Response to the Ontario Science Table report “Recommended Drugs and Biologics in Adult Patients with COVID-19”

 

Response to the Ontario Science Table report “Recommended Drugs and Biologics in Adult Patients with COVID-19”

After reviewing the recommendations of the Clinical Practice Guideline Summary: Recommended Drugs and Biologics in Adult Patients with COVID-19, I am dismayed by the lack of consideration of ivermectin for both prevention and treatment of this disease. While it has recommended tocilizumab, the evidence for inclusion of ivermectin is much stronger. Accordingly, I ask that you reconsider your position on ivermectin.

It appears that the main strikes against ivermectin are (a) the majority of clinical trials supporting ivermectin for COVID-19 arose in developing countries, (b) lack of support from a gold standard large-scale, randomized, double-blind, placebo-controlled clinical trial and (c) World Health Organization (WHO) position.

Let me examine points (a) and (b) together. Whether it is acknowledged openly or not, research from unknown authors working in developing countries is not valued as highly as that originating in well-known institutions in the USA and Europe. It is doctors in developing countries who first observed the possible value of ivermectin because ivermectin is used widely primarily in developing countries. This is because these areas bear the greatest burden of parasitic diseases for which ivermectin was developed. It follows then that the trials were initiated by doctors working in environments with limited resources. Unfortunately this has resulted in many of the clinical trials on ivermectin lacking some of the features that panels like the Advisory Table deem essential. As ivermectin is well past its patent protection period, there is no major pharmaceutical company willing to invest in a gold standard trial to validate its effectiveness. But this does not mean that the research on ivermectin is without value, which I will address below.

The position on ivermectin taken by WHO is understandable when you consider the context in which it operates. Ivermectin has been generously donated by Merck for the treatment of parasitic diseases since 1987; one major recognition of the success of this program is the award of a Nobel Prize to Satoshi Omura (Japan) and William Campbell (Merck, USA). This ongoing support by Merck is of substantial value to WHO. Merck has decided not to pursue the application of ivermectin to COVID-19; this is understandable as the company has a major stake in seeing its new antiviral drug molnupiravir succeed. See Ridgeback Biotherapeutics and Merck Announce Preliminary Findings from a Phase 2a Trial of Investigational COVID-19 Therapeutic Molnupiravir - Merck.com In this context, it is easy to see that WHO cannot promote the use of ivermectin for COVID-19 without jeopardizing its anti-parasitic program. Under the circumstances, I urge the Advisory Table to weigh the WHO position very lightly.

Let me respectfully disagree with the statement “There is insufficient evidence to support the use of ivermectin in the treatment of critically ill patients with COVID-19 outside of clinical trials”. I bring my point of view as Professor Emeritus of Pharmacology after a 44-year career of teaching and research at Queen’s University; admittedly none of my research was on ivermectin or viruses. Nevertheless I entered the pandemic with an interest in vitamin D because of its evolution from a simple vitamin into a pro-hormone with many implications. See https://vitamindcovid.blogspot.com/2020/05/vitamin-d-covid-19-and-me.html. As the pandemic evolved, I became interested in ivermectin and read an abundance of the primary publications as well as meta-analyses regarding its use in COVID-19. Independently, I concluded that ivermectin could prevent ~90% of the cases and ~75% of the deaths. These numbers are similar to those contained in the meta-analyses performed by American and British groups with substantial resources and qualifications that far exceed mine. One of the British analysts, Tess Lawrie is perhaps the best qualified person to have lent her time to the question of ivermectin in COVID-19 being both research and medically trained, and having the experience of over 50 Cochrane Systematic Reviews under her belt.

The American Front Line COVID-19 Critical Care Alliance (FLCCC) has a well-established website that deals exclusively with COVID-19- https://covid19criticalcare.com/. They are dedicated to exploring treatments and prophylaxis of the disease. FLCCC alliance, which comprises credible physicians and scientists, was founded by Paul Marik who has published more than 700 papers. Among their accomplishments is an excellent summary of the information regarding drug prevention and treatment of COVID-19; see https://covid19criticalcare.com/wp-content/uploads/2020/11/FLCCC-Ivermectin-in-the-prophylaxis-and-treatment-of-COVID-19.pdf. This paper has been accepted for publication in the American Journal of Therapeutics. Two groups from the UK have conducted meta-analyses of the data regarding ivermectin for COVID-19; one is led by Tess Lawrie and the other by Andrew Hill; as of today neither of these have been peer-reviewed and published. The British Ivermectin Recommendation Development panel has made their manuscript available to the public and has sent it to many governments around the world. It can be found at https://b3d2650e-e929-4448-a527-4eeb59304c7f.filesusr.com/ugd/593c4f_1324461135c749dab73ed7c71e47d316.pdf

Lawrie concludes that “ivermectin substantially reduces the risk of a person dying from COVID-19 by ... 65% to 92%” and it may reduce “COVID-19 infections, probably somewhere in the region of 88%.” “Placebo-controlled trials of ivermectin treatment among people with COVID-19 infection are no longer ethical and active placebo-controlled trials should be closed.” I haven’t seen a manuscript from Dr. Andrew Hill’s group but there are video presentations of their work available such as https://www.youtube.com/watch?v=AYW9LV6AK7w. There are other meta-analyses and sources of information such as https://c19early.com/, which maintains coverage of nine drugs that have been tested in COVID-19; interestingly tocilizumab is not covered. One way to appreciate the overall effectiveness of any treatment is to view Forest Plots, see below. The first two plots describe ivermectin while the third addresses tocilizumab. Clearly, ivermectin compares well with tocilizumab. Ivermectin should be recommended in the Science Advisory Table report for both prophylaxis and treatment of COVID-19.

Caution is required. There are a number areas in which caution is required. The first is with respect to potential toxicity of veterinary ivermectin products. People are buying such preparations for use by their families, as I have been told directly. I’m not so concerned about the ivermectin therein but I do have some concerns about other ingredients, especially in preparations made for topical use on animals. If human preparations are not made available, we run the risk of people using veterinary drugs. While we are on the topic of toxicity, I should mention that ivermectin is among the least problematic drugs available. According to data from the Vigiaccess international database of adverse effects of drugs, there were 1470 adverse effect reports for ivermectin in 2020; there were 5932 such reports for tocilizumab. These are raw data and do not take into account widespread use of ivermectin and the limited use of tocilizumab; thus, it is safe to assume that ivermectin is much, much safer than tocilizumab. The second issue that we should consider is legal liability. With the strength of evidence supporting ivermectin efficacy and its low risk of toxicity, the Province should make this drug available to its citizens. Not to do so could be considered criminal behaviour or at least unethical. The Province of Ontario doesn’t need a lawsuit on its hands in addition to the pandemic. I don’t think that this is alarmism because families in New York state have sued successfully to have parents treated with ivermectin. I recognize that the legal jurisdictions differ but I am aware of a current Ontario lawsuit involving COVID-19. A third consideration is cost. The actual cost of administering tocilizumab to a COVID patient in Ontario was not available to me but based on Canadian information obtained by internet searches, it would be in the thousands of dollars. In comparison, the Stromectol brand of ivermectin is estimated to cost less than C$100 when it is available. The generic equivalent would be much less although perhaps not as inexpensive the Indian cost of less than US$3.

Please note that I am not against the approval of tocilizumab. I support the use of vaccines, PCR tests, antibody tests, masks, social distancing and hand hygiene. With the appropriate use of ivermectin we could save many lives, prevent many cases of COVID-19 and save a ton of money not to mention getting our lives closer to a pre-pandemic normal.

 

 

 

Annex 1 is from British Ivermectin Recommendation Development report.

  

 

This figure is from https://c19ivermectin.com/

 

 

Figure 5 is from Khan FA et al. Systematic review and meta-analysis of anakinra, sarilumab, siltuximab and tocilizumab for COVID-19. Thorax 2021 Feb 12;thoraxjnl-2020-215266. doi: 10.1136/thoraxjnl-2020-215266. Online ahead of print.