A timeline of ivermectin-related events in the COVID-19 pandemic
Mika Turkia M.Sc., [email protected],
April 3, 2021
Abstract
Background
Ivermectin is a multifaceted medication invented in Japan in 1975 by professor Satoshi Omura, for which ¯ he won the 2015 Nobel Prize in medicine. Several billion doses of ivermectin have been administered since 1981. Currently, ivermectin preparations are available off-patent from many sources, with the production cost of a single dose estimated to be less than 0.1 US dollars.
Review
The interest in ivermectin with regard to COVID-19 was initiated by an Australian in vitro study published on April 3, 2020, indicating that a single treatment with ivermectin effectively eliminated the SARS-CoV-2 virus in cell culture. A few days later, two doctors in Peru begun treating a COVID-19 outbreak in a prison with ivermectin, later also treating the local police.
In the second and third quarter of 2020 the use of ivermectin spread to other South and Central American countries, Egypt, India and Bangladesh, and later to Lebanon, Southern Africa and Southeastern Europe, with Slovakia being the first European Union country to adopt it.
Ivermectin treatments raised controversy in many European Union countries and the United States which ignored ivermectin, referring to a lack of evidence of its efficacy and safety and demanding large-scale clinical trials. The World Health Organization (WHO) and the European Medicine Agency (EMA) advised against using ivermectin even after results of 26 randomized clinical trials were available in March 2021. In contrast, many developing countries adopted ivermectin with little evidence.
In the United States, government funding was allocated to the development of a novel pharmaceutical estimated to possess an efficacy comparable to ivermectin but priced several magnitudes higher. Social media companies censored ivermectin researchers and research, with for example YouTube censoring results of a meta-analysis commissioned by the WHO. Traditional media appeared to either ignore ivermectin or publish negative commentaries only.
Conclusion
There was widespread disagreement on the fundamentals: which methods were appropriate as a basis for decision making, what counted as evidence, and what was ethical. Societies appeared disorganized, unable to
Extract from Discussion section"
Comparing five CovidAnalysis group’s meta-analyses from November 26 (n=21), December 29 (n=28), January 26 (n=35), February 27 (n=42), and March 31 (n=49) [438], calculated improvements in clinical indicators, with probabilities of an equal or greater percentage of positive results from an ineffective treatment, were as follows: improvements in prophylaxis (pre-exposure/post-exposure or total) were 98%/87% (p=0.063/0.25), 91%/90% (p=0.0078/0.25), 90% (p=0.00098), 89% (p=0.00049), and 89% (p=0.00024), respectively. In early treatment, the improvements were 91% (p=0.13), 87% (p=0.016), 84% (p=0.00098), 83% (p=0.00012), and 80% (p=0.0000076). In late treatment, the improvements were 60% (p=0.00024), 48% (p=0.00012), 39% (p=0.000031), 51% (p=0.0000038), and 50% (p=0.00000095). All together, the improvements were 75% (p=0.00000048), 78% (p=0.0000000037), 74% (p=0.000000000029), 75% (p=0.00000000000023), and 72% (p=0.000000000000002). It appears that in 2021 the variation in estimated efficacy due to addition of more studies to the meta-analysis was too small to be clinically meaningful. Therefore, more studies provided little additional clinically relevant information, and the argument against the treatment was solely based on the assumed unreliability of all the existing data.
The panel which prepared the WHO guideline of March 30, 2021 included in its meta-analysis only five studies that directly compared ivermectin with standard of care and reported mortality [428]. The result indicated 64% reduction in mortality (RR 0.36, 95% CI 0.17-0.75, no p value given, n=915, very low certainty evidence). The meta-analysis of six studies by Hill et al. indicated 75% reduction in mortality (RR 0.25, CI 0.12-0.52, p=0.0002, n=1,255) [275]. The March 31, 2021 meta-analysis of eight randomized controlled trials by the CovidAnalysis group indicated 70% reduction in mortality (RR 0.31, 95% CI 0.16-0.61, n=1,729, p<0.00032) [437]. The meta-analysis of thirteen trials by Bryant et al. devised using Cochrane standards indicated 68% reduction in mortality (RR 0.32, 95% CI 0.14-0.72, n=1,892, low to moderate-certainty evidence) [387]. The FLCCC group’s meta-analysis of four observational and six randomized controlled trials indicated an overall 69% reduction in mortality (RR 0.31, n=3,508, p<0.0001) [168]; [214].
In addition to presenting the new meta-analysis, the guideline presented data from the WHO living guideline [439]. The living guideline analysis indicated 70 deaths per 1,000 patients (7%) for standard of care, and 14 (1.4%) for ivermectin, respectively, i.e. an absolute difference of 56 patients (5.6%) with a 95% confidence interval of 64 to 44 fewer deaths, and a relative mortality reduction of 80%. The odds ratio for mortality was 0.19 (OR 0.19, 95% CI 0.09-0.36) based on 1,419 patients in seven studies. The certainty of evidence was estimated to be very low due to serious risk of bias and very serious imprecision. This imprecision was explained as follows: “for mortality there were only 31 deaths across all 915 patients randomised - an extremely small number of events on which to base conclusions” (referring to five studies instead of seven), suggesting unsuitability of the chosen methodology for evaluation of medicines that might significantly reduce mortality, as conclusions could then not be made.
As a reference for the above data the guideline cited Siemieniuk et al. [440] which did not contain the above results but instead presented a third set of mortality results, indicating a mortality of 130 per 1000 patients (13%) for stardard of care. For a combination of doxycycline and ivermectin, the estimated reduction in deaths was 130 (95% CI 130-123). For ivermectin alone, the reduction was 103 (95% CI 117-78). For proxalutamide, the values were 130 (95% CI 130-118), for colchicine 78 (95% CI 110-9), and significantly less for other included options......
.....Based on their meta-analyses the other groups (FLCCC, CovidAnalysis, BIRD) recommended treatment, the WHO panel did not, referring to “the strong likelihood that chance may be playing a role in the observed findings” [441]. None of the authors of the WHO-funded meta-analysis by Hill et al. were included in the panel. The low cost and wide availability of ivermectin did not, in the panel’s view, mandate the use of a drug with uncertain benefits and possible harms. Resource considerations, accessibility, feasibility and impact on health equity “did not alter the recommendation”. The panel worried about drug shortages in helminth control and elimination programmes [441]; [428]. The panel listed the risk of severe adverse events leading to drug discontinuation as a reason for non-adoption, apparently suggesting that a pharmaceutical should not be adopted at all if a small subset of patients might stop using it. For some reason the panel “inferred that almost all well-informed patients would want to receive ivermectin only in the context of a randomized trial,...
...Considering the estimated efficacy of ivermectin around 90% in prophylaxis and the option of an early outpatient treatment with an estimated efficacy around 75%, an early introduction of ivermectin might have prevented a large part of COVID-19 infections post first wave in many European Union countries and in the United States. Administrative issues, inconsistent requirements of evidence related to the evidence-based medicine paradigm, and possibly conflicts of interest with patentable, commercial products in development prevented introduction of early outpatient ivermectin treatments in the last quarter of 2020 and the first quarter of 2021. This lack of response is likely to have caused unnecessary deaths and difficult-to-repair financial and health consequences in the affected societies....
