Since the beginning of the COVID-19 pandemic, humanity has been searching for effective treatments and preventatives for the virus. Responses have ranged from the wearing of facemasks and “social distancing” to the development of new vaccines and treatments. Researchers have also looked at existing medications to see if they can be helpful in combating the illness.
One existing medication has received considerable attention recently: ivermectin, an antiparasitic that is widely used in the developing world. Many commentators, including several health officials, have dismissed the drug’s usefulness against COVID. Yet, these dismissals seldom cite empirical evidence, or if they do, they don’t detail the findings.
Ivermectin works through a variety of mechanisms to kill the targeted parasites. Some of those mechanisms have also been found to attack single‐strand RNA viruses like SARS‐CoV‑2, which causes COVID. That led scientists to test the medication in vitro, finding that it does in fact kill the virus in cell cultures.
Because ivermectin has been around for decades, can be taken as an oral pill, is safe, and is now off‐patent and therefore cheap, it would be an ideal drug to give to COVID patients — if it is, in fact, effective in the body and not just in the petri dish. Is it?
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Gideon Meyerowitz-Katz, epidemiologist1, Sarah Wieten, assistant professor2, María de Jesús Medina Arellano, researcher3, Gavin Yamey, professor of global health and public policy4
Flawed research means we still do not know if the drug is safe or effective
During disease outbreaks, it can be tempting to sacrifice the scientific rigour of research in favour of speed, given the urgency to develop new treatments. After the 2014-16 Ebola outbreak in west Africa, however, a report on the ethics of research from the US National Academy of Medicine stated clearly that “research during an epidemic is still subject to the same core scientific and ethical requirements that govern all research on human subjects.”1 Early in the covid-19 pandemic ethicists warned researchers against “pandemic research exceptionalism”—lowering ethical standards because of the urgency of the crisis.2 Despite these warnings, there have been many examples of researchers treating covid-19 as exactly that: an exception to the rigorous standards to which we should hold medical research.3 There is no better example of such exceptionalism than the research into ivermectin for covid-19.
Ivermectin is used to treat a range of parasitic diseases, including onchocerciasis and helminthiases. On the basis of in vitro activity against SARS-CoV-2,4 the drug was tested as a possible treatment and prevention for covid-19. Initial randomised trials and systematic reviews suggested large benefits from the drug, including reduced hospital admissions and improved survival rates.56 It turns out that many of the results were—literally—too good to be true.7
An analysis of 26 major trials of ivermectin for covid-19 found that over one third had “serious errors or signs of potential fraud.”7 One prominent meta-analysis that suggested a large survival benefit from the drug was retracted.6 The authors did a re-analysis and found that the effect of ivermectin on survival that they had shown in their retracted study “was dependent on the inclusion of studies with a high risk of bias or potential medical fraud.”8 The editor of the American Journal of Therapeutics published an expression of concern about another high profile meta-analysis, noting suspicious data in several of the included studies and concluding that “exclusion of the suspicious data appears to invalidate the findings regarding ivermectin’s potential to decrease the mortality of covid-19 infection.”9
Ethics scandals
Two recent ethics scandals have cast a further shadow over ivermectin research. First, a report of an experimental study in Mexico City that gave almost 200 000 ivermectin based medical kits to residents with covid-19 was retracted from the preprint server SocArXiv.10 The report was retracted, says SocArXiv’s director, because the experiment was conducted “without proper consent or appropriate ethical protections.”11 Second, in an experiment in a jail in Arkansas, USA, four incarcerated men developed severe side effects after a physician gave them high dose ivermectin as a supposed covid-19 treatment without their knowledge.10 The four men are suing the jail.
Lack of consent was not the only ethical violation in these two scandals. The research participants were exposed to a risk of drug side effects without knowing they had been given ivermectin. In Mexico, the failure to give information to the participants infringed on a human right established in Mexico’s constitution: the right to access information.12 The Arkansas case raises additional concerns as it involved incarcerated people, who risk coercion and exploitation when they are enrolled in clinical research.
It is also arguably unethical and a waste of resources to conduct drug research in an emergency that is of such low quality that no conclusions can be drawn about the drug’s efficacy. That is the situation we find ourselves in today—it is still unclear whether ivermectin is safe or has any benefit in the treatment or prevention of covid-19.13 The flawed and potentially fraudulent research represents a huge missed opportunity to answer an important research question.
Abandoning research exceptionalism
The pressure to act quickly and do something instead of nothing in a global health emergency can lead researchers to cause harm or add to already existing injustices. But the answer is not to abandon research during crises, which could itself lead to “inadequate, ineffective, or even harmful care.”14 The answer is to abandon research exceptionalism.
Such exceptionalism is not needed to run fast, informative trials during a pandemic. The Recovery trial, for example, was a collaborative triumph that allowed clinicians quickly and efficiently to discard ineffective treatments such as lopinavir-ritonavir while adopting effective ones such as dexamethasone.1415 The trial started in March 2020 and released its first results in June 2020, finding an effective treatment for covid-19 just 10 weeks after enrolling the first participant while maintaining high ethical standards.16
The Nuffield Council on Bioethics has recommended several ways to conduct ethical research even under crisis conditions.17 These include research teams developing study protocols with input from the local community to ensure that a trial is acceptable. Research funders should require inclusive community engagement plans in all proposals and should collaborate with governments, national research institutions, and multilateral agencies at the start of an emergency to agree research priorities. Research ethics committees must consider “whether the proposed consent processes are the most appropriate and sensitive that they can be in the circumstances.”17 The urgency of a pandemic is never an excuse for poorly designed studies, ethical misconduct, or the violation of human rights.
Footnotes
Competing interests: We have read and understood BMJ policy on declaration of interests and declare the following. GM-K has been involved in uncovering potentially fraudulent papers on ivermectin for covid-19. SW’s previous post-doctoral research centre received funding from the Arnold Foundation.
Provenance and peer review: Commissioned; not externally peer reviewed.
^ So I've read the original research and the letter of rebuttal to the critique and the from what I understand although so and so has accused those two studies of having flaws, it has not been demonstrated that they had any. The letter of concern only says they are "looking into it"
Obviously if we were to apply the principle above to all situations presently relevant...need not say more...clears throat. Ehem. Gets up for dance break. "I saw the sign. It opened up my eyes...no one's gonna drag you up into the light...I saw the sign. I saw the sign. I saw the sign and it opened up my eyes."
London AJ, Kimmelman J. Against pandemic research exceptionalism. Science2020;368:476-7. doi:10.1126/science.abc1731 pmid:32327600
Abstract/FREE Full TextGoogle Scholar
↵
Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res2020;178:104787. doi:10.1016/j.antiviral.2020.104787 pmid:32251768
CrossRefPubMedGoogle Scholar
↵
Bryant A, Lawrie TA, Dowswell T, et al. Ivermectin for prevention and treatment of COVID-19 infection: a systematic review, meta-analysis, and trial sequential analysis to inform clinical guidelines. Am J Ther2021;28:e434-60. doi:10.1097/MJT.0000000000001402 pmid:34145166
The "Horse Paste" episode from the media was all most of us needed to be convinced to the utility of this wonder drug.
Having dispensed it for decades, I was already aware of the anti-viral uses which were in effect, well known.
<3
Have you seen the latest attempt to debunk it? It's actually funny if it weren't heartbreaking. I'll try to find it.
From the BMJ
Unethical studies of ivermectin for covid-19
BMJ 2022; 377 doi: https://doi.org/10.1136/bmj.o917 (Published 14 April 2022) Cite this as: BMJ 2022;377:o917
Article
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Gideon Meyerowitz-Katz, epidemiologist1, Sarah Wieten, assistant professor2, María de Jesús Medina Arellano, researcher3, Gavin Yamey, professor of global health and public policy4
Author affiliations
Correspondence to: G Yamey gavin.yamey@duke.edu
Flawed research means we still do not know if the drug is safe or effective
During disease outbreaks, it can be tempting to sacrifice the scientific rigour of research in favour of speed, given the urgency to develop new treatments. After the 2014-16 Ebola outbreak in west Africa, however, a report on the ethics of research from the US National Academy of Medicine stated clearly that “research during an epidemic is still subject to the same core scientific and ethical requirements that govern all research on human subjects.”1 Early in the covid-19 pandemic ethicists warned researchers against “pandemic research exceptionalism”—lowering ethical standards because of the urgency of the crisis.2 Despite these warnings, there have been many examples of researchers treating covid-19 as exactly that: an exception to the rigorous standards to which we should hold medical research.3 There is no better example of such exceptionalism than the research into ivermectin for covid-19.
Ivermectin is used to treat a range of parasitic diseases, including onchocerciasis and helminthiases. On the basis of in vitro activity against SARS-CoV-2,4 the drug was tested as a possible treatment and prevention for covid-19. Initial randomised trials and systematic reviews suggested large benefits from the drug, including reduced hospital admissions and improved survival rates.56 It turns out that many of the results were—literally—too good to be true.7
An analysis of 26 major trials of ivermectin for covid-19 found that over one third had “serious errors or signs of potential fraud.”7 One prominent meta-analysis that suggested a large survival benefit from the drug was retracted.6 The authors did a re-analysis and found that the effect of ivermectin on survival that they had shown in their retracted study “was dependent on the inclusion of studies with a high risk of bias or potential medical fraud.”8 The editor of the American Journal of Therapeutics published an expression of concern about another high profile meta-analysis, noting suspicious data in several of the included studies and concluding that “exclusion of the suspicious data appears to invalidate the findings regarding ivermectin’s potential to decrease the mortality of covid-19 infection.”9
Ethics scandals
Two recent ethics scandals have cast a further shadow over ivermectin research. First, a report of an experimental study in Mexico City that gave almost 200 000 ivermectin based medical kits to residents with covid-19 was retracted from the preprint server SocArXiv.10 The report was retracted, says SocArXiv’s director, because the experiment was conducted “without proper consent or appropriate ethical protections.”11 Second, in an experiment in a jail in Arkansas, USA, four incarcerated men developed severe side effects after a physician gave them high dose ivermectin as a supposed covid-19 treatment without their knowledge.10 The four men are suing the jail.
Lack of consent was not the only ethical violation in these two scandals. The research participants were exposed to a risk of drug side effects without knowing they had been given ivermectin. In Mexico, the failure to give information to the participants infringed on a human right established in Mexico’s constitution: the right to access information.12 The Arkansas case raises additional concerns as it involved incarcerated people, who risk coercion and exploitation when they are enrolled in clinical research.
It is also arguably unethical and a waste of resources to conduct drug research in an emergency that is of such low quality that no conclusions can be drawn about the drug’s efficacy. That is the situation we find ourselves in today—it is still unclear whether ivermectin is safe or has any benefit in the treatment or prevention of covid-19.13 The flawed and potentially fraudulent research represents a huge missed opportunity to answer an important research question.
Abandoning research exceptionalism
The pressure to act quickly and do something instead of nothing in a global health emergency can lead researchers to cause harm or add to already existing injustices. But the answer is not to abandon research during crises, which could itself lead to “inadequate, ineffective, or even harmful care.”14 The answer is to abandon research exceptionalism.
Such exceptionalism is not needed to run fast, informative trials during a pandemic. The Recovery trial, for example, was a collaborative triumph that allowed clinicians quickly and efficiently to discard ineffective treatments such as lopinavir-ritonavir while adopting effective ones such as dexamethasone.1415 The trial started in March 2020 and released its first results in June 2020, finding an effective treatment for covid-19 just 10 weeks after enrolling the first participant while maintaining high ethical standards.16
The Nuffield Council on Bioethics has recommended several ways to conduct ethical research even under crisis conditions.17 These include research teams developing study protocols with input from the local community to ensure that a trial is acceptable. Research funders should require inclusive community engagement plans in all proposals and should collaborate with governments, national research institutions, and multilateral agencies at the start of an emergency to agree research priorities. Research ethics committees must consider “whether the proposed consent processes are the most appropriate and sensitive that they can be in the circumstances.”17 The urgency of a pandemic is never an excuse for poorly designed studies, ethical misconduct, or the violation of human rights.
Footnotes
Competing interests: We have read and understood BMJ policy on declaration of interests and declare the following. GM-K has been involved in uncovering potentially fraudulent papers on ivermectin for covid-19. SW’s previous post-doctoral research centre received funding from the Arnold Foundation.
Provenance and peer review: Commissioned; not externally peer reviewed.
^ So I've read the original research and the letter of rebuttal to the critique and the from what I understand although so and so has accused those two studies of having flaws, it has not been demonstrated that they had any. The letter of concern only says they are "looking into it"
Obviously if we were to apply the principle above to all situations presently relevant...need not say more...clears throat. Ehem. Gets up for dance break. "I saw the sign. It opened up my eyes...no one's gonna drag you up into the light...I saw the sign. I saw the sign. I saw the sign and it opened up my eyes."
London AJ, Kimmelman J. Against pandemic research exceptionalism. Science2020;368:476-7. doi:10.1126/science.abc1731 pmid:32327600
Abstract/FREE Full TextGoogle Scholar
↵
Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res2020;178:104787. doi:10.1016/j.antiviral.2020.104787 pmid:32251768
CrossRefPubMedGoogle Scholar
↵
Bryant A, Lawrie TA, Dowswell T, et al. Ivermectin for prevention and treatment of COVID-19 infection: a systematic review, meta-analysis, and trial sequential analysis to inform clinical guidelines. Am J Ther2021;28:e434-60. doi:10.1097/MJT.0000000000001402 pmid:34145166
CrossRefPubMedGoogle Scholar
↵