An extension to a previous timeline covering April 2020–March 2021. The new timeline covers the period from April 2021 to June 2021.
Read the timeline by going to the source link.
The final discussion and conclusion is copied below.
Topics:
WHO's role and its funding, Gavi, COVAX, Trusted News Initiative, International Fact-Checking Network, the role of private philanthropy, Frontiers issue, comparison to the H1N1 pandemic, new treatment protocols, causal modeling.
Introduction
Ivermectin is a multifaceted medication invented in collaboration between Japanese professor emeritus Satoshi ¯ Omura from Kitasato University and US researcher William Campbell from Merck & Co/MSD between 1973 and 1979 [1];[2]. Each of them received one quarter of the 2015 Nobel Prize in physiology or medicine for their discoveries [3]. Ivermectin is best known as an antiparasitic agent, with approximately four billion doses having been administered since 1981, predominantly in Africa. Merck &Co/MSD’s patent expired in most countries in 1996, and ivermectin preparations are currently available internationally from many sources, with the production cost of a single dose estimated to be less than0.1 US dollars [4].
This article extends the timeline of ivermectin related-events described in a previous preprint available in two versions, March 30, 2021 and April 3, 2021 [5];[6]. The latter preprint covered the period from April 1, 2020 to March 31, 2021. This preprint extends the timeline to cover April–June 2021, as well as adding a few earlier events. Some caveats of the review are described in the previous preprint. Due to resource limitations, details of many developments are not covered in detail but only mentioned briefly,and omissions have been unavoidable. The focus of this review entails the social, organizational, financial and legal aspects of the situation with ivermectin, with less emphasis placed on presenting clinical trial results and biomedical research.Some of the main events in the previously covered period from April 2020 to March 2021 were an Australian in vitro study which initiated the interest in ivermectin [7]. This was followed by adoption of ivermectin in several South and Central American countries, the state of Uttar Pradesh in India, and Bangladesh in the second and third quarter of 2020. In late October 2020, the Front Line COVID-19Critical Care Alliance (FLCCC) published its ivermectin-based outpatient protocol called I-MASK+ [8];[9];[10].
A month later, another group called CovidAnalysis begun publishing a meta-analysis of ivermectin trials [11] and a list of ivermectin studies [12]. A main event in December 2020 was the US Senate hearing of Pierre Kory of the FLCCC [13]. The hearing raised interest of Lawrie et al. and Bryant et al. who produced additional meta-analyses [14];[15]. In conjunction, another group called British Ivermectin Recommendation Development (BIRD) was founded.
Another main event was the introduction of a preprint of a Unitaid/WHO-funded meta-analysis by Hillet al. [16]. Yet another notable event was the publication of an extensive review by a Japanese group including the discoverer of avermectins, the Nobel prize winner Satoshi ¯ Omura [2];[17].
In the first quarter of 2021, ivermectin had been adopted in several additional countries including Slovakia as the first European Union member country. However, in March 2021 both the European Medicine Agency (EMA) and the World Health Organization (WHO) advised against the use of ivermectin except in clinical trials, ignoring the various meta-analyses and the results of 26 existing randomized clinical trials, in addition to a similar amount of observational trials and other studies.
The majority of indications and the safety of ivermectin have been described in the previous preprint [6].In addition, in April 2021 ivermectin was found to effectively inhibit hepatitis E virus replication [18]. There is also a relatively large amount of research about the treatment of cancers with ivermectin [19][20][21][22][23][24][25], including breast cancer [26][27][28][29][30][31][32], ovarian cancer [33][34][35][36][37][38][39], cervical cancer [40], oesophageal squamous cell carcinoma [41], renal cancer [42], glioma [43][44][45], nasopharyngeal carcinoma [46], melanoma [47][48], gastric cancer [49][50], liver cancer [51] and leukemia [52][53] (list from [54]).
Recently, mass distribution of ivermectin has been studied for prophylaxis of malaria [55];[56];[57]. Ivermectin has also been found to promote wound healing partly through modulation of the inflammatory process and the levels of transforming growth factor beta 1 (TGF-β1) and vascular endothelial growth factor (VEGF) [58]. Ivermectin has also been proposed for the treatment of autoimmune disorders [59].
Omura has characterized ivermectin as “a panacea for resource-poor communities” [60]. Ivermectin has also been said to “continue to surprise and excite scientists, offering more and more promise to help improve global public health by treating a diverse range of diseases, with its unexpected potential as an antibacterial, antiviral and anti-cancer agent being particularly extraordinary” [61]. Possible issues include environmental toxicity [62];[63] and the emergence of ivermectin resistance [64].
April 2021...
Read the timeline by going to the source link. The final discussion and conclusion is copied below.
Discussion
In the United States and the European Union, most of the year 2020 appeared to have been characterized by an attempt to collect ivermectin-related data. The period from the beginning of November 2020 tothe end of March 2021 appeared to be characterized by disputes about interpretation of this data. The change of administration in the United States did not appear to significantly change its ivermectin-related health policy, likely to the disappointment of ivermectin proponents. Beginning from the March 30 guideline decision by the WHO against ivermectin, a period of a kind of trench warfare appeared to emerge. Ivermectin proponents, especially the FLCCC, announced they had resigned their attempts to influence the US National Institutes of Health, the Food and Drugs Agency, the European Medicines Agency and the World Health Organization. Similarly, the BIRD group turned directly to clinicians and the public. Changes to existing treatment protocols were mostly minor. Fluvoxamine emerged as an option and was added to many protocols including the FLCCC’s. The FLCCC introduced two new protocols: the I-MASS protocol for mass prophylaxis and the I-RECOVER for long haul COVID-19syndrome (LHCS). An interesting new development was the recognition of the role of mast cell activation and histamine release in LHCS [456].
The US NIH announced a new trial, ACTIV-6, for repurposed medicines, estimated to finish in March2023, almost two years in the future, rendering the trial practically irrelevant for the purposes of handling the pandemic. Simultaneously, pharmaceutical companies continued their attempts to finish their trials of new outpatient treatment pharmaceuticals as swiftly as possible, and new projects for the development of such treatments were initiated in the US and the UK.
A third concurrent process was the slower-than-expected progress of vaccination programs. A fourth concurrent process was the adoption of ivermectin in countries outside the US and EU. The countries who had adopted ivermectin previously, including Slovakia, implicitly disregarded the March 2021 guideline set by the WHO [171];[457]. India adopted ivermectin nationally after the announcement of the WHO guideline, then mostly dropped it, with the current situation being somewhat unclear. Legal action against the WHO was initiated in India. At the end of the period, Indonesia adopted ivermectin.With regard to researchers and clinicians, medical professionals whose practices appeared to be predominantly based on following existing regulations and protocols appeared to feel criticism against them unjustified and unfair. Similarly, medical professionals whose interest was in the further development of the protocols felt criticism against them unjustified and unfair. The first group may have perceived the latter group as deviants, whereas the latter group may have perceived the first group as anti-innovative.Presumably, both groups saw each others’ practices as somewhat unethical and antisocial. The difference was possibly due to different perspectives on collegiality and the perception of the role of patients. The first group appeared to put more weight on collegial cohesion and rule-adherence, with less weight put on individual patient outcomes, assumedly perceiving that patient outcomes were predominantly the product of the inflexible regulations which lay beyond their responsibility. The second group appeared to put less weight on collegial cohesion and regulations, placing more weight on individual patient outcomes, assumedly perceiving that patient outcomes superseded the rules and that validation of rules was the responsibility of individual clinicians.
With regard to COVID-19, knowledge about the mechanisms and treatments was somewhat scarce especially in the early phase of the pandemic. A recent study described that in such a situation, it would be adaptive to seek further information to resolve uncertainty and obtain a more accurate worldview but biases in such information-seeking behavior could contribute to the maintenance of inaccurate views [458].
The study indicated that more dogmatic individuals were less likely to seek out new information to refine an initial perceptual decision, leading to a reduction in overall belief accuracy despite similar initial decision performance. In addition, dogmatic participants placed less reliance on internal signals of uncertainty, rendering them less likely to seek additional information to update beliefs derived from weak or uncertain initial evidence. Dogmatism is often defined as a viewpoint or system of ideas based on insufficiently examined premises. Thus, differences in openness to research evidence may have been due to differences in personalities and habits which, in turn, may be seen as products of the life experiences(environments) of the individuals, including their medical education.
At times, the views appeared to differ up to a point in which the existence of a shared reality could be questioned, and the practice of presenting opposite conclusions on the same, existing data was in effect making further research irrelevant.
Validity of statistics-based research
In the context of clinical trials, the fundamental validity of the statistics-based research in general is rarely discussed. In 2011, Penston said that the extent and depth of the criticisms of statistics-based research usually comes as a surprise to investigators, doctors and other health care professionals who use the data from large-scale RCTs and epidemiological studies, as they rarely have the time, inclination and skill to read the related literature [459]. He questioned the large size of a study as a sign of strength,saying that as the number of patients recruited to a study increases, statistical significance may be achieved but causal inference is weakened, adding that the source of the problem was the belief that causal relationships of value can be derived from extremely heterogeneous samples. He also said that the methodology of statistics-based research cannot be tested independently of statistics; therefore it is unknown whether the causal inferences drawn from the data of large-scale RCTs and epidemiological studies are valid. According to him, lack of understanding of diseases and the properties of drugs, i.e.ignorance, were driving up the size of studies, and we had witnessed “an inexorable increase in the size of epidemiological studies and RCTs over the past 50 years without any concern for the consequences”.
Saint-Mont discussed the effect of randomization, detailing various false assumptions related to it, concluding that randomization does not lift experimental procedures in the medical and social sciences to the level of classical experiments in the natural sciences but may lull researchers into a false sense of security instead [460]. Both Saint-Mont and Penston stressed the importance of the existence of sound background theory as crucial for the success of science. Theory allows for stricter definitions of concepts and the identification of homogeneous reference classes that ensure regularity and, hence, reliable causal inference. In the context of COVID-19, the FLCCC appeared to present their conclusions more in the context of background theory (especially the MATH+ protocol [77]), while most others appeared to relymore on statistics.
An alternative or adjunct to RCTs to investigate could be causal modeling [461];[462];[463];[464]. According to Sgaier et al., causal modeling allows testing for causality in individuals and population groups faster and more efficiently, along with the ability to unravel the underlying complexity, and allows researchers and program designers to simulate an intervention and infer causality by relying on already available data [461]. Karvanen has provided examples of causal models for a case-control study,a nested case-control study, a clinical trial and a two-stage case-cohort study [463].
Journalistic ethics
With regard to journalistic ethics, the censorship discussion of April 11 appeared to indicate that journalistic principles that should have been self-evident no longer were, such as the responsibility of the media “to tell the truth” [165]. As described already for the period preceding April 2021, the financial press (e.g. the Wall Street Journal [163] and the Financial Express [171]) seemed to be more in favor of repurposed medicines, whereas the generalist press mostly continued to ignore or oppose them [217]. MacLeod has written about practices of the mass media in the United States, stating that corporate shareholders have no interest in the veracity of the news, only in short-term profits, and that reporting that challenges corporate profits is strongly discouraged [465]. A key factor shaping the content of the media is its reliance on advertising from large businesses for revenue. Advertisers wish to appeal to the groups and individuals with a greater spending power and to avoid controversial and critical content. Also, the collapse in advertising revenue in the traditional media has led to an increasing dependence on official sources, government and corporations which effectively subsidize the media by providing free content but expect something in return. In addition, in many cases, journalists are preselected based on their obedience to authority and their credulousness, and they increasingly come from the elite themselves [466]. The media houses also depend on social media for visibility which may be easily denied of them. Yet another factor are ideologies which in the United States were traditionally anti-communist but more recently anti-Trump and anti-Russian, for example. In the US media, ivermectin was often associated with hydroxychloroquine, and hydroxychloroquine with president Trump [467].
The dismissal of ivermectin in the press appeared to be related to the Trusted News Initiative (TNI) founded by Associated Press (AP), Agence France-Presse (AFP), British Broadcasting Corporation(BBC), Canadian Broadcasting Corporation (CBC), European Broadcast Union (EBU), Facebook, Financial Times, First Draft, Google, YouTube, The Hindu, Microsoft, Reuters, Twitter and Washington Post [321]. TNI appeared to function as some kind of peer-to-peer structured censorship mechanism.
Social media fact-checkers
In its COVID-19 medical misinformation policy, YouTube explicitly forbade treatment misinformation including “content that recommends use of ivermectin or hydroxychloroquine for the treatment of COVID-19” and “claims that ivermectin or hydroxychloroquine are effective treatments for COVID-19” [468]. The policy forbade also a large amount of peer-reviewed medical publications, in effect making YouTube an anti-science organization.
In a similar manner the policy forbade “prevention misinformation”, explicitly defined as “content that promotes prevention methods that contradict local health authorities or WHO”, specifically mentioning“content that recommends use of ivermectin or hydroxychloroquine for the prevention of COVID-19”. It also explicitly disallowed discussions of efficacy and possible adverse effects of vaccines which “contradict expert consensus from local health authorities or WHO”. Also diagnostic, transmission, social distancing and self-isolation information contradicting local health authorities or WHO were banned. The definitions of “expert” and “consensus” remained undefined, making the policy arbitrary, subsequently making YouTube an unpredictable promoter and enforcer of possibly arbitrary or authoritarian practices. In addition, technically, where local health authorities and WHO disagreed, application of the “or” operator banned content contradicting with either of them. Therefore in countries such as Slovakia and India,YouTube could not be used for content that recommended either for or against ivermectin for prophylaxis of COVID-19.
Clarke mentioned that YouTube and Facebook were relying on third party fact checkers funded partly by Charles Koch Institute [373];[374];[372]. Koch was listed as one of the 18 major funders of Poynter Institute, each with an undisclosed sum of at least USD 50,000, making it impossible to compare funders’ contributions [469];[470]. The International Fact-Checking Network (IFCN) is a unit of the Poynter Institute [471]. In May 2020, Facebook stated that all of its fact-checking partners were certified byIFCN [472]. IFCN stated it led an alliance of over 100 fact-checkers [473]. Poynter Institute described that the alliance was launched in January in response to “rampant misinformation globally” which the WHO classified as an “infodemic”, with the alliance “on the front lines in the fight against it”.
IFCN and the alliance also maintained a database of checked facts [474]. The database was updated daily, with members collaborating on the “massive crowdsourcing project” by using a shared spreadsheet and instant messaging apps. Poynter said the international collaboration had allowed the members to respond faster and reach larger audiences. All of the over 80 items found in the database with search term “ivermectin” dated between April 2020 and May 2021 were labeled either as no evidence, unproven, exaggerated, misleading, missing context, partly false, or false (the most common label), with two items labeled as explanatory [474]. Most of the items originated from South American partners such as Estadão Verifica in Brazil.
Some of the other major funders of Poynter included Facebook, Google News Initiative [475], Foundationto Promote Open Society (FPOS) of George Soros, a primarily US government funded agency National Endowment for Democracy (NED) [476], Democracy Fund created by eBay founder Pierre Omidyar, funding especially PolitiFact [477], and the Omidyar Network/Luminate also of Omidyar, Craig New-mark Foundation of Craigslist founder Craig Newmark, with at least USD 6 million donated to PoynterInstitute [478], and Rita Allen foundation involved in medical research, with its stated goal of “investing in transformative ideas in their earliest stages to promote breakthrough solutions to significant problems” [479].
It was of note that the major funders of Poynter included several individuals who were billionaires. Assumedly, they may have possessed influence over guidelines for what qualified as “facts”. While there was not enough information to ascertain whether the observed patterns of social media censorship were related to the values and previously observed practices of the any of the funders specifically, it was also not possible to rule out such influences.
An example may illustrate what kind of issues may arise from the use of donations as a tool for gaining political influence. With regard to funding by Koch, a report by Mayer in the New Yorker described the Koch brothers as “longtime libertarians who believe in drastically lower personal and corporate taxes,minimal social services for the needy, and much less oversight of industry .. . their combined fortune of thirty-five billion dollars is exceeded only by those of Bill Gates and Warren Buffett . . . many of the organizations funded by the Kochs employ specialists who write position papers that are subsequently quoted by politicians and pundits. David Koch has acknowledged that the family exerts tight ideological control. ‘If we’re going to give a lot of money, we’ll make darn sure they spend it in a way that goes along with our intent .. . and if they make a wrong turn and start doing things we don’t agree with, we withdraw funding’ ” [480];[481].
A republican political consultant commenting Kochs’ strategies for opposing climate change related oil industry reforms said that “the key .. . was to question the science – a public-relations strategy that the tobacco industry used effectively for years to forestall regulation”. As an example of health related interests, David Koch had served on the US National Cancer Advisory Board without disclosing his conflicts of interests as a major producer of formaldehyde, while simultaneously lobbying to prevent theUS Environmental Protection Agency (EPA) from classifying formaldehyde as a carcinogen, and funding members of Congress who had stymied the EPA, requiring it to defer new regulations until more studies would be completed.
Mayer’s article described Kochs’ operations as “covert”, referring to David Koch’s description of their businesses as “the largest company that you’ve never heard of”. According to Source Watch, in addition to denying climate change, other issues on the Kochs’ agenda included repealing health reform Obamacare), dismantling collective bargaining rights, fighting reductions in carbon emissions, keeping corporate money in elections and fighting internet neutrality [482];[483]. With regard to COVID-19, Koch Industries were producing test kit materials, sanitizers, alerting systems, healthcare IT systems related to COVID-19diagnostic testing, ventilators, and personal protective equipment [484].
Poynter’s largest custom training partners in 2019-2021 included Facebook, Huffington Post, Market-place, MRC Media, Middle East Broadcasting Networks, National Public Radio (NPR), Newsweek, New York Times, Southern Newspapers Publishers Association, Washington Post, TikTok, USA Today Network, Vice and Voice of America [469].
Academic journals
Regarding the academic journal publisher Frontiers Media SA’s, one of the members of its board of directors responsible for the financial and governance oversight of the company was Steve Koltes, founder and co-chairman of CVC Capital Partners Ltd [485]. In 2019, CVC Capital Partners, one of the world’s largest private equity and investment advisory firms, was said to have USD 75 billion of assets under management [486]. CVC announced that a group of its executives had helped fund University of Oxford’s vaccine research [487];[488]. CVC had also invested in System C, a company providing key software being used for planning and managing the UK’s COVID-19 vaccination programme [489]. The Times described CVC as “powerful, successful and extremely low profile” [490].
In 2015, Frontiers had removed 31 editors after the editors had complained that company staff were interfering with editorial decisions and violating core principles of medical publishing [491].
The WHO
During the period, an intensifying critique of the WHO emerged as a result of the March 2021 ivermectin guideline lacking transparency and breaking established practices of meta-analysis and research.Presenting criticism towards the feasibility of the vaccines-only approach and its possible relationship to financial interests of the pharmaceutical industry, or possible failures of entities such as WHO, FDA,NIH and EMA, has been difficult during the pandemic. Regardless, it is necessary to consider whether funding-related biases might exist with regard to the current practices of these agencies, especially the WHO.
First we may note that the main funders of the WHO for the 2018/2019 biennium were United States(USD 893 million), Bill and Melinda Gates Foundation (USD 531 million), United Kingdom (USD435 million), Gavi The Vaccine Alliance (USD 371 million), Germany (USD 292 million), Japan (USD214 million), UN Office for the Coordination of Humanitarian Affairs (UNOCHA) (USD 192 million),Rotary International (USD 143 million), World Bank (USD 133 million), European Commission (USD131 million), National Philanthropic Trust (USD 108 million), Canada (USD 101 million), China (USD86 million), Norway (USD 86 million), UN Central Emergency Response (USD 86 million), Sweden (USD77 million), France (USD 76 million), Kuwait (USD 70 million), Republic of Korea (USD 70 million) and Australia (USD 67 million) [492];[493];[494].
The Bill and Melinda Gates Foundation stated that its focus was on vaccine equity [307]. Also Gavi The Vaccine Alliance had been founded by the Bill and Melinda Gates Foundation in 1999, and the Gates foundation had invested a total of USD 4 billion in Gavi [495]. Gavi described the Gates foundation as“a key Gavi partner in vaccine market shaping”. The Gates Foundation also had long-term partnerships with Rotary International (polio vaccinations), National Philanthropic Trust, and the World Bank. Together, the USD 902 million contributions of the Gates Foundation and Gavi exceeded the United States contributions of USD 893 million, making the Gates-Gavi cluster the largest funder of the WHO in the2018/2019 biennium (in April 2020, president Trump announced that US halted funding to the WHO; the effects of this remained unclear [496];[497]). In addition, the Global Fund to Fight AIDS, Tuberculosis and Malaria (GFATM) contributed 33 million. Co-founded by the Bill and Melinda Gates Foundation in 2002, the foundation has contributed a total of USD 2.49 billion to GFATM [498]. Considering the recent USD 4 billion donation by the United States government to Gavi [89], one interpretation of the situation might be that the US outsourced a large part of its public health policy setting to Gavi and, subsequently, to Gates.
Yet another member of the Gates cluster was the Seattle-based PATH (Program for Appropriate Tech-nology in Health), one of the largest nonprofit organizations in global health [499]. In 2021, its website presented with a banner saying “600 million people are vaccinated. 7 billion haven’t had a shot. Help PATH today”. PATH’s CEO Nikolaj Gilbert, previously the global partnerships director for the United Nations Office for Project Services (UNOPS) and an employee of Novo Nordisk, described PATH’s priorities: “the partnership with the Bill and Melinda Gates Foundation and the U.S. government has shaped what this organization is all about today .. . so one of my key priorities will be to see: how can we sustain and grow those relationships that we have, how can we continue to be the preferred partner for those donors, and how can we also help them with their priorities?” [499].
A 2017 Politico article described Gates as “the world’s most powerful doctor”, saying his sway over the WHO spurred criticism about misplaced priorities and undue influence [500];[501]. The article quoted Gates’ critics saying that “Gates’ priorities have become the WHO’s . .. he is treated liked a head of state,not only at the WHO, but also at the G20”. Top WHO officials were said to have raised concerns that the foundation was distorting research priorities. Over three quarters of the WHO’s budget was coming from voluntary contributions which were usually earmarked for specific projects or diseases so that the WHO could not freely decide how to use them. The article stated that the Gates foundation’s focus on delivering vaccines and medicines, rather than on building resilient health systems, had drawn criticism.Changes had been made to the WHO’s budget approval process to in order to decrease the foundation’s influence. Yet a senior fellow for global health at the Council on Foreign Relations commented that “the foundation’s impact on the WHO is enormous . . . if they weren’t there, if they walked away with their money, the deleterious impact would be profound, and everyone is all too aware of that”.
Importantly, it should also be noted that the other top 20 funders predominantly represent high-income countries of the North America and Europe. None of the countries that had officially adopted ivermectin country-wide for COVID-19 up to April 2021 were represented [502]. Similarly, Coalition for Epidemic Preparedness Innovations (CEPI), an organization aiming to accelerate the development of vaccines against emerging infectious diseases and enable equitable access to these vaccines for people during outbreaks was founded by the governments of Norway and India, Bill and Melinda Gates Foundation, UK Wellcome Trust, and the World Economic Forum [503]. It had later secured financial support from Australia, Austria, Belgium, the Bill and Melinda Gates Foundation, Canada, Denmark, the European Commission, Ethiopia, Finland, Germany, Hungary, Iceland, Indonesia, Italy, Japan, Kuwait, Lithuania, Luxembourg, Malaysia, Mexico, Netherlands, New Zealand, Norway, Panama, Romania, Saudi Arabia,Serbia, Singapore, Switzerland, The Republic of Korea, United Kingdom, USAID, and UK Wellcome Trust. Of these countries, as of June 2021, ivermectin had been officially adopted in Mexico, Panama and Indonesia, as well as mixed use or occasional off-label use in some other countries [502].
Additionally, CEPI had received support from undeclared private sector entities as well as public contributions through the UN Foundation COVID-19 Solidarity Response Fund [503]. Each investor was to get one representative to an Investors Council providing guidance and oversight of CEPI activities, with four members serving on the CEPI board. Another entity, a Joint Coordination Group, was intended to discuss how to best enhance CEPI’s efforts to deliver and deploy vaccines, and had a role in planning for rapid response to a priority pathogen or an unknown pathogen. The Joint Coordination Group included the WHO, Gavi, European Medicine Agency (EMA), United States Food and Drug Administration Agency (FDA), Médecins Sans Frontières (MSF), UNICEF, International Federation of Red Cross and Red Crescent Societies (IFRC), African Vaccine Regulatory Forum (AVAREF), UK National Institute for Biological Standards and Control (NIBSC) and UK Wellcome Trust.
The Wellcome trust had been previously found out to secretly invest in companies that contributed to the same problems the trust said it wanted to solve [504]. The trust’s known investments through offshore companies in the Cayman Islands amounted to USD 891 million in 2018.
In 2010, the Bill and Melinda Gates Foundation, Gavi, WHO, US NIH/NIAID, CDC, UNICEF, PAHO and several research organizations launched a Decade of Vaccines collaboration, initiated by the Gates Foundation [505]. The intention was to enable greater coordination across all stakeholder groups – national governments, multilateral organizations, civil society, the private sector and philanthropic organizations. The five-member leadership council included the director general of WHO, Anthony S. Fauci of the National Institute of Allergy and Infectious Diseases (NIAID), executive director of UNICEF, an representative of African Leaders Malaria Alliance, and the president of global health at the Bill and Melinda Gates Foundation. All the relevant organizations had thus intimately and for the long term participated in the vaccine-centric collaboration initiated by Gates.
According to a recent study, in 2020, governments had spent a total of EUR 93 billion on COVID-19 vaccine and therapeutics development projects, with 95% allocated to vaccines and 5% on therapeutics [506]. 32% of the funds came from the US, 24% from the EU, and 13% from Japan and SouthKorea (a total of 69%). Only 7% of funds were preferred loans or conventional grants. 93% were advance market commitments (AMCs), i.e. binding agreements to subsidize purchases of vaccine doses prior to availability. Interestingly, 71% of the vaccine funding was allocated to Small and Medium Enterprises(SMEs) and MidCaps, with only 18% allocated to large pharmaceutical manufacturers. The figures did not include private sector investments.
The Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) public-private partnership program initiated by the US National Institutes of Health aimed at developing a coordinated research strategy for prioritizing and speeding development of the most promising treatments and vaccines [228]. Its public partners included Biomedical Advanced Research and Development Authority (BARPA), Centers for Disease Control and Prevention (CDC), Department of Defense, Department of Veterans Affairs,European Medicines Agency (EMA), National Institutes of Health (NIH), The Operation (formerly known as Operation Warp Speed), and US Food and Drug Administration (FDA). Industry partners included AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Dewpoint Therapeutics, Eisai, Eli Lillyand Company, Gilead, GlaxoSmithKline, Johnson & Johnson, Merck & Co/MSD, Moderna, Novartis,Novavax, Pfizer, Rhythm Therapeutics, Roche-Genentech, Sanofi, Takeda, and Vir Biotechnology. Nonprofit partners included Bill and Melinda Gates Foundation, Fred Hutchinson Cancer Research Center,Foundation for the National Institutes of Health, and RTI International.
According to the International Federation of Pharmaceutical Manufacturers & Associations (IFPMA), as of February 2021, there were approximately 382 vaccine candidates in development, of which 24 in Phase I, 34 in Phase II and 23 in Phase III [507]. In addition to vaccines, there were over 1,000 clinical trials for therapeutics, of which 190 in Phase III. For example, Eli Lilly and Company and the Bill and Melinda Gates Foundation had entered into an agreement to facilitate access to future Lilly therapeutic antibodies under development, to benefit low- and middle-income countries.
Bill and Melinda Gates Foundation
According to Schwab, in five years up to 2020 the Gates Foundation had invested at least USD 250 million in companies that were currently working on COVID-19 vaccines, therapeutics, diagnostics or manufacturing [508];[509]. He also noted that Wellcome Trust had invested at least USD 1.25 billion to COVID-19 related industries [510]. Both funders were thus positioned to potentially gain from the pandemic financially. Wellcome’s director had a position on the Scientific Advisory Group for Emergencies advising the UK government on COVID-19, as well as a board seat on the Coalition for Epidemic Preparedness Innovations (CEPI). Earlier, the UK’s Scientific Advisory Group for Emergencies had failed to publicly disclose competing interests related to COVID-19. A Canadian professor emeritus of health policy and management commented that the funders were assumedly “acting the way they always have .. . looking after their own financial interests [and] pursuing their own privately developed objectives without being responsible to anybody but their own boards of directors”. Schwab said that despite the outsize role of the private charities in the pandemic response their financial interests had been little scrutinized, likely because foundations were not subject to the same oversight mechanisms as public institutions. A professor of sociology in the UK commented that the foundations were giving a false ideological impression that they are solving the problem even when they’re not.
The Gates foundation had also donated almost USD 2 billion to for-profit businesses, including USD 89 million to Novavax Inc., USD 65 million to GlaxoSmithKline Biologicals, USD 63 million to Evotec and Just Biotherapeutics, USD 61 million to Biologial E. Limited, USD 53 million to LG Chem Ltd., USD43 million to Dimagi Inc, USD 40 million to Inventprise, USD 38 million to Bharat Biotech International Ltd., USD 37 million to Janssen Vaccines and Prevention BV, and USD 35 million to AJ VaccinesAS [510]. Schwab claimed the foundation was subsidizing private companies’ research costs, opening up markets for their products, and bankrolling their bottom lines. He also claimed the foundation had funded groups pushing for industry-friendly government policies and regulation, including the Drug Information Association. He was also said to have funded nonprofit think tanks and advocacy groups that wanted to limit the role of government or direct its resources toward helping business interests. Schwab also noted that despite having given away USD 23.5 billion in the last five years up to 2020, Bill and Melinda Gates Foundation’s income from its investments had exceeded USD 28.5 billion in the same period [510].
Other commentators asked whether the Gates Foundation was addressing or reinforcing systemic problems raised by COVID-19, citing lack of transparency, dogmatic defence of intellectual property rights and monopolies, and intimate involvement with large pharmaceutical corporations as the main issues [511]. A 2016 report by Curtis gave details about Microsoft’s tax avoidance practices and its monopolistic nature, the foundation’s excessive global influence and support to various questionable practices including industrial agriculture with patented genetically modified seeds, Gates family’s “considerable personal access to senior levels of the WHO”, Gavi’s alleged overpaying for vaccines leading to excessive increases in vaccine prices, Gates’ dismissal of the issue, and the foundation’s agenda skewing health priorities and distorting health programmes [512]. Curtis wrote that one problem with the foundation’s heavy focus on developing new vaccines was that it detracted from other, more vital health priorities such as building resilient public health systems. As a rationale, Gates was said to have provided the following: “Vaccines are an extremely elegant technology. They are inexpensive, they are easy to deliver, and they are proven to protect children from disease. At Microsoft, we dreamed about technologies that were so powerful and yet so simple.. . all 193 member states, you must make vaccines a central focus of your health systems”. Curtis commented that Gates had “a fixation on vaccines”. He also claimed the foundation was stifling criticism through its media and NGO influence built on donations. An US professor of media, culture and communications was quoted saying the foundation “wielded enormous propaganda power”. A 2009 editorial in the Lancet, describing the foundation’s governance principle of being “driven by the interests and passions of the Gates family” as “whimsical”, proposed that the foundation should be more transparent and accountable and listen to opinions of external parties [513];[514].
In April 2020, the Bill and Melinda Gates Foundation awarded a five-year grant of USD 50 million to Unitaid to fight against HIV, tuberculosis and malaria, in addition to previous contributions of USD 100 million since 2006. Unitaid’s budget for the year 2021 was approximately USD 32 million [515]. In late 2020, Unitaid partially funded the ivermectin meta-analysis by Hill et al. published as a preprint [16].This meta-analysis was later ignored by the WHO in its March 2021 decision against the use of ivermectin except in clinical trials [6]. On April 22, the chief of Unitaid stressed the need to increase commercialresearch and development of new pharmaceuticals for the treatment of COVID-19 [242]. A core function of Unitaid is Medicines Patent Pool, a tool or practice to negotiate patents for low-income countries; this emphasis may have made unpatentable products seem foreign to the organization [516];[517]. Gates foundation was the chair of Unitaid’s Finance and accountability committee and a member of its policy and strategy committee [518].
Comparing the countries most heavily involved in the development and funding of vaccines to the countries with interest in ivermectin it can be noted that the two sets of countries have little overlap. Also, it can be noted that if influence is related to the amount of funding given, the first set of countries likely had more influence in the WHO in comparison to the rest of the countries.
The WHO, the philanthropic entity Bill and Melinda Gates Foundation, the public-private partnership Gavi, The Vaccine Alliance, and the philanthropic-commercial entity CEPI appeared to be strongly interconnected with each other and with high-income nation states. Major financial investments and commitments likely created propensities for various biases and a vulnerability to the sunk cost fallacy [519]. A haphazard or ideological commitment solely to vaccines (95% of government spending) may have overlooked considerations of cost-effectiveness and feasibility, such as vaccines likely being more expensive and more vulnerable to viral variants than repurposed medicines, their long-term safety being unclear, and vaccines likely requiring constant redevelopment and revaccinations, in addition to not being suitable for self-administration and requiring refrigerated delivery systems. With regard to the sunk cost fallacy, it would be more economical for the governments to reconsider the vaccine and investigative pharmaceuticals dominated pandemic policy and at least adjunct it with broad-spectrum repurposed medicines.
Comparisons to the H1N1 pandemic
After the H1N1 ‘swine flu’ pandemic of 2009-2010, the WHO was accused of malpractice when conflicts of interests of key WHO scientists led to unfeasible WHO recommendations which in turn led to billions of public money spent on inefficacious antivirals for H1N1 influenza [520];[521];[522];[523]. In her book, Abeysinghe has written about the role of the WHO [524]. A review by Andres summarizes keypoints, including the monopoly of the WHO to declare a pandemic [525]. In the case of H1N1, WHO was retrospectively criticized for unnecessarily declaring a pandemic, as for example the European Centre for Disease Control (ECDC) did not agree that the disease should be qualified as severe (measured by mortality), which at the time was considered a requirement for a pandemic but is no longer mentioned. At the time, an epidemiologist commented that the WHO, public health officials, virologists and pharmaceutical companies had “built this machine around the impending pandemic . . . there’s a lot of money involved, and influence, and careers, and entire institutions .. . all it took was one of these influenza viruses to mutate to start the machine grinding” [526].
WHO was later criticized by the Council of Europe for giving too much importance to vaccination and for not sufficiently emphasizing other measures such as the use of antivirals even though some arguments suggested that other measures, such as taking antivirals preventively, could be at least as efficacious as vaccines [525];[521];[522]. WHO emphasized mass vaccination as the most effective strategy against H1N1 [524]. According to Abeysinghe, this emphasis was a result of the path-dependent institutional reaction of the organization, where prior experience with infectious disease (including notable victories using mass vaccination strategies) resulted in the favoring of this reaction, whereas other potential actions were disregarded or underemphasized.
In June 2010, the rapporteur of Council of Europe Parliamentary Assembly described the acts of the WHO as foolish, saying “this is not going to go away” [524]. The rapporteur assumedly meant the criticism was not going to go away; yet it appears instead that the organizational patterns did not go away, leading the WHO and the national governments to repeat the same issues a decade later in theCOVID-19 pandemic.
Legal responsibility of public-private partnerships and the WHO
Clarke has noted that the regulation of global health has partially shifted from the hands of states and international organizations into the hands of public-private partnerships such as Gavi, The Vaccine Alliance and the Global Fund [527];[528]. These partnerships then become capable of also adversely impacting the rights of individuals, leading to concerns of responsibility under international law. However, the private entities in public-private partnerships typically fall outside the framework of responsibility under international law, and thus cannot be held responsible under it. In addition, in certain instances the partnerships have been granted immunity from the jurisdiction of domestic courts. This immunity applies to the staff, funds, properties and assets of these partnerships. The situation regarding Gavi andthe Global Fund appeared especially complicated and the legal details were therefore considered out of the scope of this review.
With regard to the WHO, Gostin has described WHO’s regulatory powers as extraordinary, noting that it may set regulations on a broad range of health topics including the safety, potency, and advertising of biologicals and pharmaceuticals, and a nomenclature for diseases, causes of death, and public health practices [529];[530]. These regulations, unlike most international law, are binding on member states unless they proactively “opt out”. In addition, also the WHO enjoys several privileges and legal immunities. Regardless of the original purpose of these privileges, the possibility of abuse of these privileges by the WHO also exists. Also here the details were considered out of the scope of this review.
Private philanthropy, society and science
In his recent book, Callahan discussed the role of private philanthropy, noting the rising influence and political significance of elite philanthropy, asking who is making choices over public life and who actually benefits from those choices [531]. Callahan described “today’s era of austerity” as a result of an orchestration of the upper class to reduce its taxes and the size of government, even so that in some US states, cuts to higher education specifically helped finance tax reductions for the wealthy and corporations. He noted that in a decade, Bill Gates and Warren Buffett, the main funders of the Bill and Melinda Gates Foundation, had added USD 25 billion and USD 80 billion, respectively, to their wealth, and that the Koch brothers had increased their wealth from USD 9 billion in 2005 to USD 85 billion in 2015.In a book review, Saunders-Hastings asked whether elite philanthropists are a counterweight to other, self-interested elites or to democracy itself, and noted that the distance between elite “charity” and elite political influence is small and shrinking, and that donors’ motivations matter less than the results of their actions [532].
Broad wrote that due to cuts to public funding and increase in private donations, “American science, long a source of national power and pride, is increasingly becoming a private enterprise” and quoted a policy analyst commenting that “the practice of science in the 21st century is becoming shaped less by national priorities or by peer-review groups and more by the particular preferences of individuals with huge amounts of money” [533].
Callahan proposed putting some curbs in place against the private philanthropy, yet noted that foundations and nonprofit trade groups are strongly against any new restrictions, partly due to their dependency on philanthropy. He noted that “rethinking philanthropic freedom is a Pandora’s box that almost nobody wants to open”, saying the current situation was a result of “yesterday’s mantras about philanthropic freedom and the dated regulation upholding it”.
Vaccines vs repurposed medicines
In Finland, a team led by two leading Finnish professors, Kari Alitalo and Seppo Ylä-Herttuala, had a patent and intellectual property free adenovirus-based nasal spray COVID-19 vaccine ready in May 2020. Despite taking approximately EUR 18 billion of public debt to mitigate damages caused by societal lockdowns and using hundreds of millions of Euros on diagnostic tests only, the Finnish government refused the approximately EUR 50 million needed to fund a phase III patient trial for the vaccine [534];[535].
The above case illustrates that the issue at hand is fundamentally not even about vaccines versus repurposed medicines or new pharmaceuticals versus repurposed medicines. Based on this data it is difficult to say whether it is about excessive adherence to inflexible regulations, subconscious biases present in corporate cultures and individuals, intellectual property enforcement, or intentional misleading for profit; likely, it is a mixture of all these factors. Personal biases, organizational cultures and commercial incentives of the vaccine cluster may have lead to attempts to build near-monopolies mass-producing proprietary but inferior products that outcompete more feasible alternatives. In Finland, significantly less interest has been present for any repurposed medicine than for the patent-free vaccine, with the sole exception of the company which developed the ivermectin-containing nasal spray not yet on the market [356].
More generally, the situation may partly be a result of the unprepared and rushed way in which the pandemic has been handled by the governments. Assumedly, from the perspective of governments with 95% of their funding committed to vaccines and international co-operation led by the WHO, paradigm change inducing innovations from outsiders may be perceived as unwanted disturbances. Considering these paradigms, the dismissal of ivermectin might be perceived as cultural discrimination, an instinctive reaction to avoid unfamiliar ideas. As a result of the chosen policy of vaccines and new pharmaceuticals only, in order to avoid losing the sunk costs and credibility, the interests of the governments and the pharmaceutical industry appeared to align with each other but likely not with the public health interest.
The concept of “regulatory capture” may be described as the agencies tasked with protecting the public interest coming to identify with the regulated industry and protecting its interests against those of the public, with the result of government failing to protect the public [536]. Whether rejection of ivermectin may be seen as an example of “regulatory capture” depends on how the vaccines-only policy was selected: primarily to align with the interests of the pharmaceutical industry, or because a better option could not be imagined. Curiously, options could be imagined early on in many low-income countries, but not in the high-income countries, possibly as a result of “technological capture”: when access to advanced technology exists, every problem looks like a problem to be solved with advanced technology, even though such solutions would be suboptimal due to being overly complex and unnecessarily expensive. For example, the idea of spending tens of billions of dollars per year for testing 20 percent of the global population every week assumedly for a single pathogen (SARS-CoV-2) appeared irrational at best [89]. Gates’s speeches repeated terms such as “war and “battle plan” [537]; these talks may easily be interpreted as priming fear in the public. Gates is also famous for regularly predicting the next pandemics [538].
Since the beginning of 2021 at the latest it should have been obvious that the continuing denial of early treatments could not be characterized either as accidental or as a rational choice with respect to public health interest. During the pandemic, a large part of the medical community seemed incapacitated like an old-fashioned military unit lacking leadership. The model based on the fear of losing medical license and an inflexible hierarchical chain of command appeared unsuitable for ensuring proper care of populations.While denial of treatments for certain illnesses such as drug addictions, post-traumatic stress disorder or “treatment-resistant” depression for years or decades for example by denying funding for the research of psychedelic therapies has become normalized, it was unexpected that in the case of COVID-19 this antisocial behavior on behalf of governments and the pharmaceutical industry would be extended to literally everyone in the world. In a comment suggesting adoption of ivermectin, a patent attorney and a former director of a pharmaceutical company referred to “potential civil/criminal liability for censorship, scientific misconduct for misrepresenting ivermectin and other generics” [387].
The exact causes of the situation remained unclear. Regardless, the consequences remain to be seenand felt. One way forward might entail the majority of governments halting their funding to the WHOin order to dissolve the whole organization which appeared beyond repair. Another necessary changemight be the eviction of the so-called philanthropic entities from healthcare contexts. In the long term,another beneficial action might be a worldwide conversion of the pharmaceutical industry into a nonprofit operation. Continuing on the current path may result in a further polarization or destabilization of societies.
Near-future objections to adoption of ivermectin will undoubtedly include the possible environmental impacts. In the mid-to-long term, due to the need to reduce water usage and enable better retention of nitrogen, phosphorus and ammonia [539], transition from water based sewer systems to toilet systems not using water and not requiring wastewater processing but utilizing for example composting and new kind of treatments to degrade pharmaceuticals will become inevitable in many areas in any case.
Conclusions
During this period, ivermectin was officially adopted in South Africa but not widely used, adopted but later dropped in most of India, and adopted in Indonesia. In the United States and the United Kingdom, projects with involvement of both the governments and commercial companies were announced for development of new pharmaceuticals for early outpatient treatment of COVID-19, indicating unclear boundaries between these entities. The dismissal of repurposed medicines including ivermectin continued in high-income countries due to very differing views on what constituted evidence of efficacy. The divide between ivermectin proponents and opposers remained mostly unchanged during the period, indicating a stagnated situation.
There was a noticeable centralization of power, with pandemic response and public discussions largely directed by a few organizations that were largely funded by a few billionaires which, in turn, were affectedby their own personal preferences and biases such as obsessive-compulsive attachment to testing and new technologies, primarily vaccines. Legal responsibilities of these organizations appeared, in the words of one researcher, “obscure”.
Commercial interests appeared to override public health interests during this period. As a result, several low-and-middle-income countries and regions either implicitly or explicitly disregarded the WHO guidance, accelerating an erosion of WHO’s credibility.