Ivermectin as a Covid-19 treatment - what's stopping its authorisation?

Covid-19 has been with us, sadly, for just over a year and a half. Despite advancements in research – to understand the virus better – and the advent of vaccines, we’re still no closer to finding a treatment for Covid (in the early stages, at least). Vaccines may be effective, but they’re not full proof. We only have to look to Israel to see what’s happening there. Despite myriad citizens receiving their vaccine, the ever-spreading Delta variant has seemingly evaded the Pfizer shot’s protection. According to The Wall Street Journal, over half the adults infected by the new strain were fully vaccinated, prompting the nation to reimpose mask wearing (indoors, at least). Below, Rebecca Giersiefen looks at ivermectin, a cheap drug that many believe has the ability to prevent many Covid-related deaths. As she writes, there’s more evidence for ivermectin than there is for remdesivir – it also costs a lot less, too. “Ivermectin only costs a handful of dollars. The price of remdesivir on the other hand is over $2,000 for five days of treatment.” Giesiefen discusses this in relation to pharma companies and their desire for profit, as well as the reasons various institutions have given for not authorising ivermectin. A very thought provoking – and thoroughly researched – piece. – Jarryd Neves

By Rebecca Giersiefen*

We are a year and a half into the pandemic, and there are still no treatments for early Covid. Even with vaccines, the disease is not going away completely, and treatments remain relevant. So far, however, there is no authorised medication doctors can prescribe when you get Covid in a Western country. Treatment only starts when you go to hospital. There, people receive supportive care like intravenous fluids or ventilation,[1] and Covid-specific drugs like corticosteroids that have been proven to reduce mortality in critically ill patients.
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The story of how corticosteroids became the standard of care for Covid did not unfold as a straight line. In March 2020, the WHO initially advised against using them for Covid. Front line doctors who prescribed the medication off-label saw benefits, but others thought the risks of using an as of yet unproven drug outweighed the potential benefits. In the absence of unambiguous studies, taking the right decision is not easy for doctors in ICUs, who see people die every day, and the moral debate around this may never fully resolve. Finally, the British Recovery trials picked up the corticosteroid dexamethasone. A single day after the unequivocally positive results of this single (but very large) study were made public, doctors started giving it to their patients. Later, the WHO changed its recommendations, and dexamethasone is now used to treat Covid in intensive care units across the globe.

Meanwhile, there are over 20 randomised controlled trials—the type of trial that is usually considered ‘the gold standard’ of clinical research—which all show a clear improvement in Covid-19 patients if treated with ivermectin at different stages of the disease, from mild to moderate to severe. Many of these are small trials, but taken together, they provide the data of over 5,000 subjects, which is a good amount (there were 6,000 patients in the Recovery trial for dexamethasone).[2] A rigorous meta-analysis by doctors Andrew Bryant and Theresa Lawrie that summarises 22 trials in treatment and three trials in prophylaxis has just been published in June 2021.[3] It calculates that “ivermectin reduced the risk of death by an average of 62%” and concludes: “The apparent safety and low cost suggest that ivermectin is likely to have a significant impact on the SARS-CoV-2 pandemic globally.”

There are other papers that make the case for ivermectin being a highly effective treatment of Covid-19, like a review by Kory et al. that was peer-reviewed and published in the American Journal of Therapeutics in early May 2021.[4] It combines both data from observational studies as well as from randomised controlled trials and ends with the words: “ivermectin should be globally and systematically deployed in the prevention and treatment of COVID-19”. The message could hardly be clearer.

Despite the accruing evidence and the expert recommendations, no large, powerful organisation has included ivermectin in their treatment guidelines. For months, there has been more evidence for the efficacy of ivermectin than for remdesivir. Yet, while the British MHRA, the American FDA and the European EMA have approved remdesivir a long time ago, none of them have done the same for ivermectin. The WHO first approved remdesivir, but later retracted its decision.

There are important differences between the drugs. With billions of people in the developing world having taken ivermectin for parasites, its safety profile is extremely good. So far, ivermectin has also been shown to be very safe in the trials conducted on Covid-19 patients, at any dose. There is an Italian randomised controlled trial which dispenses the highest doses of ivermectin ever used for Covid-19 (1200 μg/kg) to patients. While final results have not been published yet, the leader of the trial has confirmed to me over the phone that the treatment has proven very safe, and there have not been any severe adverse events.[5]
As for remdesivir, severe side effects[6] were noted even in small trials for Covid-19[7].

Another difference is that like other drugs used in tropical medicine, ivermectin only costs a handful of dollars. The price of remdesivir on the other hand is over $2,000 for five days of treatment.[8] According to GILEAD’s latest data, over 10 days of treatment are necessary to achieve a statistically significant improvement with remdesivir, which more than doubles the cost.[9]

The fact that there is a very busy ‘revolving door’ between the pharma industry and institutions like the MHRA & the American FDA is no secret.[10] Because of this and other factors (for example funding[11]) the pharma industry’s influence on these institutions is considerable. Might the pharma companies’ aim for profit have played a role in how differently these two drugs were evaluated? Or is the science that supports ivermectin actually deficient?

Let’s look at the reasons these institutions give for not authorising ivermectin.

The WHO advises against use of ivermectin out of a trial setting. Their website states that the evidence is “of very low certainty due to the small sizes and methodological limitations of available trial data”. There is a video in which Dr. Lawrie, one of the authors of the meta-analysis that has just come out discusses the WHO’s statement and the data shown on their website.[12] The conclusion puzzles her. The WHO does not make it clear which studies they excluded from their analysis and on what grounds, and the figures simply do not match the data that is known to Lawrie.

The American FDA writes on its website: “The FDA has not reviewed data to support use of ivermectin in COVID-19 patients to treat or to prevent COVID-19”.

If you read that again, they openly admit they have not even looked at the studies.

They then advise against ivermectin for safety reasons. As already discussed, there is a lot of evidence that ivermectin is safe for human use. Drugs without any side effects do not exist. Even OTC drugs like ibuprofen have a risk of serious side effects like clotting and stroke and may actually be riskier to take than ivermectin.[13][14]

The statement the European equivalent EMA has put out is: “Most studies EMA reviewed were small and had additional limitations, including different dosing regimens and use of concomitant medications.” [15] This sounds like they simply did not include the larger RCTs in their evaluation. They also do not enter into the details of what the “additional limitations“ are in their opinion.

In short, none of these institutions delivers a detailed point-by-point analysis why any of the existing studies would not be reliable.

The data scientist and mathematician Flavio Abdenur[16] commented on Twitter: “Arguing for the blanket exclusion of the RCTs as “low quality” is a copout. For a “hard”, unambiguous outcome such as death, only massive, coordinated fraud across continents by the researchers running these RCTs would explain these results.”[17]

IDSA, the Infectious Disease Society of America, acknowledges the positive results of the studies in a bizarre, almost comical way: “[T]here were concerns about publication bias, as the available evidence consisted mostly of positive trials”.[18] Not a word is lost about the elephant in the room: The fact that positive trials are what would be expected if a drug actually worked.

Some think that one reason for these studies not being taken seriously is due to racism. Ivermectin being an antiparasitic, it’s in developing countries that people are familiar with it, and most of the trials on it were done in countries like Argentina, Iran and Egypt. The only RCT with a negative outcome for ivermectin had the “benefit” of having been conducted in California.[19]

Whenever opponents of ivermectin make their arguments, they focus on this one single study, which was led by Dr. Lopez-Medina. While nobody has individually taken apart any of the trials in which ivermectin was shown to be effective and shown the supposed errors contained in them, three doctors (Scheim/Hibberd/Chamie-Quintero) considered the flaws of the Californian study so important that they wrote a paper about it.[20]

One thing that you notice when reading the study itself is that the ivermectin branch in this double-blind trial did in fact do better than the control branch. Since the other randomized controlled trials were all positive, this article in Nature[20.1] from 2019 seems relevant: It warns that “studies currently dubbed ‘statistically significant’ and ‘statistically non-significant’ need not be contradictory and such designations might cause genuine effects to be dismissed.”

The reason why the result of the Lopez-Medina trial was not statistically significant was not because the treatment group did badly, but because the control group did exceptionally well, better than what would have been predicted from averages. Scheim, Hibberd & Chamie-Quintero mention that ivermectin is freely available in many places in California, so it is possible that some people who realized they were in the placebo-group obtained the drug elsewhere to treat themselves. Having demoralized patients in the control group resort to self-medicaton is a known risk with placebo-controlled trials.

Another point critics of ivermectin often mention is Merck’s famous statement against ivermectin for Covid-19. Merck is the company that was originally behind ivermectin. Many people still assume Merck would cash in if ivermectin became the standard of care for Covid-19. It is important to know that the patent Merck had on the drug has expired, and the company does not earn a cent anymore from ivermectin. The statement published on their website reads: “[There is n]o meaningful evidence for clinical activity or clinical efficacy in patients with [Covid-19]”. Again, the only explanation is ignorance or willful denial that the studies on ivermectin even exist. They do not explain in any detail what would be wrong with any of the studies.

Rather than benefitting from ivermectin’s success, Merck actually expects to lose money if it is approved. For most of the past year, Merck was working on its own new Covid medication, molnupiravir. Randomized controlled trials of high quality are very expensive, and of course, pharma companies hope for returns on that kind of huge investment. By the time a drug has reached phase III trials, the pharma company behind it may have put hundreds of millions of dollars into the process.[21] Currently, Merck already has a bill of $170 million dollars for an intravenous Covid-drug they tested, but that was discontinued.[22] It goes without saying that from Merck’s perspective molnupiravir should become the standard of care, not ivermectin.

If you think pharma companies would not discredit effective drugs just for profit, think again. Scandals in the pharmaceutical industry are uncovered somewhere in the world every few years (here are examples from the US[23a], the UK[23b] and France[23c], but the list goes on). For some reason, people understand perfectly well that the car or oil industries are motivated by profit first and can be potentially corrupt, but when it comes to Big Pharma, many somehow believe they always have our best interest in mind. People always seem to think “that was a one-off, it’s in the past, something like this won’t happen again”. And yet it does.

As for Merck specifically, in 2004, the company was at the center of a scandal causing over 27,000 heart attacks and sudden cardiac deaths from their arthritis drug Vioxx. It turned out that Merck had manipulated the results of clinical trials to hide the evidence of the severe side effects.[24]

In sharp contrast to Merck, Dr. Satoshi Ōmura, the Japanese scientist who in 2015 won the Nobel prize in medicine for developing ivermectin, has come out in favor of using it for Covid. In March this year, he was quoted by a large Japanese magazine as saying “I haven’t seen a single study that says it does not work”.[25] Unfortunately, people in positions of power in large institutions are not willing to look at those same studies.

More trials are currently going on worldwide, so maybe there is still hope for a breakthrough. Dr. Andrew Hill[26], a research fellow at Liverpool University who specializes in HIV and who worked on a preliminary meta-analysis on ivermectin for Covid in January[27], says there are 85 randomised clinical trials still in progress right now, which include over 30,000 patients[28]. Hopefully the evidence coming from the additional trials will be enough to make a change. Since geographical bias seems to play into this, it is good to know that the PRINCIPLE study in Oxford has announced that they will add ivermectin to their trial. Unfortunately, there has been criticism because the researchers are planning to treat patients only for three days with ivermectin, which is very short.

References:

[1] https://bestpractice.bmj.com/topics/en-us/3000168/management-approach

[2] https://ivmmeta.com/

[3] https://journals.lww.com/americantherapeutics/abstract/9000/ivermectin_for_prevention_and_treatment_of.98040.aspx

[4] https://journals.lww.com/americantherapeutics/fulltext/2021/06000/review_of_the_emerging_evidence_demonstrating_the.4.aspx

[5] https://clinicaltrials.gov/ct2/show/NCT04438850?term=Ivermectin&cond=covid&cntry=IT&draw=2&rank=1

[6] https://www.thelancet.com/action/showPdf?pii=S0140-6736%2820%2931022-9

https://www.medpagetoday.com/infectiousdisease/covid19/86582

[7] https://www.biospace.com/article/data-from-gilead-s-compassionate-use-of-remdesivir-for-covid-19-looks-promising/

[8] https://www.gilead.com/news-and-press/press-room/press-releases/2020/6/an-open-letter-from-daniel-oday-chairman–ceo-gilead-sciences

[9] https://www.gilead.com/news-and-press/press-room/press-releases/2020/6/gilead-announces-results-from-phase-3-trial-of-remdesivir-in-patients-with-moderate-covid-19

[10] FDA’s revolving door: Companies often hire agency staffers who managed their successful drug reviews | Science | AAAS (sciencemag.org)

Stephen Lightfoot Appointed New Chair Of UK MHRA | Pharma Intelligence (informa.com)

FDA: For Big Pharma, the revolving door keeps spinning | TheHill

FDA’s revolving door: Companies often hire agency staffers who managed their successful drug reviews | Science | AAAS (sciencemag.org)

HHS, CDC: Knock Knock, Who’s There?: The Revolving Door Between Big Pharma and the Government | National Women’s Health Network (nwhn.org)

EMA: Europäische Arzneimittelagentur – Lobbypedia

EMA’s revolving door with Big Pharma – alive and well | Corporate Europe Observatory

FPÖ – Hauser: EMA-Direktorin hat ihr ganzes Arbeitsleben mit Lobbying für die Pharmaindustrie verbracht | Freiheitlicher Parlamentsklub – FPÖ, 01.04.2021 (ots.at)

[11] “ Since 1989, when the then prime minister, Margaret Thatcher, took drug regulation out of the hands of the Department of Health, the MHRA has been 100% funded by the pharmaceutical companies.”

The drugs industry and its watchdog: a relationship too close for comfort? | Health | The Guardian

FDA: Why is the FDA funded in part by the companies it regulates? (theconversation.com)

[12] 27:45 https://www.youtube.com/watch?v=D2ju5v4TAaQ

[13] 34:38 https://www.youtube.com/watch?v=vYF8bnmdQfY&t=17s

[14] https://www.healthline.com/health/pain-relief/ibuprofen-advil-side-effects#serious-side-effects

[15] https://www.ema.europa.eu/en/news/ema-advises-against-use-ivermectin-prevention-treatment-covid-19-outside-randomised-clinical-trials

[16] https://www.researchgate.net/profile/Flavio-Abdenur

[17] https://twitter.com/AbdenurFlavio/status/1398726844787134479

[18] https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/

[19] https://jamanetwork.com/journals/jama/fullarticle/2777389#247640979

[20] https://osf.io/u7ewz/

[20.1] https://www.nature.com/articles/d41586-019-00857-9