Ivermectin is the new hydroxychloroquine, take 6: Incompetence and fraud everywhere!

I’ve long been saying that ivermectin is the new hydroxychloroquine, so much so that I have to say now that ivermectin is no longer new, even as I speculate what new “miracle cure” for COVID-19 will become the “new ivermectin”. Readers might remember that, very early in the pandemic, hydroxychloroquine, a widely used antimalarial drug with mild immunosuppressive properties that make it also useful to treat some autoimmune diseases, was seized upon as the (then) only effective treatment for COVID-19 based on reported observations in Wuhan, China during the first major outbreak. There, a group of Chinese researchers reported that none of a group of their 80 patients with lupus erythematosus who were taking hydroxychloroquine went on to become infected with SARS-CoV-2. Based on that very thin gruel, hydroxychloroquine for a time became part of the de facto standard of care around the world, including in one of the hospitals that I practice at. The devotion to hydroxychloroquine spread, thanks to promotion by Dr. Oz, then-President Donald Trump, and a veritable rogues’ gallery of quacks, and it took a long time for the evidence to catch up and kill it. There was a reason why I called hydroxychloroquine the Black Knight of COVID-19 treatments, because no amount of evidence appeared able to kill it, until it did. Even so, a year later there remains a contingent of quacks who still promote it not just as a treatment but as a preventative.

At the time, at least early last year, I could understand why so many doctors latched onto hydroxychloroquine. After all, patients were getting deathly ill and dying in droves, and they didn’t know what to do beyond supportive care that tried to keep them from dying long enough to clear the infection. Under circumstances like those, it’s human nature to try something like hydroxychloroquine, nor was it unethical then, at least initially, to try it, at least until there was more evidence. These days, not so much. We know hydroxychloroquine doesn’t work, and there are vaccines and potential treatments.

Enter ivermectin, an anthelmintic drug commonly used around the world to treat diseases caused by parasitic roundworms in both animals and humans. Based on a recent BBC news report, “Ivermectin: How false science created a Covid ‘miracle’ drug“, it’s looking more and more as though the clinical trial base for the drug as a treatment for COVID-19 is almost all either fraudulent or so badly done that it might as well be fraudulent. Given the publication of that news report, now seems to be as good a time as any to revisit ivermectin and look at the massive fraud that’s fueled massive grift and many conspiracy theories.

Ivermectin: Bad science helps feed a craze

As Scott Gavura and I have written a number of times, these days ivermectin has supplanted hydroxychloroquine as the “drug of choice” of antivaxxers, quacks, grifters, and ideologues, and the propaganda and astroturf campaigns to promote it as a “miracle cure” or preventative as good or better than the vaccines. There have also been a number of clinical trials testing ivermectin, some with seemingly—if you’ll excuse the term—miraculous results, so much so that there have been meta-analyses.

Ivermectin suffers from two problems in terms of evidence. First, it was first touted based on studies from over a year ago that showed it to have activity against SARS-CoV-2, the virus that causes COVID-19, in cell culture. Unfortunately, what made ivermectin’s prior plausibility low is the fact that the concentration required to achieve this antiviral activity in vitro is many times higher than what can be achieved in the bloodstream with normal dosing. Anyone who does drug development research—as I’ve done, and with a repurposed drug, yet!—knows that this is a huge problem for any drug that an investigator proposes to take to the clinic. Basically, for a drug to look promising to have a high probability that it works in animals (and then in humans) as well as it works in cell culture, its effective concentration can’t be so high that it can’t be achieved in the bloodstream with even high doses. There are occasional exceptions to this rule, such as when a drug’s mechanism in vivo turns out to be different than the mechanism observed in cell culture, but ivermectin isn’t one of those.

The most widely touted evidence for the efficacy of ivermectin against COVID-19 are meta-analyses by advocacy groups touting ivermectin as a way out of the pandemic, such as the BIRD Group in the UK and the Front Line COVID-19 Critical Care Alliance (FLCCCA) in the US, that supposedly show, based on an aggregation of existing clinical trials of COVID-19, that ivermectin is highly effective as a preventative after exposure and as a treatment that prevents progression of mild disease to severe disease. Unfortunately, these meta-analyses are highly dependent on a small number of highly “positive” trials, which, if removed, turn positive meta-analyses into negative meta-analyses. Seemingly not coincidentally, these very highly “positive” clinical trials are also the most dodgy, either very badly done at best or outright fraudulent at worst.

The first mainstream news report about this came to us, courtesy of BuzzFeed News, about a month ago in the form of a story by Stephanie Lee and Ken Bensinger titled “A Prominent Study Said Ivermectin Prevents COVID, But The Data Is Suspect“, which built on the analyses of Gideon Meyerowitz-Katz, an epidemiology postdoc at the University of Wollongong in Australia whom we’ve met before on the topic of dodgy ivermectin studies, and Kyle Sheldrick, who has also been analyzing questionable COVID-19 studies. Oddly enough, I haven’t discussed this news report here on SBM, but it’s worth looking at because it sets the stage for the BBC report.

The BuzzFeed report focuses on a study done in Argentina and led by Dr. Hector Carvallo, which led to a lot of hype of this sort:

And, from BuzzFeed:

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.”

And:

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 briefly right here. Any study that concludes that a drug is 100% effective is very suspect right off the bat. Why? 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 for a large number of diseases. As I also like to say, in medicine the only thing that is 100% certain is death. Each and every one of us will die someday of something.

The BuzzFeed article and an article by Meyerowitz-Katz detail the numerous problems with this study, just beginning with:

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.

Also:

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.

I could go on and on (e.g., about one of the authors withdrawing her name from the paper when Carvallo couldn’t answer questions about it to her satisfaction), but I want to get on to the more recent findings of the BBC. Read the BuzzFeed report and Meyerowitz-Katz’s articles for the gory details of what looks to me like probable fraud. To me, the BBC report is even more damning because it strongly suggests a wider pattern of shoddy research mixed with outright fraud than previous reports, to the point where I’ve started to wonder if there is any legitimate, non-shoddy, non-fraudulent ivermectin trial that showed a positive result. (I’ve pointed out before how the better quality ivermectin studies showed no activity against COVID-19.)

Ivermectin: A false “miracle drug” for COVID-19

In their reporting on ivermectin for the BBC, reporters Rachel Schraer and Jack Goodman were aided by the aforementioned Gideon Meyerowitz-Katz and Dr. Kyle Sheldrick, along with two additional fraud hunters, Dr. James Heathers and Dr. Nick Brown. The findings are incredible. After repeating the unfortunate history of the drug as a COVID-19 treatment and mentioning how antivaxxers and antimaskers have wholeheartedly embraced it, we learn:

The BBC can reveal that more than a third of 26 major trials of the drug for use on Covid have serious errors or signs of potential fraud. None of the rest show convincing evidence of ivermectin’s effectiveness.

Dr Kyle Sheldrick, one of the group investigating the studies, said they had not found “a single clinical trial” claiming to show that ivermectin prevented Covid deaths that did not contain “either obvious signs of fabrication or errors so critical they invalidate the study”.

Major problems included:

• The same patient data being used multiple times for supposedly different people
• Evidence that selection of patients for test groups was not random
• Numbers unlikely to occur naturally
• Percentages calculated incorrectly
• Local health bodies unaware of the studies

The scientists in the group – Dr Gideon Meyerowitz-Katz, Dr James Heathers, Dr Nick Brown and Dr Sheldrick – each have a track record of exposing dodgy science. They’ve been working together remotely on an informal and voluntary basis during the pandemic.

And observational trials don’t get a pass either, given how they’ve been used as propaganda tools to promote ivermectin:

The team also looked at six particularly influential observational trials. This type of trial looks at what happens to people who are taking the drug anyway, so can be biased by the types of people who choose to take the treatment.

Out of a total of 26 studies examined, there was evidence in five that the data may have been faked – for example they contained virtually impossible numbers or rows of identical patients copied and pasted.

In a further five there were major red flags – for example, numbers didn’t add up, percentages were calculated incorrectly or local health bodies weren’t aware they had taken place.

On top of these flawed trials, there were 14 authors of studies who failed to send data back. The independent scientists have flagged this as a possible indicator of fraud.

The BBC, of course, has to be circumspect, as do the intrepid team of ivermectin study investigators who uncovered these problems, but I don’t. This reeks to high heaven of fraud, particularly given that it was primarily the studies that found large positive effects against ivermectin due to the drug were the ones with the biggest problems. As the BBC reports, the worst problems were found “all in the studies making big claims for ivermectin—in fact, the bigger the claim in terms of lives saved or infections prevented, the greater the concerns suggesting it might be faked or invalid, the researchers discovered.” Sheldrick, for instance, concedes that it’s very difficult to rule out human error, but to me these errors are so bad that they are virtually indistinguishable from fraud. Moreover, if these were in fact human errors, then the investigators behind these trials have no business being anywhere near anything resembling clinical trials or human subjects research—or any medical research of any kind. I wouldn’t even want them in a position to experiment on mice.

It’s worth it to go to the horse’s mouth, so to speak, to see what’s wrong with many of these studies:

A recent study in Lebanon was found to have blocks of details of 11 patients that had been copied and pasted repeatedly – suggesting many of the trial’s apparent patients didn’t really exist.

The study’s authors told the BBC that the “original set of data was rigged, sabotaged or mistakenly entered in the final file” and that they have submitted a retraction to the scientific journal which published it.

I like to use this particular brief clip whenever I hear a claim as ludicrous-sounding as this:

What I fear is that the authors might well try to resubmit the paper, only with more cleverly designed fraudulent patients. Yes, I said it. This is not the sort of clinical trial error that happens innocently.

Then, from Iran:

Another study from Iran seemed to show that ivermectin prevented people dying from Covid.

But the scientists who investigated it found issues. The records of how much iron was in patients’ blood contained numbers in a sequence that was unlikely to come up naturally.

And the patients given the placebo turned out to have had much lower levels of oxygen in their blood before the trial started than those given ivermectin. So they were already sicker and statistically more likely to die.

But this pattern was repeated across a wide range of different measurements. The people with “bad” measurements ended up in the placebo group, the ones with “good” measurements in the ivermectin group.

The likelihood of this happening randomly across all these different measurements was vanishingly small, Dr Sheldrick said.

It almost certainly didn’t happen randomly. Sure, it’s possible that it did, but the odds against it are so long that, for all intents and purposes, it is reasonable to assume that this was not random. Either that, or one must assume that the investigators were so incompetent at propensity score matching that, again, they should have no business being anywhere near clinical trials or human subjects research or, yes again, any scientific research. Again, take your pick.

As usual, Meyerowitz-Katz has summarized the problems on Medium:

I don’t think this was an honest mistake either, and, as the headline states, this study (Niaee et al) is the sole remaining randomized trial that shows a benefit from COVID-19 in treating COVID-19. Kyle Sheldrick has also written about it:

Dr Niaee and colleagues claim to have randomised 180 patients into six different treatment groups. I do not believe this claim is true.

The six groups have 30 patients each. Two groups did not receive ivermectin (one received a placebo and one did not). Four groups received ivermectin at different doses and frequencies.

Traditionally in table one of an RCT authors describe certain characteristics of patients in each group. Something immediately caught my eye. The number of participants in each arm who had not actually tested positive for the virus was wildly different:

Control Group: 40%
Placebo Group: 53%
Ivermectin Group 1: 23%
Ivermectin Group 2: 23%
Ivermectin Group 3: 3%
Ivermectin Group 4: 30%

The authors claim this had a p value of 0.421 from a Chi Square test. Just eyeballing this it seemed wildly off to me, and when calculating this I got a p value of about 8*10^-4. (The authors now accept that the actual p value should be <0.001 and state this was “a typographical error.”)

I contacted the corresponding author on the address given in the journal article and requested raw data but received no response. I then attempted through an email address I found online on an earlier preprint and also received no response. I then attempted through his institutional contact details at his university and also received no response. At that point I gave up and posted a comment to pubpeer pointing out the very unexpected imbalance in baseline data and suggested the trial should not be included in meta-analyses unless IPD could be provided and reviewed.

And:

A few of the first things to jump out at me where:

– All patients with missing baseline data (6 patients) occurred in a single arm. This is extremely unlikely with less than a 1 in 10,000 chance of occurring if only random chance is at play.

– While the averages from the summary data were similar between groups, the range of values between arms were wildly different.

– Far fewer patients with low oxygen levels (<90) occurred in the ivermectin arms.

– Hypotensive patients appear far more frequently in some arms than others.

So I ran some statistical tests on how unlikely some of these mismatches were. The numbers below are slightly less extreme than those I presented in my first round of criticism to Dr Niaee. Dr Niaee objected to grouping arms into single-dose and multi-dose groups, and demanded I rerun the analysis with 6 independent groups of 30. I agreed.

We already knew that the chi square for whether patients had actually tested positive to corona virus was 21 with a p value of 0.0008, this means the chance of a mismatch this extreme happening in genuinely randomised groups is less than 1 in 1,000.

There’s more, of course. Again, read Meyerowitz-Katz’s article (if you can) and Sheldrick’s article for the gory details. Suffice to say that Meyerowitz-Katz has concluded:

This is the fifth part in this ongoing saga, and honestly I’m unsure that there will be many more. At a certain point, you have to accept that the evidence-base is so corrupted that the message that has been pushed for months by eager promoters of the drug is very unlikely to be true. If ivermectin does have a benefit in the treatment of Covid-19, it is probably going to be small, and certainly not as impressive as people have been arguing for the last year.

Moreover, there are serious concerns with the studies on prophylaxis too. While it is plausible that ivermectin has some use against Covid-19, the staggering scale of the fraud has made it almost impossible to say anything for certain, except that people rarely fake trials for effective drugs.

Ultimately, we have to wait for larger randomized trials to really know whether ivermectin has a benefit from Covid-19. Unfortunately, it appears that the benefits spruiked for months are most likely based on seriously flawed, and in some cases potentially fraudulent, research.

This is one place where I now strongly disagree with Meyerowitz-Katz,even as I deeply admire his work exposing the incompetence and fraud behind existing ivermectin studies. Now, my position has evolved. We don’t need to wait for larger randomized trials to know if ivermectin works to treat or prevent COVID-19. The existing evidence base is quite clear. It almost certainly doesn’t; that is, if you take a Bayesian approach that looks at the prior probability based on preclinical basic science studies that show that the drug can’t reach a concentration in the bloodstream sufficient to show antiviral activity. As I like to say, very low to nonexistent prior probability based on basic science plus equivocal clinical trial evidence equals, “the drug almost certainly doesn’t work” (especially if you add the huge element of fraud). If you prefer, my conclusion can be phrased a bit more carefully and precisely as, “The odds that ivermectin has a meaningful clinical effect in preventing or treating COVID-19 are so low as to be, for all practical intents and purposes, indistinguishable from not working”.

In fact, I’m now ready to go one step further. It is now arguably no longer ethical to design and carry out new clinical trials of ivermectin against COVID-19. There is no good preliminary evidence that it works in humans to justify such trials, meaning that the only potential effect left is possible harm to clinical trial subjects. If you prefer, I can phrase this proposition more carefully and precisely and say that the chances that clinical trial subjects participating in a randomized trial of ivermectin against COVID-19 will be harmed are so much greater than the chances that any will be helped that it is unethical to do such a trial. I’d love to hear the counterargument, but I’m having a hard time not becoming less and less tentative in this conclusion the more I learn.

The pushback

I’ve often wondered why there has been such a flood of bad papers touting ivermectin as a “miracle cure” or “miracle preventative” for COVID-19 given that we didn’t see that for hydroxychloroquine last year. Don’t get me wrong. The evidence for hydroxychloroquine was not strong. Quite the opposite, it was incredibly weak. However, there didn’t appear to be any major fraud. There were plenty of small studies, bad studies, and the like, but no evidence of fraud except for, ironically enough, one study that linked hydroxychloroquine to dangerous and fatal cardiac arrhythmias, which briefly came close to fooling even me. (I expressed skepticism about the study but in retrospect not nearly enough and thereby learned a valuable lesson.)

Both drugs achieved a cult-like snake oil miracle cure status among antivaxxers, antimaskers, and ideologues, and for much the same reason: If there exists a miracle cure or preventative for COVID-19, then all the public health interventions that these activists hate (lockdowns, mask mandates, vaccine mandates) all become unnecessary. Business can go back to making money, and life can revert to near normal, all without pesky government interventions on behalf of public health or any collective action of any kind. The ideological motivation for promoting hydroxychloroquine (at least after the first wave of the pandemic had crested, while doctors still believed the Chinese experience and recommendations for the drug) has been the same for ivermectin. So it’s not surprising that ivermectin cranks are pushing back hard against the growing reports of fraud and incompetence behind the most commonly cited studies claiming that ivermectin is a potent treatment for COVID-19.

For instance, after the BuzzFeed report, one famous conspiracy site known for COVID-19 minimization, antimask and antivaccine propaganda, and conspiracy theories about the pandemic, defended Hector Carvallo and portrayed the BuzzFeed article and the work of Meyerowitz-Katz and Sheldrick as —you guessed it!—a conspiracy on the part of the “mainstream medical establishment” to “silence” the brave maverick doctors trying to cure COVID-19. Amusingly, Carvallo even quotes Arthur Schopenhauer:

He is confident that eventually, ivermectin will be widely used against COVID-19. “All truth passes through three phases,” he told BuzzFeed. “First it is ridiculed, then it is violently opposed, then it is accepted as self-evident. We are in phase two now.”

Yes, he’s quoting Arthur Schopenhauer. This is a quote that I laugh at, because those who quote it erroneously think that they have an unpopular “truth” that will go through these stages, forgetting that untruth or fraud will never make it past the second stage. In fact, here’s a variation of my retort:

All “fake medicine” truth passes through three stages. First, it is ridiculed by the rationally inclined because it is ridiculous and based upon feelings, conspiracy theories, bad science, and pseudoscience instead of reality. Second, it is opposed by the rationally inclined. Third, the more complete the science and information that falsify it, the more vehemently it is embraced as “self-evident” by its non-rationally inclined believers.

I think we’re in the third stage now, given some of the other responses coming from ivermectin believers:

And, of course, there is a fake “meta-analysis” that ivermectin frauds still cite:

I really should do a post on that website, but it so much resembles websites maintained for hydroxychloroquine back in the day (and, indeed, seems to be maintained by the same astroturf groups) that I’ve had a hard time motivating myself.

And this isn’t all:

I’m going to strongly disagree with Dr. Sheldrick here too, just as I did with Meyerowitz-Katz, even if I risk being too repetitive and say again that I admire the whole crew’s work digging out the inconsistencies and omissions that strongly suggest fraud in these studies. One last time, from a Bayesian perspective we can now reasonably conclude that the chances that ivermectin produces a clinically relevant benefit against COVID-19 in humans are so infinitesimally small that it really isn’t necessary—or even desirable—to do any more large clinical trials reach a reasonable scientific conclusion that, for all practical purposes, ivermectin doesn’t work. (That is a different statement.) It’s also arguably unethical to design new clinical trials, for the reasons I’ve discussed above, as well as a waste of resources, in particular, the most precious research resource of all, human subjects.

I also understand another argument that I sometimes hear in other quarters, namely that we need a couple of slam-dunk large randomized clinical trials for ivermectin as a treatment or preventative for COVID-19 to convince doctors that it really doesn’t work. (This has been the same argument for decades for the need to do yet another large epidemiological trial looking at whether vaccines are associated with an increased risk of autism.) Then I ask myself: Really? If they’re not convinced now, what makes anyone think that another one, two (or three or four or ten) large RCTs would convince them?

Sadly, the ideology behind the antimask, antivaccine, and COVID-19 minimizing movement is a powerful drug that will, as antivaccine beliefs have, stand up against any evidence that science can produce, and, even if that weren’t the case, there’s just way too much grifting potential there.