Even this far into the COVID-19 pandemic, it seems that I can’t go more than three or four weeks (at most!) without revisiting the topic of ivermectin as a “miracle cure” for COVID-19. I’ve entitled this series Ivermectin is the new hydroxychloroquine for the simple reason that it is, although, for all the HCQ conspiracy theories last year about its being the drug “they” don’t want you to know about, fraud and outright fraudulent studies were not as huge a component of the HCQ story as they have been for ivermectin In any event, ivermectin, as you might recall, is a drug commonly used in veterinary medicine to deworm livestock and pets, and it really irritates believers in the drug when you refer to ivermectin as a “horse dewormer” or “sheep dewormer,” even though it is. Ivermectin is also very useful in humans to treat diseases caused by parasitic roundworms, and its believers love to point out that the discoverers of ivermectin won the Nobel Prize in 2015, but just because they did does not mean that the drug has any usefulness against COVID-19. Rather, it’s nothing more than an explicit (and rather tiresomely obvious) rejoinder to referring to ivermectin as a livestock dewormer, which really, really gets under the skin of ivermectin promoters.
When last I discussed fraud and ivermectin, it was in the context of Gideon Meyerowitz-Katz’s reanalysis of a certain meta-analysis by the ivermectin-promoting BIRD Group in the UK and how it turned out that when Meyerowitz-Katz’s reanalyzed the BIRD meta-analysis (which had concluded that ivermectin reduces death from COVID-19 by a seemingly impressive 60%) excluding one widely cited study from Egypt (Elgazzar 2020) that had some very serious methodological problems and dicey numbers, the once seemingly mighty and positive meta-analysis turns into a negative meta-analysis that demonstrates zero benefit from ivermectin. I also pointed out elsewhere that a better meta-analysis that did exclude Elgazzar 2020 was a negative meta-analysis. None of this stopped the conspiracy theories about “them” (or should I say “Them”?) “suppressing” all the wonderful evidence proving that ivermectin crushes COVID-19 from flowing.
Unsurprisingly, since Elgazzar 2020 was shown to be likely fraudulent (or, if not fraudulent, so utterly incompetently performed as to render its conclusions meaningless), epidemiologists and others have been on the lookout to see if other positive studies of ivermectin for COVID-19 suffer from some or all of the same problems, given how conspiracy theorists like Bret Weinstein had been pushing the drug:
We’ve discussed Weinstein’s role as a molecular biologist turned incompetent epidemiologist and clinical trialist promoting ivermectin as a “miracle cure” for COVID-19 before. Also, whenever anyone oh-so-piously and condescendingly tells me that ivermectin isn’t being promoted as a “miracle cure” I like to point to Tweets like the ones above.
In any event, it was no surprise to learn that—surprise! surprise!—there are other “positive” ivermectin studies that reek of fraud! Last week, before the holiday, I had been meaning to write about this, but better late than never, I say, as the intrepid Meyerowitz-Katz discussed nearly a week ago in the context of claims that ivermectin prevents 100% of COVID-19 infections (and therefore vaccines aren’t necessary). Yes, the claim and the study upon which it was based on reek of fraud:
Let’s start with the Buzzfeed story by Stephanie Lee and Ken Bensinger:
For anti-vaccine activists, the clinical trial results couldn’t have been better. The drug ivermectin, scientists in Argentina announced last year, prevented 100% of COVID-19 infections.
That glowing finding helped spark a craze for the decades-old medication, which is normally used to delouse people and deworm livestock, and drive the perception that it is a silver bullet against the pandemic.
Let me just stop right there. Any study that concludes that a drug is 100% effective is very suspect right off the bat. Why? Almost nothing in medicine is 100% effective, and a claim of 100% efficacy would be far higher than the known efficacy of treatments that have been demonstrated to be extremely efficacious. As our friend Meyerowitz-Katz put it in his article on the topic:
On top of that, the effect size is simply implausible. There aren’t any medications ever that have 100% benefit for anything — this would make ivermectin more effective than antibiotics for tuberculosis or AZT for HIV. So even on face value, this study by Carvallo et al appears to be worrisome.
In brief, if a claim of 100% efficacy is made in a trial, one has to wonder if the study was too small (such that it didn’t include enough patients to see a failure of treatment even if the treatment was very effective or there was some sort of major bias or problem with study design and data collection. In other words, a claim of 100% efficacy, particularly against a viral illness against. backdrop of much more limited efficacy of existing antivirals, is a huge red flag. This is even more true for a repurposed drug with a low prior plausibility based on the high drug concentration required in cell culture to inhibit the replication of SARS-CoV-2, the coronavirus that causes COVID-19, compared to the much lower concentration achievable in human plasma with even high doses of the drug.
Indeed. As I like to say, the only thing that is 100% effective in medicine is death. Every person will die one day. Other than that, there really isn’t anything. Sure, you can see very high effect sizes with some interventions, and these are the most effective medical or surgical interventions we have. But 100%? Nope.
Extreme implausibility of the effect size reported aside, more importantly, as documented by Buzzfeed and Meyerowitz-Katz, it appears exceedingly unlikely that this study ever took place as reported. Even worse, the study’s methodology was terrible:
The study in question is a perfect case in point — it is reportedly a prospective observational trial where medical staff working in one of several hospitals either took ivermectin and a nasal spray made from seaweed and used normal PPE or a control group with just normal PPE. Of those who took the nasal spray and ivermectin, none got Covid-19, while up to 90% of the medical staff who didn’t take these prophylactics contracted the dread disease.
Now, even at face value this study is incredibly shoddy. As I pointed out on twitter, the study was “peer reviewed” in less than a week, the tables have incorrect numbers, the results contradict results the authors posted elsewhere online, the graphs were made, badly, in Excel using default settings, there are no descriptions of most pertinent details about the trial, and the journal the study is published in is about as predatory as journals get.
This study was so implausible and so bad, that people on Twitter were saying things like this:
Actually, I’d have countered Joe Hilgard’s lament by saying, “‘The data are ridiculou’ is a judgment based on an empirical analysis of the data.” But that’s just me. In any event, it really is rather funny that someone would go to the trouble of faking a trial that bad, if fraud is really what happened.
According to Buzzfeed, though:
“If you take it, you will not get sick,” an ivermectin-boosting physician told a Senate committee in December, describing it as a “wonder drug” and citing in part the trial “from Argentina.”
But there are signs that at least some of the experiments — as written up in a paper published in November — didn’t happen as advertised. After BuzzFeed News raised questions about how the study’s data was collected and analyzed, a representative from the Journal of Biomedical Research and Clinical Investigation, which published the results, said late Monday, “We will remove the paper temporarily.” A link was removed from the table of contents — but was reinstated by Thursday. The journal’s explanation, provided after this story was published, was that the author “informed us that he has already provided the evidence of his study to the media.”
The numbers, genders, and ages of the study’s participants were inconsistent. A hospital named in the paper as taking part in the experiments said it has no record of it happening. Health officials in the province of Buenos Aires have also said that they also have no record of the study receiving local approval.
And the researcher overseeing the project, Hector Carvallo, a retired endocrinologist and professor of internal medicine at the University of Buenos Aires, has declined to widely share his data — including with one of his own collaborators, emails show.
It’s definitely a red flag when a study’s principal investigator refuses to share his data and makes up a transparent excuse like “until the pandemic is over” to justify his refusal, or, as Kyle Sheldrick put it:
I tend to disagree with Sheldrick’s last statement. Sure, it’s possible to be a co-author of a study and have been blissfully oblivious of problems with the data collection and analysis, but by the time the Buzzfeed article was published these allegations and concerns had been percolating for over a month and it would have been difficult to be a co-author of the study and not have been contacted about them, although one author has apparently removed himself:
Lest you think that this study hasn’t had an effect, let me point you to the way that it’s been widely cited by the usual suspects promoting ivermectin, as documented in Buzzfeed, starting with the Tweet above by Bret Weinstein and going far, far beyond that:
The fervor has grown ever since. “A near-perfect COVID prophylactic,” tweeted Bret Weinstein, a biologist who is best known for resigning from Evergreen State College in 2017 after he criticized an anti-racism education event. He has declared that the medication renders vaccines irrelevant. “If ivermectin, a drug out of patent, is safe and effective for treating and, more importantly, preventing COVID,” he told Fox News’ Tucker Carlson this summer, “then there shouldn’t be vaccines that we’re administering.”
Carvallo’s findings have been a powerful data point in this argument. The Front Line COVID-19 Critical Care Alliance (FLCCCA), a group of physicians that formed in March 2020, cites Carvallo’s study, along with others, in recommending that ivermectin be “systematically and globally adopted” as both a cure and preventative against COVID-19.
The head of the organization, pulmonologist Pierre Kory, talked up the study to Joe Rogan — the podcast star who said this week that he is now taking ivermectin, among other drugs, after testing positive for COVID. Kory also invoked it during a Senate committee hearing in December, when he asserted that ivermectin “basically obliterates transmission of this virus.”
Indeed, Carvallo and the FLCCC are very much collaborators in promoting ivermectin:
Carvallo, who has written a handful of papers about ivermectin’s COVID-fighting potential over the last year, has publicly voiced his enthusiasm alongside Kory and other FLCCCA members. In the interview with BuzzFeed News, Carvallo compared ivermectin to penicillin and other drugs that were developed for one use and later found to be helpful for another. He called them “repurposed drugs,” saying that that’s a “bad word” in the scientific community.
Actually, repurposed drugs are far from a “bad word” in the scientific community. I myself have been funded to study a drug for Alzheimer’s disease as a potential treatment for a subtype of breast cancer. Indeed, cancer researchers, at least, are very interested in repurposing existing drugs when there is a plausible molecular mechanism to justify doing so. Of course, the advantage of turning a supposed hostility to “repurposed drugs” on the part of the biomedical community into a conspiracy theory has the added advantage of also appealing to lefties who distrust big business in general and big pharma in particular. Why? Because an inherent advantage of repurposing a drug is that all the heavy lifting getting the drug FDA-approved has been done. It’s a lot easier to get clinical trials on the off-label use of an approved drug approved by institutional review boards (IRBs) and regulatory agencies than it is to win approval of a clinical trial of a brand new drugs. The phase 1 studies aren’t as difficult. (Maybe the dose is different for the new indication, but you already have previous phase 1 trials to guide you in designing new clinical trials.) Everything is easier if there is a compelling rationale based on preclinical data testing the drug for the new indication.
The conspiracy theory that scientists aren’t interested in repurposed drugs aside, I’ve written about the antics of the grifters and conspiracy theorists behind the FLCCC before. Again, I’ll emphasize one thing yet again. The promotion of ivermectin (and of hydroxychloroquine last year) as a “miracle cure” or treatment for COVID-19 almost always comes down to two things: Conspiracy theory and ideology. First, it’s the “cure” that “They” don’t want you to know about, which is the central conspiracy theory behind all quackery and antivaccine pseudoscience. Second, if there is such an amazingly effective treatment for COVID-19 (or so the conspiracist “reasoning” goes), then vaccine and vaccine mandates become unnecessary. Mask mandates become unnecessary. “Lockdowns” (which, except in authoritarian countries like China, have seldom been true lockdowns) become unnecessary. There is a certain anti-government, anti-public health, right wing populist ideology to whom the mandates necessary to deal with a global pandemic are deeply offensive, making conspiracy theories like this very attractive to its adherents.
The articles by Meyerowitz-Katz and Buzzfeed are detailed; so I’ll restrain myself from retrodding the ground they’ve both already trod so well and simply summarize why this study appears to be either so incompetent as to be useless or outright fraudulent. First, both note that Carvallo and his group had other publications on ivermectin other than the one in question, but that they were very low quality. Then, implausibilities build on implausibilities in this two-stage study, which started with a pilot study reportedly carried out at Hospital Dr. A. Eurnekian near Buenos Aires’ international airport, followed by a larger trial run at multiple hospitals. I could go into how the timelines for the two trials are off, but Buzzfeed and Meyerowitz-Katz do a fine job of documenting that aspect of the study.
Here’s one big implausibility that came to light after the paper started circulating, as documented in Buzzfeed:
Once the paper started circulating, staffers at the Hospital Cuenca Alta, about an hour outside of Buenos Aires, grew alarmed. In December, its board of directors sent word to Argentina’s health ministry that it had no idea why it was listed as having participated.
“Although the aforementioned article contains data referring to patients from this [hospital] as participants in the respective clinical trial, they are false since this hospital did not participate in the investigation carried out,” a letter shared with BuzzFeed News read. The hospital’s ethics committee also did not receive any request to conduct the study.
Carvallo’s explanation is that the hospital wasn’t asked to participate as an institution. “It was not through ethics committees,” he said. Essentially, he claimed, staffers at local hospitals had heard about the pilot study’s promising results through word of mouth and individually wanted to participate at a time when no COVID vaccines were available.
But if those hospitals did not formally help administer the study, how, then, did Carvallo ensure that hundreds of volunteers correctly self-administered the ivermectin and carrageenan doses multiple times per day or week for months? His answer: the honor system.
At this point, it seems almost pointless to continue to discuss how bad this trial was and how unethical Carvallo was if this truly happened and hospital employees took part in the trial without a valid ethics board approval at Hospital Cuenca Alta.
The Hospital Cuenca Alta doctors were not the only ones concerned enough to complain. When early results started circulating online, members of the health ministry of Buenos Aires province told national research ethics officials that that study — plus another, separate study of Carvallo’s about ivermectin as a COVID-19 treatment — did not have approval from any accredited ethics committee or local health officials in that province, according to correspondence seen by BuzzFeed News. The paper stated that “ethics board approval was attained prior to the commencement of this study and all participants provided informed consent prior to study enrollment.”
When other scientists — including one of Carvallo’s own collaborators — tried to get answers, they say they were kept in the dark.
It gets even worse, as far as the reek of probable fraud goes. When Sheldrick wrote to Carvallo to ask for an anonymized version primary data stripped of patient identifiers. Carvallo refused. (It is common practice for investigators to make this information available to other investigators after a study has been published in the peer-reviewed literature, and the refusal to do is so unusual as to be a huge red flag.) Sheldrick pushed back, adding study co-investigators to the email chain, one of whom, Alkis Psaltis, a head and neck surgeon at the Queen Elizabeth Hospital near Adelaide, Australia, asked Carvallo to accede to Sheldrick’s request, concluding, “Please oblige, Hector.” Psaltis also asked for the same data but only received a summary, leading him to remove his name from the paper.
As if that weren’t bad enough, Meyerowitz-Katz lays down a little lesson on the logistics of clinical trials that make this trial look incredibly implausible:
For those who have never been involved in clinical research it might be worth adding some context here. Recruiting people into a clinical trial takes ages — you have to give them consent forms, get them to read and sign the forms, then take a whole bunch of biological measurements, and finally teach them how to use the drug you’re testing. You then have to follow-up every single person to make sure they’ve done their tests and take their doses, because at least 20% will have forgotten, usually more. Just signing people up in the two clinical trials I’m involved with takes at least 60 minutes per person, never mind the follow-up time.
Let’s be INCREDIBLY generous, and say that these authors were the most efficient triallists in the world and that they can travel instantaneously between their 4 sites — they can sign up, train, and send people off in just 30 minutes. With the total number of 1,424 clinicians involved in this trial, that means that they’d be spending about 712 hours just on recruitment, which in turn would mean that each of the three authors involved would’ve had to spend more than 8 hours a day for the entire month of June just signing people up. That’s not entirely impossible, but it’s extraordinarily unlikely, and doesn’t make sense for three busy clinicians who were all presumably also treating Covid-19 patients at the same time. Moreover, every participant is reported to have had 5 physical exams, which would’ve at least doubled this amount of time.
Australia sounds just like the US when it comes to the difficulties doing clinical trials. It does indeed take ages to recruit patients, counsel them about risks and benefits so that the can read and sign a detailed informed consent. While it is true that hospitals and cancer center (like mine) often have an entire office or department devoted to clinical trials, it’s rare that there are enough personnel to make a scenario like the one above feasible or even plausible. (Indeed, if anything, clinical trial offices tend to be understaffed.) The bottom line is that signing patients up for clinical trials, assigning them to groups, and then following them for as long as the clinical trial protocol requires, all while carefully recording data relevant to the endpoints specified in the trial, is an incredibly labor-intensive and expensive task. Just the expense alone of such a trial makes me doubt it, given that there was no large pharmaceutical company backing it. This study would not necessarily have been incredibly expensive as clinical trials go, but where did the money come from? As Meyerowitz-Katz notes:
And then there’s the cost — a trial like this would be quite expensive. Every participant is reported to have had 5 PCR tests (baseline, then one a week for a month) and they would’ve given out at least 100,000 doses of the nasal spray as well as 10,000s of doses of ivermectin. Even if you ignore the timelines, that would cost somewhere in the region of $400,000 USD, probably more. How was this all paid for if the authors were not funded? Did they spend $100,000s of their own cash?
To be honest, $400,000 is not very much money for a clinical trial, given that even relatively modest-sized clinical trials can rapidly reach costs in the millions of dollars. However, it is important to note that this is just one expense. It ignores the expense of employees, regulatory monitoring, and much more. Again, where did the money come from? Carvallo claims that a local Rotary Club donated $30,000 to purchase PPE, and that the ivermectin and the carrageenan (which was used along with ivermectin) were donated by two drugmakers in Argentina. Even so, things don’t add up.
The bottom line is that existing evidence strongly suggests that ivermectin is ineffective against COVID-19, which is no surprise given the low prior plausibility based on the disconnect between the high drug concentrations needed to inhibit SARS-CoV-2 in cell culture and the concentrations achievable without serious toxicity in humans. Moreover, although it hasn’t been published yet, the most definitive clinical trial on ivermectin versus COVID-19 to date is not looking promising. In light of the increasing drip-drip-drip of negative evidence for ivermectin and the increasing whiff of fraud in at least two of the major positive studies of ivermectin in COVID-19, it’s safe to say that, as wonderful a drug as it is to treat parasitic worms in animals and humans, ivermectin almost certainly doesn’t work against COVID-19. Why should it? It’s not an antiviral at concentrations achievable in humans.
I’ll conclude with one last observation. I keep saying that ivermectin is the new hydroxychloroquine, and that has been true. As evidence showed that HCQ was ineffective against COVID-19, quacks and cranks quickly pivoted to ivermectin. However, I wonder. This observation seems to be becoming less apt as time goes on, because ivermectin grift has now been going on much longer than hydroxychloroquine promotion has. Also, the case of HCQ was far more understandable, given how it arose so early in the pandemic when we knew so much less about COVID-19 and the coronavirus that causes it than we do now and there were no vaccines and no known effective treatments. Doctors were treating dying patients but had little but supportive care to offer them; so it was understandable that they were throwing everything but the kitchen sink at them. Desperation will lead to that. Over a year and a half later, we don’t have that excuse any more, and ivermectin has become nothing more than grift, conspiracy theory, and a badge of ideology.
Ivermectin is also, quite likely, a badge of fraud as well, given how Meyerowitz-Katz has said that there are likely to be more fraudulent studies out there, but that goes along with the grift.