I must admit that I approached this week’s topic initially with a distinct lack of enthusiasm. The reason is quite simple: Been there, done that. The topic is ivermectin, the new-old wonder drug to treat COVID-19 that evidence can’t seem to kill, and I’m definitely getting flashbacks to a year ago when the first “miracle drug” for COVID-19 was being widely touted, used, and studied. That drug was hydroxychloroquine, and ivermectin is basically the new hydroxychloroquine, as Scott Gavura pointed out a couple of months ago.
So why write about ivermectin again now? For one thing, it’s still being touted, despite an evidence base that can be described most charitably as weak. Second, two new new review articles were published last week and are being touted by ivermectin fans as significant evidence that we should take the drug seriously as a treatment for COVID-19. Hint: They’re not.
To see why I’m getting a strong “hydroxychloroquine” vibe from ivermectin, let’s briefly review what happened with hydroxychloroquine early in the pandemic. After that, I’ll discuss the narrative about the drug being promoted by quacks like Joe Mercola. Finally, I’ll address the evidence for ivermectin in COVID-19, including the two papers cited above.
Hydroxychloroquine: A brief history
When the COVID-19 pandemic first hit early in 2020, it was a truly frightening time, particularly in hospitals in the hardest-hit areas, which were deluged with incredibly sick patients and no treatments other than supportive ones. Faced with dying patients for whom they couldn’t do a lot, doctors felt desperate and started trying something—anything—to save their patients’ live. They thus often threw “everything but the kitchen sink” at the disease, which, again, was understandable early on, when there was no evidence, but is less so now.
In that time of desperation, one drug was more popular than any other. It was an antimalarial drug, hydroxychloroquine (HCQ), which had been repurposed to treat COVID-19 based on in vitro observations of antiviral activity, its known mild immunosuppressive effect that had led it to become a mainstay of the treatment of autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosis, and observations in Wuhan, China during the first epidemic that ultimately led to the pandemic.
How did hydroxychloroquine become the first “miracle drug” for COVID-19? In brief, Chinese researchers reported that none of their 80 patients with lupus erythematosus who were taking hydroxychloroquine went on to become infected with SARS-CoV-2. As a result of that and old evidence of antiviral activity for the drugs, they became interested in using these antimalarial drugs to treat COVID-19. (Never mind that immunosuppressed patients are exactly the patients most likely to assiduously follow the recommendations of public health authorities during a pandemic.) A number of clinical trials were registered, and, based on anecdotal reports and small clinical trials (nearly all of which are as yet unpublished), in February 2020 the Chinese government published an expert consensus recommending CQ or HCQ for patients with COVID-19. Soon after, a number of nations followed suit. From there, a French “brave maverick scientist” named Didier Raoult latched onto the drug as the “answer” to the COVID-19 pandemic, publishing risibly bad studies claiming to show its efficacy. Tech bros such as Elon Musk discovered the claims about hydroxychloroquine and Raoult’s bad science, leading to Donald Trump Tweeting favorably about his study and, ultimately, to the FDA issuing an emergency use authorization for the drug to treat COVID-19.
Unfortunately, it was not long before a drip-drip-drip of negative studies started to cast doubt on whether hydroxychloroquine had any activity against COVID-19, and by summer’s end last year it was pretty obvious that there was no “there” there with hydroxychloroquine, that it didn’t work. Even so, the drug continued to be promoted with enthusiasm ranging from just suggesting that it could prevent COVID-19 after exposure to the virus to full-blown “miracle drug” claims. I once referred to hydroxychloroquine as the “Black Knight” of COVID-19 treatments, a reference to the scene in Monty Python and the Holy Grail in which the Black Knight refuses to admit defeat even as Arthur lopped off limb after limb because evidence just couldn’t seem to kill it. The saga of hydroxychloroquine demonstrated the importance of randomized clinical trials, even in a pandemic, and the price of abandoning science- and evidence-based medicine in the face of hucksters and astroturf groups promoting the drug with bad science and “miracle cure” testimonials the drug and physicians making an honest effort to try something—anything—to save their patients.
As it became clear from more and more evidence that hydroxychloroquine doesn’t work against COVID-19, the narrative started to—shall we say?—evolve? For instance, Dr. Vladimir Zelenko claimed that you had to use zinc with hydroxychloroquine. Others started coming up with cocktails of drugs, vitamins and supplements willy-nilly, with no evidence for efficacy of any of the individual components except the steroids sometimes included in the mix, with grand claims that the cocktail was the miracle cure. Truly, 2020 was a year of physicians behaving badly.
In the midst of this massive shifting of goalposts came ivermectin, which many, including Scott and myself, have dubbed “the new hydroxychloroquine.”
Enter ivermectin, the new hydroxychloroquine
Just as hydroxychloroquine was repurposed based on in vitro (cell culture and biochemical) studies showing antiviral activity that didn’t translate to in vivo (in experimental animals or humans) activity, it was proposed to repurpose ivermectin based on in vitro observations of antiviral activity. Just as hydroxychloroquine was widely used despite a marked lack of evidence, so, too, in many parts of the world ivermectin is being used to treat COVID-19 patients despite a marked lack of evidence. Just as an astroturf effort to promote hydroxychloroquine as an effective treatment for COVID-19 popped up, so, too, an astroturf campaign, complete with conspiracy theories about ivermectin—like hydroxychloroquine!—being an inexpensive drug that “they” don’t want you to know about because its wide use would harm big pharma profits and the sales of COVID-19 vaccines, has emerged.
As we’ve seen, hydroxychloroquine is an antimalaria drug that also has modest immunosuppressive effects sufficient to be useful for some autoimmune diseases, but what is ivermectin? Basically, as Scott Gavura described, ivermectin (Stromectol) is an antiparasitic drug used to treat intestinal strongyloidiasis (threadworm, caused by infection from Strongyloides stercoralis), onchocerciasis (river blindness, caused by the parasitic worm Onchocerca volvulus, and spread by the Simulium blackfly), and roundworm infestations. In veterinary medicine, ivermectin is commonly used to prevent heartworm in dogs and cats and is also used off-label to treat a number of other parasitic infections in animals, including mites in dogs (demodectic mange, scabies, and ear mites) and intestinal parasites (hookworms, roundworms), and Capillaria. In farming, the drug is also used as a deworming medicine in cattle, swine, sheep, goats, and horses.
The interest in ivermectin appears to have originated in an Australian study published early in the pandemic that showed that high concentrations of ivermectin in vitro demonstrated antiviral activities. I’m not going to rehash that study in detail, as Scott has already discussed it, other than to repeat and emphasize that the concentrations used in the experiments published were not concentrations that were achievable in the plasma using standard dosages and to cite a short article from June 2020 that pointed out that pharmacokinetic considerations made ivermectin a poor candidate as an antiviral drug, regardless of how much antiviral activity it might have exhibited at high concentrations in vitro. Basically, the article pointed out that it is likely not possible to achieve the same concentrations of the drug in the plasma, because the drug itself is tightly bound to blood proteins and that even 8.5X the FDA-approved dose (1,700 μg/kg) resulted in blood concentrations far below the dose identified for antiviral effects. I’ll also point out that Scott nicely summarized earlier studies that failed to find a significant impact on the clinical course of COVID-19.
Unfortunately, as was the case with hydroxychloroquine before, conspiracy theories have arisen around the supposed “suppression” of ivermectin. I hasten to point out that hydroxychloroquine hasn’t gone away. Indeed, it is still being touted in Brazil now, fed by the misinformation promoted by Brazilian President Jair Bolsonaro, even as Brazil’s death toll has hit 500,000 and looks likely to surpass that of the US, whose death toll recently hit 600,000 but is slowing down markedly as more and more people are vaccinated. Even so, ivermectin is the new hydroxychloroquine in much of the rest of the world, particularly in the antivaccine, COVID-19-minimizing conspiracy world. One example is how, a month ago, ivermectin was being offered to every citizen of India as the pandemic was killing thousands of people a day in that country.
Let’s look at the narrative.
COVID, ivermectin and the “crime of the century”
Last week, über-quack Joe Mercola published an article entitled “COVID, Ivermectin and the Crime of the Century“, naming it after an episode of Bret Weinstein’s podcast. It features an interview with Dr. Pierre Kory, one of the most prominent proponents of ivermectin for COVID-19 by evolutionary biologist Bret Weinstein, who has become prominent as a COVID-19 contrarian and spreader of disinformation, particularly about the “lab leak theory” of SARS-CoV-2 origins and now likes to Tweet about “persecution” by Twitter:
If they were laypeople making a heterodox case they would be deserving of a fully-throated defense. But they’re top clinicians publishing an impressive body of evidence
— Bret Weinstein (@BretWeinstein) May 29, 2021
It also turns out that Dr. Pierre Kory is president of the Frontline COVID-19 Critical Care Alliance (FLCCC) and has testified before Congress. During that testimony, Dr. Kory claimed that ivermectin, used with other medicines such as vitamin C, zinc and melatonin, could “save hundreds of thousands of people,” and cited more than 20 studies.
The narrative of Mercola’s article is eerily similar to the narratives we heard about hydroxychloroquine a year ago, namely that ivermectin is a cheap, safe, and effective drug that “they” don’t want you to know about that could have saved hundreds of thousands of lives if not for doctors’ fetish for randomized clinical trials.
Yet, despite stellar credentials and being on the frontlines treating hundreds of COVID-19 patients, they have been dismissed as “kooks on the fringe, making wild-eyed claims,” Weinstein says. How can that be? Initially, the FLCCC insisted, based on the evidence, that COVID-19 was a corticosteroid-dependent disease and that corticosteroids were a crucial part of effective treatment.
Since those early days, the FLCCC has been vindicated and corticosteroids, as well as blood thinners, are now part of the standard of care for COVID-19 in many places. The same cannot be said for the remainder of the protocols, however, including the use of ivermectin, which continues to be suppressed, despite robust clinical evidence supporting its use in all phases of COVID-19.
I do like how the FLCCC claims the “brave maverick doctor” and “brave maverick scientist” role and assumes that, because Dr. Kory was on the right side of a couple of areas then he must be right about everything. I also can’t help but note that Dr. Kory, contrary to his “brave maverick” claims, was nowhere near the only one proposing the use of anticoagulants and steroids as part of the supportive treatment of severe COVID-19. These were being debated at my hospital in March 2020 (admittedly, along with hydroxychloroquine).
And, of course, Dr. Kory pulls the favorite gambit of doctors promoting dubious treatments, the “we can’t do randomized clinical trials because it’s unethical” gambit:
With regard to calls for randomized controlled trials, Kory points out that once you can see from clinical evidence that something really is working, then conducting controlled trials becomes more or less unethical, as you know you’re condemning the control group to poor outcomes or death.
And, of course, ivermectin is being “suppressed”:
As noted by Weinstein, ivermectin appears to be intentionally suppressed. It’s simply not allowed to be a go-to remedy. The obvious question is why? Don’t they want to save lives? Isn’t that why we shut down the world?
“I would have these data arguments,” Kory says. “But it’s not about the data. There’s something else. There’s [something] out there that is just squashing, distorting, suppressing the efficacy of ivermectin, and its egregious.”
Indeed, as noted by Weinstein, it’s not even difficult to prove that ivermectin is being suppressed and censored. Censorship of certain COVID-related information, such as ivermectin, is written into the community guidelines. You’re not allowed to talk about it. If you do, your post will be censored, shadow-banned or taken down. If you persist, your entire account will be taken down.
Meanwhile, journalist Matt Taibbi, someone who really should know better but apparently does not, is promoting the conspiracy theory with an article on Substack entitled ‘Why Has “Ivermectin” Become a Dirty Word?’ Its subtitle? “At the worst moment, Internet censorship has driven scientific debate itself underground.”
Ask yourself if this sounds familiar:
A consequence is that issues like the ivermectin question have ended up in the same public bucket as debates over foreign misinformation, hate speech, and even incitement. The same Republican Senator YouTube suspended for making statements in support of ivermectin, Ron Johnson, has also been denounced in the press for failing to call the January 6th riots an insurrection, resulting in headlines that blend the two putative offenses.
“You have these ideas about the need to censor hate speech, calls for violence, and falsity,” Kory says, “and they’ve put science on the same shelf.”
Congratulations, Mr. Taibbi! You’ve used an argument identical to one that I’ve seen used by antivaxxers and quacks on many an occasion dating back 16 years, complete with a false characterization of quality control as “censorship.” Indeed, fans of cancer quack Stanislaw Burzynski loved to use similar arguments, claiming that their hero’s work was being “suppressed.”
Taibbi even uncritically quotes ivermectin fans saying just that:
Ivermectin may never be proven effective as a Covid-19 treatment, but its story has already appeared as a powerful metaphor of the Internet’s transformation. Once envisioned as a vast democratizing tool, which would massively raise global knowledge levels by allowing instant cross-global communication between all people, it’s morphed instead into a giant unaccountable bureaucracy for suppressing dialogue, run by people with an authoritarian vision for information flow. Many ivermectin advocates believe discussion of the the [sic] drug is being suppressed because of its status as a threat to a billion-dollar vaccine business, but it’s just as likely that its reputation worldwide as a “populist” treatment, a medicine taken by people not waiting for official validation, has made it a target of censors and pundits alike.
“I think what happened is that at the outset of the pandemic, it was decided that all information must go in one direction, from the Gods of Science down,” says Kory. “But that’s not the way it works. Science happens on the ground. That’s where the little discoveries are made. They don’t happen at the top of the mountain.”
As I said, Dr. Kory is pushing a classic conspiracy theory very much like the classic conspiracy theory about hydroxychloroquine last year, that ivermectin is a cure for COVID-19 that “they” don’t want you to know about. (And it’ll render vaccines unnecessary.) I see echoes of Kevin Trudeau.
— David Gorski, MD, PhD (@gorskon) June 20, 2021
But what about the evidence?
Mercola cites in the interview the various lines of evidence listed by Dr. Kory. It turns out that Scott already dealt with a number of those studies. I’m going to focus mainly on the two that I cited initially. Both are being touted on Twitter.
Here’s the first:
***MORE PUBLISHED IVM EVIDENCE: “Although several drugs received Emergency Use Authorization for COVID-19 w/unsatisfactory supportive data, #Ivermectin, on the other hand, has been sidelined irrespective of sufficient convincing data supporting its use.” https://t.co/VeAH54967e
— FLCCC Alliance (@Covid19Critical) June 19, 2021
And here’s the second:
Let’s dig in, starting with the “clinical review article.”
Mechanisms of ivermectin against SARS-CoV-2?
The first article is labeled a “clinical review article”. That immediately puzzled me, because it’s far more a basic science review article than it is a clinical review. The vast majority of the article is a rehash of in vitro studies showing antiviral activity of the drug at high concentrations, as listed in Table 2. It is not really a systematic review, and it’s published in a relatively minor journal by two people who are part of a pro-ivermectin advocacy group, and people on Twitter also immediately saw a lot of issues with the studies cited, for example:
I haven't had a chance to look through this paean to IVM in detail but this part is ridiculous. The virus replicates in the cytoplasm. Inhibition of importins cannot plausibly have an antiviral effect on SARS-CoV-2. pic.twitter.com/WhHzASrW3a
— Edward Nirenberg 🇺🇦 (@ENirenberg) June 17, 2021
4/n Now, this might be something of a red flag for publication in a scientific journal, but this affiliation isn't mentioned in the paper or the conflicts of interest which is a bit odd pic.twitter.com/TDmG9qf3Lg
— Health Nerd (@GidMK) June 17, 2021
Basically, the authors cite a paper that found that ivermectin inhibits the activity of a protein, importin, that, according to them, “blocking the nuclear transport of viral proteins.” Given that the viruses replicate in the cytoplasm (the rest of the cell other than the nucleus), you can see why Ed was unimpressed.
On the contrary, SARS-CoV-2 itself has several viral proteins that prevent import of host factors needed to turn on genes critical for antiviral defense. This description of IVM's MoA in fact outlines a clear mechanism for toxicity to the host.
— Edward Nirenberg 🇺🇦 (@ENirenberg) June 17, 2021
Wow, okay this is really a mess.
The paper they cite for the ionophore properties of IVM is completely speculative and presents no data to support an actual ionophore function of the IVM, let alone how that produces an antiviral effect.
— Edward Nirenberg 🇺🇦 (@ENirenberg) June 17, 2021
Perusing the totality of the paper, I noted that the authors cite a lot of biochemical papers that purport to show that ivermectin interferes with various cellular processes relevant to the replication of SARS-CoV-2 in a sort of “shotgun” approach, all with a heaping dose of speculation. For instance, they cite computer modeling (in silico) work thusly:
Another in-silico study by Swargiary et al. demonstrated the best binding interaction of −9.7 kcal/mol between Ivermectin and RdRp suggesting inhibition of viral replication . The RdRP residing in nsp12 is the centerpiece of the coronavirus replication and transcription complex and has been suggested as a promising drug target as it is a crucial enzyme in the virus life cycle both for replication of the viral genome but also for transcription of subgenomic mRNAs (sgRNAs) . Ivermectin binds to the viral rdrp and disrupts it. The highly efficient binding of ivermectin to nsp14 confirms its role in inhibiting viral replication and assembly. It is well known that nsp14 is essential in transcription and replication. It acts as a proofreading exoribonuclease and plays a role in viral RNA capping by its methyltransferase activity . Moreover, highly efficient binding of ivermectin to the viral N phosphoprotein and M protein is suggestive of its role in inhibiting viral replication and assembly .
This is a lot of handwaving and speculation. It might have value as evidence to support trying ivermectin in animal models of viral illnesses, but in and of itself, none of it is good evidence that ivermectin actually works in humans.
Then there was this red flag:
That’s a world-record time for acceptance of a review article for publication! The only other instances that I can recall of such rapid acceptance have been by “pay-to-publish” predatory journals.
Be that as it may, oddly enough, the only human evidence cited by the authors comes primarily from a pro-ivermectin website, Ivermectin for COVID-19: real-time meta analysis of 60 studies, whose abuse and misunderstanding of the use of p-values is epic:
The probability that an ineffective treatment generated results as positive as the 60 studies to date is estimated to be 1 in 2 trillion (p = 0.00000000000045).
I like how this was immediately mocked:
7/n Indeed, the authors have copied the information in this paragraph directly from this shoddy website, leading to this wonderful sentence making its way into a published scientific paper pic.twitter.com/U4NIgERNOw
— Health Nerd (@GidMK) June 17, 2021
I also can’t help but note that this ivmmeta.com website uses exactly the same dubious techniques as were used by another website, hcqmeta.com, to tout hydroxychloroquine. Indeed, it very much appears that the same people are behind the two websites, and it is rather clear to me that these websites represent an astroturf effort to promote unproven treatments for COVID-19.
There’s a saying I invoke all the time for meta-analyses: GIGO, or “garbage in, garbage out”. Neither ivmmeta.com nor hcqmeta.com is a true meta-analysis, as neither properly takes into account the quality of the studies being pooled, as is pointed out here:
10/n In fact, one of my favourite parts is where a WHO investigation that concluded that ivermectin should not be given outside of a clinical trial as the evidence is so woeful is misrepresented as showing that ivermectin is massively beneficial! pic.twitter.com/MARkZRcsR5
— Health Nerd (@GidMK) June 17, 2021
12/n Anyway, this website is what I would call solidly pseudoscientific – mimicking science closely enough to trap the unwary, but so filled with errors that the evidence is largely worthless
— Health Nerd (@GidMK) June 17, 2021
To quote the WHO analysis:
Compared with previous drugs evaluated as part of the WHO Living Guidelines for Therapeutics in COVID-19 (see below), currently there are far fewer RCT data available for ivermectin. The existing data on ivermectin also have a substantially higher degree of uncertainty, with included trials having enrolled substantially fewer patients with far fewer events.
For most key outcomes, including mortality, mechanical ventilation, hospital admission, duration of hospitalization and viral clearance, the panel considered the evidence of very low certainty. Evidence was rated as very low certainty primarily because of very serious imprecision for most outcomes: the aggregate data had wide confidence intervals and/or very few events. There were also serious concerns related to risk of bias for some outcomes, specifically lack of blinding, lack of trial pre-registration, and lack of outcome reporting for one trial that did not report mechanical ventilation despite pre-specifying it in their protocol (publication bias).
I also can’t help but note that there are other astroturf-like websites promoting ivermectin too, such as c19ivermectin.com, which has identical formatting and methodologies to a previous website for hydroxychloroquine, c19hcq.com.
We have been warned about them for a long time:
Different websites (such as https://ivmmeta.com/, https://c19ivermectin.com/, https://tratamientotemprano.org/estudios-ivermectina/, among others) have conducted meta-analyses with ivermectin studies, showing unpublished colourful forest plots which rapidly gained public acknowledgement and were disseminated via social media, without following any methodological or report guidelines. These websites do not include protocol registration with methods, search strategies, inclusion criteria, quality assessment of the included studies nor the certainty of the evidence of the pooled estimates. Prospective registration of systematic reviews with or without meta-analysis protocols is a key feature for providing transparency in the review process and ensuring protection against reporting biases, by revealing differences between the methods or outcomes reported in the published review and those planned in the registered protocol. These websites show pooled estimates suggesting significant benefits with ivermectin, which has resulted in confusion for clinicians, patients and even decision-makers. This is usually a problem when performing meta-analyses which are not based in rigorous systematic reviews, often leading to spread spurious or fallacious findings.
This is as good a point as any to move on to the meta-analysis being touted by Dr. Kory. It comes from the UK, specifically from authors associated with the BIRD Group, a pro-ivermectin advocacy group that appears to me to be very similar to the FLCCC.
The BIRD Group “meta-analysis”: Bad science and undisclosed conflicts of interest
As last week closed, I noticed this on Twitter:
Unsurprisingly, it’s being spread all over social media as “slam dunk” evidence that ivermectin works against COVID-19:
This meta-analysis of Ivermectin effectiveness is just now peer reviewed and published. The evidence of prophylactic effectiveness is particularly important. https://t.co/FKT3zETmtw
— Bret Weinstein (@BretWeinstein) June 20, 2021
Three recent fundamental papers on Ivermectin: There are no more excuses not to apply RIGHT NOW IVM for COVID treatment.
1- June 17, 2021.
Systematic Review and Meta-analysis by Dr. Lawrie PUBLISHED in the American Journal of Therapeutics.https://t.co/HOv2kDKIPl pic.twitter.com/XrR9XRE2b4
— JML (@JML21071664) June 19, 2021
"Meta-analysis of 15 trials found that ivermectin reduced risk of death compared with no ivermectin (average risk ratio 0.38, 95% confidence interval 0.19–0.73; n = 2438; I2 = 49%; moderate-certainty evidence)." https://t.co/RTnfU0RpUr
— Association of American Physicians & Surgeons (@AAPSonline) June 19, 2021
Nobody can say no to #ivermectin anymore. 62% death risk reduction. 86% infection risk reduction. Peer reviewed, published in the American Journal of Therapeutics. @BIRDGroupUK https://t.co/bYCYIq6OVE https://t.co/N4IR3VKEPj
— Barend Petrus Uys (@bpuys6) June 19, 2021
A systematic review, meta analysis is the highest form of evidence since it evaluates the signal across multiple RCT's. https://t.co/9vnUUMPqWO
— Jeff Barczewski (@jeffbski) June 19, 2021
No, this is not what meta-analyses necessarily do.
The article, published in the American Journal of Therapeutics by investigators affiliated with the BIRD Group led by Andrew Bryant, purports to be a “Systematic Review, Meta-analysis, and Trial Sequential Analysis to Inform Clinical Guidelines“. In fairness, what I can say from this meta-analysis is that, just like the case with hydroxychloroquine a year ago, it is possible that ivermectin has some clinically meaningful effect on COVID-19 disease progression and survival. It’s not particularly likely or plausible in light of the pharmacokinetics problem mentioned above, in which huge doses of ivermectin would be required to reach the same concentrations in the plasma that caused antiviral effects in the in vitro studies that I discussed above, but it’s not impossible.
I would add, however, that if there really is a clinical effect due to ivermectin on SARS-CoV-2 infection, this disconnect between pharmacokinetics and the concentration of the drug needed in vitro to see antiviral effects would strongly suggest an entirely different mechanism of action in vivo. Again, prior plausibility matters, as we have discussed so often in the context of, for example, homeopathy or reiki. No, I’m not saying that the level of plausibility of ivermectin as a treatment for COVID-19 is anywhere as low as that of homeopathy or reiki. Ivermectin is, after all, a real drug with real effects on biochemistry, not a claim that water has memory or that you can project healing energy into patients. However, overcoming this plausibility problem based on pharmacokinetics is not trivial, either. It would require high quality clinical evidence from large, well-designed, rigorous double-blind randomized clinical trials. Unfortunately, as I read, it became very clear to me that the meta-analysis does not include any large, well-designed, rigorous double-blind randomized clinical trials, which is why it suffers from the same problem that I discussed before, GIGO.
The selection strategy was described thusly:
We searched the reference list of included studies, and of two other 2021 literature reviews on ivermectin,9 as well as the recent WHO report, which included analyses of ivermectin.12 We contacted experts in the field (Drs. Andrew Hill, Pierre Kory, and Paul Marik) for information on new and emerging trial data. In addition, all trials registered on clinical trial registries were checked, and trialists of 39 ongoing trials or unclassified studies were contacted to request information on trial status and data where available. Many preprint publications and unpublished articles were identified from the preprint servers MedRxiv and Research Square, and the International Clinical Trials Registry Platform. This is a rapidly expanding evidence base, so the number of trials are increasing quickly. Reasons for exclusion were recorded for all studies excluded after full-text review.
Interesting. The authors contacted Dr. Kory and his fellow ivermectin advocates at FLCCC. I also note that the American Journal of Therapeutics published a systemic review of ivermectin for COVID-19 about a month and a half ago that basically reminds me of the “clinical review” that I discussed first. Hilariously, at one point, the FLCCC systematic review tries to compare COVID-19 case counts and death rates with areas with and without ivermectin distribution programs in order to argue that fewer people dying in areas where ivermectin was used suggests that ivermectin works. This is a fallacious ecological “analysis” very similar to the argument used a nearly a year ago by an astroturf group for hydroxychloroquine.
But back to the BIRD Group meta-analysis, the first thing I noticed was that all of the studies were small, one as small as 24 patients, many of them not double-blind, a significant number, in fact, open-label, in which everyone knows which patients are in which treatment group. The second thing that I noted is that, contrary to the way this meta-analysis is being represented, pooling data from a large number of small, low-quality clinical trials does not magically create one large, high quality clinical trials.
Another way of putting it:
Garbage in garbage out
— PaedsHaemDoc 🗿 (@dr_barrett) June 19, 2021
In fairness, the authors don’t actually say that meta-analyses of crappy studies do make good evidence, at least not in the paper. However, ivermectin advocates touting the study fans are certainly making that claim, and Dr. Kory sure did seem to me to imply the same in his interview with Bret Weinstein. In any event, one large, well-designed rigorous double-blind clinical trial for prevention, along with one large, well-designed rigorous clinical trial for treatment, could trump this entire meta-analysis.
Indeed, Gideon Meyerowitz-Katz did a reanalysis of the studies analyzed by the BIRD Group that shows that if you leave out the two studies that are as yet only preprints, are very small, and actually appear to have been miscategorized as higher quality than they are, the results are very different:
This basically shows that without those two studies, the analysis demonstrates no benefit for ivermectin at all compared to placebo, with a confidence interval that includes everything from a big benefit to a large harm from the drug. Interestingly, the between-study heterogeneity also reduces when you do this from about 50% to 6.6%, which is lower than the value the authors give in their sensitivity analysis in the paper.
What this means is that, if you exclude some of the low-quality research on ivermectin, the paper goes from showing a massive benefit to no benefit at all. On top of this, there’s an interesting point — even if you don’t agree with these assessments, taking the only three studies that the authors of the meta-analysis considered to be at a “low risk of bias” (i.e. high-quality), you find that these high-quality studies have failed to find any benefit for ivermectin.
This is, of course, what those of us who’ve questioned whether ivermectin works for COVID-19 have been saying all along. The few existing higher quality clinical trials testing ivermectin against the disease uniformly have failed to find a positive result. It’s only the smaller, lower-quality trials that have been positive. This is a good indication that the drug probably doesn’t work.
Details matter, and, particularly the classification of risk of bias in the individual studies used. There’s another problem. Look at the funnel plot, which is a simple scatter plot of the intervention effect estimates from individual studies against some measure of each study’s size or precision used to look for publication bias. Publication bias is the tendency to publish positive studies and not publish negative studies. Figure 7 shows a funnel plot that Bryant et al characterize as not seeming “to suggest any evidence of publication bias.” However, if you look at the plot, the opposite is true, as, instead of seeing studies clustered on either side of 1.0, which is what you would expect in a funnel plot showing no evidence of publication bias, there is a clear preponderance of studies on the side of the plot less than 1.0 (meaning that the risk of death is lower in the ivermectin group), most of which are smaller, lower quality studies, with the larger studies more closely clustered around 1.0 (no effect).
That’s why I’m going to go back to a warning:
Nevertheless, assessments of ivermectin as prophylaxis or treatment for mild to severe COVID-19 continue being published in preprints26 27 and protocol repositories,28 29 which do not follow the recommended process to ensure quality standards in publications; whereas peer-reviewed reports (both observational and experimental studies) are slowly emerging, yet methodologically limited by heterogeneity in population receiving ivermectin, dosis [sic] applied and uncontrolled cointerventions.28–30 Similarly, other studies that can be rapidly retrieved in ClinicalTrials.gov, medRxiv and MEDLINE make up a quite heterogeneous body of evidence31–33 (including ivermectin as intervention, but with different underlying clinical questions), among other issues that do not contribute to the certainty of evidence—according to the systematic reviews that we comment on below.
What anyone considering any meta-analysis, be it this one or any other, needs to be aware of is the existence of a number of pitfalls in meta-analyses, for example:
Meta-analysis is a powerful tool to cumulate and summarize the knowledge in a research field through statistical instruments, and to identify the overall measure of a treatment’s effect by combining several individual results . However, it is a controversial tool, because several conditions are critical and even small violations of these can lead to misleading conclusions. In fact, several decisions made when designing and performing a meta-analysis require personal judgment and expertise, thus creating personal biases or expectations that may influence the result [5, 6].
As statistical means of reviewing primary studies, meta-analyses have inherent advantages as well as limitations . Pooling data through meta-analysis can create problems, such as nonlinear correlations, multifactorial rather than unifactorial effects, limited coverage, or inhomogeneous data that fails to connect with the hypothesis. Despite these problems, the meta-analysis method is very useful: it establishes whether scientific findings are consistent and if they can be generalized across populations, it identifies patterns among studies, sources of disagreement among results, and other interesting relationships that may emerge in the context of multiple studies.
One can’t help but wonder whether the known bias of an organization dedicated to promoting COVID-19 treatments like ivermectin crept into this meta-analysis. The first author Andrew Bryant, Tess Lawrie, and the most of the authors are affiliated with the Bird Group, a UK group whose website looks like this:
The BIRD Group touts ivermectin thusly:
Partnering with worldwide clinical experts, BIRD recognises the growing body of research that shows that ivermectin is a safe, effective medicine we could use to combat Covid 19.
Although ivermectin is licensed in the UK, it cannot be prescribed for Covid 19 until it receives Government approval.
Ivermectin is readily accessible and very low cost and can effectively reach worldwide populations very quickly. Our aim is to get ivermectin approved soon in the UK and around the world. Time is critical and we know that the quicker we deploy, the more lives we can save.
Indeed, the second author, Tess Lawrie, is a founder of the group and appears tightly allied with Dr. Kory:
The seed was planted late in December, when Dr. Tess Lawrie watched Dr. Pierre Kory of the Front-Line Covid-19 Critical Care Alliance (FLCCC) testify before the US Senate on the potential of ivermectin for prevention and treatment of covid-19. She looked into the data and decided to conduct a rapid systematic review and meta-analysis to assess the data for herself. She was struck by the seeming efficacy of the drug in reducing mortality and morbidity, and, as a doctor, considered it her duty to inform the UK health authorities about this potential breakthrough treatment.
The FLCCC Alliance is listed as an affiliated organization, along with a number of others, including the Alliance for Natural Health International and the antivaccine group Physicians for Informed Consent, both of which we have encountered before.
Elsewhere, the BIRD Group claims that ivermectin can prevent “long COVID,” the syndrome of systemic illness that has been noted in some patients to last for months after recovering from the disease, and that it is “already saving lives around the world,” a claim for which there is no good evidence and identical to frequent claims by the FLCCC and other ivermectin advocates. Basically, it’s the idea that we could be saving so many lives in the US, UK, and other nations where ivermectin is not approved to treat COVID-19 if only we would change course.
Bias. It’s something one has to be very, very careful of when designing a meta-analysis, and bringing up the possibility is not an indictment of the motives of anyone involved in the study. What is an indictment of the study is that nowhere in the paper could I find a mention of the affiliation of Dr. Bryant and the other authors with the BIRD Group, although they did note that the revised meta-analysis was funded by a GoFundMe, “Help us get life-saving drug approved for covid-19“. It’s a simple recognition of human nature, and it’s particularly pernicious when it is an undisclosed conflict of interest.
Concluding, research related to ivermectin in COVID-19 has serious methodological limitations resulting in very low certainty of the evidence, and continues to grow.37–39 The use of ivermectin, among others repurposed drugs for prophylaxis or treatment for COVID-19, should be done based on trustable evidence, without conflicts of interest, with proven safety and efficacy in patient-consented, ethically approved, randomised clinical trials.
Italics mine. After all, what’s good for the goose, and all that. Ivermectin fans frequently automatically reject criticism of studies of the drug due to bias and even spread the conspiracy theory that the reason ivermectin hasn’t been widely adopted is because it’s a cheap drug off patent that big pharma can’t make much money from. It’s a fair criticism of the BIRD Group and FLCCC, and it’s an especially fair criticism given the undisclosed conflict of interest involved. I’m sure that Bryant et al. didn’t disclose it because they don’t consider a non-financial conflict of interest to be a true conflict of interest, but being associated with an advocacy group most definitely is.
Indeed, Dr. Kory himself was on Twitter the other day ranting about how his meta-analysis is a “game-changer” but “they” are “censoring” and “suppressing” it. He even completed the crank requirement of including a conspiracy theory positing that “big pharma” is “suppressing” ivermectin so that “they” can develop a new ivermectin-like drug for COVID-19 that can be patented, paving the way for lots and lots of profit:
Where the &#%!? is the major media? A historic, landmark paper identifies the real “game changer” drug in Covid.. and… they dutifully keep censoring. Memo to media: the agencies are CAPTURED. They JUST #%$! gave Pharma over 4B to… invent a new ivermectin. WTF. DO YOUR JOB. https://t.co/AnbtEer2Gi
— Pierre Kory, MD MPA (@PierreKory) June 20, 2021
Leading to these sorts of responses, which remind me, more than anything else, of the rhetoric of antivaxxers, first about Drs. Kory and Weinstein:
The real life "Jude Law" from Contagion. A miracle drug that's being suppressed by big phama while also being studied all over the world in multiple large scale clinical trials.
— Sam (@SamueldLtoronto) June 20, 2021
Ouch. Harsh, but fair, though.
Then there was this:
It’s also been noted:
What is this Tweet referring to? Simple. A few months ago, Frontiers in Pharmacology provisionally accepted a systematic review by Dr. Kory and FLCCC doctors that used many of the same studies as the current one and then decided to reject it:
Regardless of the publication stage or subject of a manuscript, if the integrity of an article is called into question, our policy is to investigate. Upon further scrutiny by our Research Integrity team about the objectivity of this paper during the provisional acceptance phase, it was revealed that the article made a series of strong, unsupported claims based on studies with insufficient statistical significance, and at times, without the use of control groups. Further, the authors promoted their own specific ivermectin-based treatment which is inappropriate for a review article and against our editorial policies.
In our view, this paper does not offer an objective nor balanced scientific contribution to the evaluation of ivermectin as a potential treatment for COVID-19. Frontiers’ has published more than 2,000 rigorously peer-reviewed articles on COVID-19 since the pandemic erupted via our Coronavirus Knowledge Hub, and we are acutely aware of just how critical high-quality, objective research in this area is at this time. Frontiers takes no position on the efficacy of ivermectin as a treatment of patients with COVID-19, however, we do take a very firm stance against unbalanced or unsupported scientific conclusions.
Which, predictably, led to cries of “Censorship!”:
"This is clear censorship. It's indefensible in science to reject a peer-reviewed paper." —Dr. @PierreKory
— FLCCC Alliance (@Covid19Critical) March 1, 2021
I’m sorry, but Dr. Kory should not be surprised that someone would point out his own very blatant conflicts of interest when discussing his review. Live by accusations of conflicts of interest, die by accusations of conflicts of interest, scientifically at least, especially when the meta-analysis is as bad as this one and doesn’t disclose that it comes from members of an advocacy group dedicated to promoting the drug being studied:
So, am I rejecting this meta-analysis out of hand? Not at all, even in spite of its many flaws and the undisclosed conflict of interest! I’m simply pointing out that, contrary to the language being used by Dr. Kory and his admirers to promote it, this meta-analysis is, at best, mildly suggestive that ivermectin might have activity against SARS-CoV-2. At worst, it’s a biased piece of scientific hackery. Certainly, given the extreme lack of biological plausibility based on the drug’s pharmacokinetics, this meta-analysis is by no means the “slam dunk” rejoinder to skeptics of the drug that ivermectin advocates think it is.
Ivermectin is the new hydroxychloroquine
Ivermectin advocates hate it when we say this, but it’s true. Ivermectin is the new hydroxychloroquine. It’s been promoted the same way and by the same people. The same conspiracy theories have sprung up around it as the scientific evidence supporting its use is weak at best, negative at worst. That’s why I’m going to go back to what I once wrote about hydroxychloroquine:
Because I’m dedicated to evidence and science when it comes to medical decision making, I always concede that it is still possible that hydroxychloroquine might still be found to have some anti-COVID-19 activity, although it’s becoming increasingly clear that, if there is any activity it will likely be very modest and require large clinical trials to detect, to the point where it’ll probably be clinically insignificant. That being said, it’s amazing how much believers in acupuncture, vitamin C to treat cancer, and hydroxychloroquine to treat COVID-19 have in common. It’s also distressing how much like the villain in a slasher flick the drug is. No matter how many times it appears to have died, it always comes back.
Substitute the word “ivermectin” for every instance of “hydroxychloroquine,” and the paragraph above is still accurate.
Again, I concede that it is possible that ivermectin has clinically relevant in vivo antiviral activity against SARS-CoV-2. Based on current evidence, however, it seems unlikely that it does, when pharmacokinetics considerations are taken into account. As I routinely used to say when discussing hydroxychloroquine, I’d be happy to change my mind if compelling scientific evidence for ivermectin were published. It’s just that neither of these reviews qualify, nor do any of the clinical trials I’ve seen thus far. That’s why I agree that ivermectin shouldn’t be used to treat COVID-19 outside of the context of a well-designed clinical trial with a strong scientific rationale.
Certainly, the conspiracy mongering by Bret Weinstein, Pierre Kory, and their fans are not leading me to reconsider that opinion.