer to an intensive care unit within seven days after inclusion and/or death from any cause. Analyses were adjusted for confounding factors by inverse probability of treatment weighting. Exclusion criteria included:

the presence of a contraindication to hydroxychloroquine at 600 mg daily (including patients under dialysis)

the start of hydroxychloroquine before admission to the hospital

treatment with another experimental drug for COVID-19 (tocilizumab, lopinavir-ritonavir, or remdesivir) within 48 hours after admission

organ failure requiring immediate admission to the ICU or continuous care unit (CCU)

ARDS at admission (defined by the need for non-invasive ventilation with provision of positive airway pressure or invasive mechanical ventilation)

discharge from the ICU to standard care

decision to limit and stop active therapeutics made at admission

opposition to data collection by the patient or her/his legal representative.

The results:

This study included 181 patients with SARS-CoV-2 pneumonia; 84 received HCQ within 48 hours of admission (HCQ group) and 97 did not (no-HCQ group). Initial severity was well balanced between the groups. In the weighted analysis, 20.2% patients in the HCQ group were transferred to the ICU or died within 7 days vs 22.1% in the no-HCQ group (16 vs 21 events, relative risk [RR] 0.91, 95% CI 0.47–1.80). In the HCQ group, 2.8% of the patients died within 7 days vs 4.6% in the no-HCQ group (3 vs 4 events, RR 0.61, 95% CI 0.13–2.89), and 27.4% and 24.1%, respectively, developed acute respiratory distress syndrome within 7 days (24 vs 23 events, RR 1.14, 95% CI 0.65–2.00). Eight patients receiving HCQ (9.5%) experienced electrocardiogram modifications requiring HCQ discontinuation.

This study, too, has significant limitations, given that it was not randomized but rather an attempt to emulate a randomized trial by collecting prospective data. Also, it used a short-term outcome as the primary outcome studied. Even so, this negative trial at the very least suggests that, if hydroxychloroquine has any activity at all against COVID-19, it is certainly not dramatic.

Also published on Friday was a case series of 85 patients with COVID-19 in Nature Medicine reporting that the combination of hydroxychloroquine and azithromycin was associated with QT interval prolongation from a baseline average of 435 ± 24 ms (mean ± s.d.) to a maximal average value of 463 ± 32 ms after three days. In a subset of nine patients who developed severe QT prolongation (greater than 500 ms, a known marker of high risk of malignant arrhythmia and sudden cardiac death), five had a normal QT interval on screening electrocardiogram, suggesting that a normal baseline ECG alone does not mean a patient’s risk from these drugs is low.

Finally, an actual attempt at a systematic review and meta-analysis of studies of hydroxychloroquine to treat COVID-19 by Iranian investigators was published on a preprint server a week ago. I approached it with caution, given that I found it hard to wrap my brain around doing a meta-analysis of studies of such disparate designs, the majority of which have not yet even passed peer review yet and exist only on preprint servers, but I was game to take a look.

The findings:

Seven studies including four clinical trials and three observational studies have entered into the study. The results of meta-analysis of clinical trials showed that there were no significant differences between patients who received the standard treatment with HCQ regimen and the patients that received the standard treatment without HCQ (RR: 1.44, 95% CI, 0.80-2.59). CT-Scan findings improved in 59% (95% CI 0.15-0.92) and nasopharyngeal culture following RT-PCR resulted negative in 76% (95% CI 0.56-0.89) of patients received hydroxychloroquine. Meta-analysis of observational studies showed 75% (95% CI, 0.54-0.88) of patients were discharged from the hospital, 34% (95% CI, 0.07-0.14) admitted to intensive care unit and 1.5% (95% CI, 0.03-0.83) have expired.

And the conclusion:

This study indicated no clinical effectiveness regarding role of HCQ for treatment of COVID-19 patients. However, further large clinical trials should be taken into account in order to achieve more reliable findings.

I concur. While existing studies don’t conclusively demonstrate that hydroxychloroquine doesn’t work or causes more harm than good, to me they are sufficient to demonstrate that, if hydroxychloroquine does have clinically relevant activity against COVID-19 it is definitely not powerful or a “game changer.” If hydroxychloroquine were a “miracle drug” for COVID-19, existing studies would have shown evidence of that. They don’t. Quite the contrary, actually, the data we are seeing now are most consistent with the conclusion that hydroxychloroquine is most likely ineffective at best against coronavirus and, at worst, harmful to COVID-19 patients.

Didier Raoult counterattacks

Unsurprisingly, the drip-drip-drip-drip of evidence suggesting that at the very least hydroxychloroquine is no wonder drug for COVID-19 and in fact might not work at all has resulted in a backlash. For example, Didier Raoult attacked Elisabeth Bik on Twitter after she tweeted about the results of the VA study:

Wow. Preprint on patient group of 368 hospitalized veterans with COVID-19. Hydroxychloroquine treatment: *higher* death rates than treatment without HC. "Rates of death in the HC, HC+AZ, and no HC groups were 27.8%, 22.1%, 11.4%, respectively."https://t.co/vkCzPph3vp pic.twitter.com/EkANISjvjx — Elisabeth Bik (@MicrobiomDigest) April 21, 2020

Raoult, in an obvious attempt to intimidate her by siccing his sycophants and fanboys on her, subtweeted her with this comment:

The witchhunter @MicrobiomDigest is not attentive to details when she judges that a study is useful to her paranoiac fights!

Control group was treated with azithromycin.

Nearly dying patients with lymphopenia were treated with hydroxychloroquine.

Fraudulent study. Fake news. https://t.co/zI8MgsfHlx — Didier Raoult (@raoult_didier) April 22, 2020

Yes, it’s true. Some of the no hydroxychloroquine group did receive azithromycin, which was not hidden. One also can’t help but marvel at the irony of a man who claimed that randomized controlled studies shouldn’t be done in infectious disease, that he was so convinced that his treatment works that he considers doing a randomized trial “unethical,” and as a result hasn’t even attempted to use a control group since his first awful paper criticizing the control group design of any study. Heck, given how awful all of his studies on hydroxychloroquine and azithromycin to treat COVID-19 have been, Raoult criticizing any study leads to intense pain due to my eyes rolling so far that they see into my eye sockets and stretch my optic nerves too far. This is very much of a piece with how Raoult reacted to criticism from a French intensivist named Dr. Damien Barraud in an interview on French television. I’ll include the video for those of you who speak French and translate a couple of key passages:

Basically, Barraud lambasted Didier for “medical populism”:

I haven’t seen a better description of what happened. Take everyone hostage and want to pass as the savior with the miracle drug that will save the world, by ignoring all the methodological and ethical rules yes, this is medical populism.

Barraud has also said that he’s “monstrously angry” with Raoult and accused him of having generated “unnecessary psychological fatigue” among caregivers, noting:

“Very early on, from the start of the patient’s arrival and the communication from the IHU, some conventional doctors were asked to prescribe this. We had to (put a policy in place), hold meetings and waste time on some something that should not have happened because at this time there is for the time being no tangible proof of any effectiveness to have a beneficial effect in the patients in general “, he assured.

We in the US have been unaware of just what a crank Dr. Raoult is, so that when he appears on The Dr. Oz Show or on Fox News he appears authoritative, but his colleagues in France have been trying to educate us.

Let’s just say that Raoult did not react well to Dr. Barraud’s criticism, posting this notice to his institute’s Twitter feed:

Here’s the original French text:

Dr. Damien Barraud médecin réanimateur au CHR de Metz-Thionville, profite en ce moment d’un quart d’heure de gloire worholien en enchainant les interviews sur RMC, BFM TV et La Marseillaise. Les propos qu’il tien dans ces interviews sont étrangement similaires à ceux tenus par le compte Twitter anonyme @fluidloading qui revendique être un médecin de la même région que le Dr. Damien Barraud. Si ce compte Twitter est bien celui du Dr. Damien Barraud, nous somes heureux que dans les interviews données en son nom, ce médecin n’ait pas repris les injures publiques et les attaques diffamatoires que le propriétaire du compte @fluidloading se permet quotidiennement. Nous espérons que, si le Dr. Damien Barraud n’est pas l’auteur des attaques portées par le compte @fluidloading, il s’en désolidarisera rapidement. Elles pourraient en effet justifier une plainte pénale et le lancement d’une procédure auprès de l’order des médecins. Poursuites que nous ne souhaitons pas lancer, car nous sommes aujourd’hui concentrés sur le soin des malades hospitalisés et suivis à l’IHU. Au-delà des polémiques nous espérons que le Dr. Damien Barraud trouvera le temps de se reconcentrer sur sa belle mission de médecin.

And here’s the translation (from a combination of Google Translate and me, although, surprisingly, I understood all but a few words of this):

Dr. Damien Barraud, critical care specialist at CHR Metz-Thionville, is currently enjoying a quarter of an hour of Warholian glory by doing serial interviews on RMC, BFM TV and La Marseillaise. The comments he made in these interviews are strangely similar to those made by the anonymous Twitter account @fluidloading who claims to be a doctor from the same region as Dr. Damien Barraud. If this Twitter account is indeed that of Dr. Damien Barraud, we are happy that in the interviews given in his name, this medicine did not take up public insults and defamatory attacks that the owner of the account @fluidloading allows himself daily. We hope that, if Dr. Damien Barraud is not the author of the attacks carried by the @fluidloading account, he will quickly dissociate himself from it. They could in fact justify a criminal complaint and the initiation of a procedure with l’Ordre des Médicins. Pursuits that we do not wish to launch, because we are today concentrating on the care of hospitalized patients and followed at the IHU. Beyond the controversies we hope that Dr. Damien Barraud will find time to refocus on his beautiful medical mission.

Lovely. Dr. Raoult just doxxed Dr. Barraud in a passive-aggressive manner. “If Dr. Damien Barraud is not the author of the attacks” by @fluidloading, we hope that he will “quickly dissociate himself from it.” Particularly amusing is his “we’re too busy taking care of patients” shtick, a diversion beloved of “brave maverick doctors” the world over to excuse their lack of evidence for their treatments. He’s also destroyed another one of my irony meters, given that le Dr. Raoult seems to have plenty of time to do media interviews and appear on The Dr, Oz Show hawking his risibly bad science.

Raoult clearly meant to sic his Twitter followers on Dr. Barraud in retribution. Unfortunately, his threat to complain to l’Ordre des Médicins is not an idle one. As discussed in February, in a time that seems fanciful in its normality from the lens of mid-April and the COVID-19 pandemic, l’Ordre des Médecins values “collegiality” and civility above all. It took the side of homeopaths against French physicians who signed a statement lambasting homeopathy as quackery and urging the French government to stop funding it, even going so far as to temporarily suspend the license of one of doctors who signed the statement. So it’s not at all clear that Dr. Barraud would be in the clear if the bully Dr. Raoult decided to follow through with his threats.

That’s not all, though. Raoult is truly melting down. He promoted a truly awful Brazilian telehealth study (the PREVENT Senior Trial) purporting to show benefit in COVID-19 patients showing early symptoms:

Un manuscrit dont la publication devrait faire parler : expérimentation de la bithérapie HCQ+AZ au Brésil. Des résultats qui vont dans le sens d'une prescription dès les premiers symptômes. https://t.co/j6XIANLKHz pic.twitter.com/K0hFEHserc — Didier Raoult (@raoult_didier) April 18, 2020

It turns out that, besides being a bad study, it was suspended because of ethical violations. It turns out that the trial had started before proper ethical approvals were obtained.

Meanwhile, the best that he can do, evidence-wise, is to post a review article to the IHU website about the pharmacology and safety of his hydroxychloroquine/azithromycin combination. He doesn’t even bother to post his papers even to preprint websites, which, although they don’t peer review papers posted to them, do subject them to a brief quality checklist before posting. Moreover, it turns out that—surprise! surprise!—Raoult is now in trouble with regulatory authorities in France for not having obtained proper consent:

Translation:

Between the pre-print and the published article, the IHU completely revised the part on the ethics committee in the first observational. With confirmation this time that no consent was requested.

Color me not surprised that Raoult apparently plays fast and loose with clinical trial ethics and regulatory compliance:

The National Agency for the Safety of Medicines and Health Products (ANSM), which did not authorize the second study on hydroxychloroquine (Plaquenil *, Sanofi) conducted at the institute hospital-university (IHU) in Marseille by Pr Didier Raoult, awaits that the investigators bring objective elements to demonstrate its observational nature, indicated Dominique Martin in an interview with APMnews.

And:

The question is whether this study is observational or interventional, he said. Observational studies are only subject to the opinion of a committee for the protection of individuals (CPP) while intervention research must have the green light from ANSM and a CPP.

Basically, Raoult appears to be dancing around the definitions of observational studies from the standpoint of regulatory compliance in France.

Meanwhile, back in the US, an NIH Expert Panel, convened by the National Institute of Allergy and Infectious Diseases (directed by US epidemics expert Anthony Fauci), amended its recommendations for treating COVID-19 on April 21 to recommend against using Raoult’s hydroxychloroquine/azithromycin combination, citing potential cardiac toxicities due to the combination. The panel also concluded that, as of that date, there was as yet insufficient evidence to recommend any kind of treatment either to prevent infection with the coronavirus or to prevent the progression of symptoms in those who are already infectious.

The malignant effect of bypassing science-based medicine

Doctors as a group tend not to deal with feelings of helplessness very well, in my experience. When a patient is dying despite our best efforts, our natural reaction is to do something—anything!—even when we do not have a specific treatment that we know to be effective. Even though supportive care is medical care, it often doesn’t feel that way, particularly when a patient is not only not getting better but is getting worse. We want to feel as though we’ve helped our patients, and just keeping them alive as long as we can in the hopes that their bodies can fight off coronavirus just isn’t as satisfying as giving them a drug that helps to eliminate the virus and save their lives. It’s thus understandable that some doctors jumped on the hydroxychloroquine bandwagon. It’s understandable even that some are still holding out hope that it will be shown to be effective.

For example, after the VA study was published:

The recent "negative" data is no more meaningful that the earlier"positive" data. We actually still have no data regarding efficacy. — Clinically Conservative Cardiologist (@DavidLBrownMD) April 23, 2020

And:

Anybody can conclude anything from confounded observational studies. There is no data that reliably tells us anything and there won't be until the results from RCTs are available. — Clinically Conservative Cardiologist (@DavidLBrownMD) April 23, 2020

This is what I like to refer to as “methodolatry,” defined as the obscene worship of the double-blind placebo-controlled randomized clinical trial as the only valid means of clinical investigation. It’s endemic in the strongest proponents of evidence-based (as opposed to science-based) medicine. It’s usually most evident when EBM proponents insist that only such trials can demonstrate whether highly improbable therapies (like homeopathy or reiki) work or not is through such trials, even when basic science alone can demonstrate that they are so improbable as to be, for all intents and purposes, indistinguishable from impossible. However, methodolatry also comes into play when EBM proponents dismiss existing observational studies about hydroxychloroquine as telling us “nothing” about whether the drug works or not against COVID-19 when in fact existing evidence is enough to tell us, at the very minimum, that if the drug does have activity, its effects are not dramatic. If they were, the existing observational studies and randomized clinical trials would have picked up at least a hint of it. They didn’t, which means that if hydroxychloroquine has any effect at all against COVID-19 it is modest enough to require large randomized clinical trials to detect. From that, I conclude that the drug should not be administered to COVID-19 patients outside of the auspices of such clinical trials.

Methodolatry among physicians aside, though, the premature promotion of hydroxychloroquine has had a number of deleterious effects on our nation. I’ve already discussed how Trump’s boosterism resulted in panic prescribing and hoarding, leading to shortages of the drug for patients with autoimmune diseases who need it. I’ve also speculated how the EUA and promotion of the drug will make it harder for scientists to complete the randomized clinical trials that our above cardiologist and I are waiting for. After all, if you are led to believe a drug works, why would you consent to be on a clinical trial where you might be randomized to receive a placebo? You wouldn’t, of course, and that’s what happened in France, with four out of five patients offered enrollment in Discovery, a randomized trial to study the efficacy of hydroxychloroquine and other treatments, refusing to be enrolled and refusing any treatment other than hydroxychloroquine.

It’s worse than that, though. Not only has the hydroxychloroquine craze made it harder to do the clinical trials necessary to determine if the drug benefits COVID-19 patients, but it’s derailing research into other drugs:

People with COVID-19 who arrive at the Salvador Zubirán National Institute of Medical Sciences and Nutrition in Mexico City to search for treatment can choose from a menu of clinical trials, carefully presented by a worker trained to offer an unbiased portrait of the potential risks and benefits. But neurologist Sergio Iván Valdés-Ferrer already knows which trial most will choose — and it’s not his. Instead, many people opt for one involving hydroxychloroquine, a malaria drug that has been touted by US President Donald Trump and other influential figures as an effective coronavirus treatment. High demand for the drug in Mexico has quickly depleted the country’s supply. Its use is now limited to hospitals, and patients are eager to ensure that they receive it. “There’s a tremendous bias,” says Valdés-Ferrer, who is studying the effects of a dementia drug on COVID-19. “Studies of any other drug that are enrolling all ages and degrees of severity are in big trouble.”

And:

Psychiatrist Eric Lenze of Washington University in St. Louis, Missouri, recently launched a trial of an antidepressant that he hopes could lessen the immune response linked to some severe COVID-19 cases. The trial has so far enrolled ten participants; three others declined to take part because they were already planning to take hydroxychloroquine. And Sauer says that she and her colleagues have encountered similar resistance while enrolling participants into a trial of the antiviral drug remdesivir.

So many people are taking hydroxychloroquine or insisting on being prescribed it that some doctors are compromising rigorous study design and allowing patients to take hydroxychloroquine anyway. Either way, the hype is making the interpretation of clinical trials for other drugs difficult:

Data from clinical trials can also be skewed by excluding participants who refuse to give up chloroquine treatment. Chloroquine can cause heart arrhythmias, for example, and so may not be given to some people who have pre-existing heart problems. That means that a trial that excludes chloroquine-takers could end up enrolling a disproportionately large number of participants with heart conditions, says Malhotra. But allowing participants to take chloroquine could muddle efforts to interpret data. Chloroquine’s effects, especially its effect on the immune system, could take days to fade, says Malhotra. This could make it difficult for trial investigators to distinguish the effect of the treatment they are testing from the effect of the chloroquine.

Exactly, and there are now over 100 clinical trials of hydroxychloroquine or chloroquine. Many are duplicative and the sheer number of clinical trials is not justified by the existing data concerning these drugs. One of the scientists in the article notes that the question of whether hydroxychloroquine is effective against COVID-19 could have been answered already if there had been a concerted effort to develop a handful of rigorous clinical trials, instead of the current situation. In the meantime, how many people have been harmed by what might well be an ineffective drug?

As the situation stands, CQ and HCQ, unproven drugs without clear evidence of benefit for COVID-19 but with evidence suggesting harm, became de facto standard of care before rigorous science supporting their use had been completed and remained so for nearly three months. Only now are doctors and government health authorities rethinking the situation and abandoning the drugs outside the auspices of clinical trials, thus coming into line with what I and others have been saying all along, that there was insufficient evidence that these drugs are effective against COVID-19 to justify using them indiscriminately. It turns out that, even during a pandemic, no good comes from abandoning science- and evidence-based medicine.