Discussion

We compared the quality of evidence on the use of ivermectin to treat COVID-19 with the timing of announcements on the mass distribution of ivermectin as part of COVID-19 kits by eight governments in Latin America. We found that all eight governments initially decided to distribute COVID-19 kits to their populations despite the scarcity of high-quality evidence on the efficacy of ivermectin for prevention, hospitalisation, and mortality in COVID-19 patients. In fact, only one RCT (which had ‘risk of bias’) in favour of using ivermectin had been published when seven of the eight governments made their distribution decisions. The eighth, Mexico City, announced the use of ivermectin after seven RCTs had been published; all of those studies presented ‘risk of bias’” only three had reported favourable results, and one was later retracted. Furthermore, the large majority of RCTs published by April 2022 were not directly relevant to the question of whether mass distribution of ivermectin to treat COVID-19 was effective in preventing hospitalisations (which was the stated purpose of distributing kits to the population).

Our findings are highly concerning for several reasons that range from clinical to political. First, in 8 (25%) of the 33 Latin American countries, local or national governments made decisions that exposed hundreds of thousands of individuals to ivermectin for the purpose of prevention or treatment of COVID-19 despite a lack of clinical evidence. Furthermore, at the time of the mass kit distributions, none of these countries’ medicines regulatory authorities had either reviewed or approved applications from manufacturers for market authorisation of ivermectin for the indication of prevention or treatment of COVID-19. There is a large body of bioethics literature on the precautionary principle, which means that a proactive approach is needed to risk mitigation in the face of serious and irreversible threats to human health and the environment amid scientific uncertainty.37 For instance, in relation to the SARS outbreak in Canada in the early 2000s, the Commission to Investigate the Introduction and Spread of SARS in Ontario concluded that the precautionary principle was one of the most important lessons learnt from the outbreak concluding ‘[…]to err on the side of caution when dealing with a little understood new disease’.38 Most importantly, the precautionary principle urges researchers, policy-makers, and the public to make decisions based on the weight and credibility of evidence rather than awaiting elusive scientific certainty.37 In this study, we used GRADE to assess the weight and credibility of evidence available at the time and concluded that the evidence had low credibility and weight to justify the use of ivermectin. Furthermore, at the time the countries made decisions on the use of ivermectin as part of COVID-19 kits, international organisations, including the Pan American Health Organization (PAHO), concluded that ‘there is insufficient evidence to draw a conclusion on benefits and harms. The effectiveness is being evaluated in various randomised clinical trials’39 and ‘the use of medications such as ivermectin, antivirals, and immunomodulators, among others, should be done in the context of patient consented, randomised clinical trials that evaluate their safety and efficacy’.40 Unfortunately, many clinical trials studying the effects of potential treatment of COVID-19 were not randomised, significantly limiting their scientific value41 or, in the worst cases, not adhering to best clinical trial practices.42

Second, despite the low quality of evidence on the efficacy of ivermectin with COVID-19, many government officials, including heads of state, claimed that the COVID-19 kits contained medications that had been shown to be effective and safe for the prevention or treatment of COVID-19. Some mentioned that the medication is ‘mild’ or that ‘there is no reason to fear’ the medicines included in the COVID-19 kits. Several government officials added that the medicines have to be taken ‘in a timely manner’ or ‘taken on time’. The information releases by the Honduran Ministry of Health went even so far as to claim that the kits reduced viral load by 90%. However, the analysis of the scientific publications does not corroborate any of these claims. These public statements and justifications by authorities may have contributed to the erosion of trust in governments that have characterised the COVID-19 pandemic; this lack of trust will likely continue to have long-term effects on the acceptance of other future health interventions.4 43 44 For instance, experts in Brazil have noted that the population lost trust in the federal government due to a series of false and misleading statements about the safety of COVID-19 treatments.45 Re-establishing trust in governments is a complex endeavour. Moreover, in some countries such as Mexico, guidance on the use of medicines included in the COVID-19 kits at the national level contradicted the local level, further undermining the legitimacy of the government guidance. Whereas federal guidelines and declarations of high-rank health officials in Mexico aligned with PAHO recommendations against the use of ivermectin, the government of Mexico City distributed kits with ivermectin against national guidelines.44 The largest hospital network (Mexican Institute of Social Security (IMSS)) included ivermectin in its standard treatment guidelines46 and studied the effects on hospitalisation without the consent of those involved.47

Third, the large scale of COVID-19 kits distribution (in some countries, over a million) represents a waste of the limited resources available for health in general and COVID-19 in particular. For example, Mexico City invested a total of US$1 431 000 in kits,44 Brazil’s government under President Jair Bolsonaro spent more than US$16 million on COVID-19 kits,48 and Guatemala invested US$650 000 in 100 000 kits.6 These resources could have been invested in interventions that have been shown to be effective in preventing the overburdening of hospitals, such as e-health, where patients are monitored via phone calls and text messages at home.49 Similar inefficiencies related to the use of ivermectin occurred in the USA, although this was driven by individual prescribers, not government policy or decision-making.50 Indeed, it is noteworthy that a proposal by some politicians in the US state of Alaska to make it easier to dispense ivermectin was rejected on the advice of medical experts.51

Fourth, it is highly concerning that politicians without medical expertise facilitated and encouraged the population-wide use of an unproven treatment. While the impulse to ‘do something’ is understandable, at the time of the kit distribution, there were neither high-quality RCT results nor guidelines or recommendations from recognised international organisations such as the WHO to support ivermectin use.52 Other governments outside the Americans decided to support their population with the effects of COVID-19 by including tools for symptom relief (such as ibuprofen) and prevention-oriented devices such as masks, as was done in Japan.53 That is, it was possible for governments by the time of the distribution of the COVID-kits in May to make strong and symbolic gestures through mass distributions based on evidence54 without wasting resources and risking harm. Furthermore, this may have prevented other unintended consequences, such as the shortages of those medicines included in the COVID-19 kits that were essential to treat other diseases in which they had proven to be effective (eg, hydroxychloroquine for the treatment of rheumatological conditions).55

Fifth, our findings raise important questions about individual countries’ institutional capacities to appraise clinical evidence, as well as concerns about political influence on technical decision-making. The latter is particularly problematic when it is wielded in the absence of (or in defiance of) technical expertise when there is the potential to achieve political gains. It is noteworthy that, in six of the eight countries we studied, the heads of state—not technical experts such as the heads of public health agencies—announced the kit distributions. Preparing for future pandemics will require strengthening the capacities and public profiles of institutions dedicated to assessing health technologies and making recommendations about appropriate use.

We recognise that this study had limitations. We do not know whether policy-makers had access to other evidence that was not in the public domain. However, it could be argued that governments should be transparent about the scientific evidence that informs policy decision-making. Furthermore, this analysis did not examine the quality of scientific evidence available at the time of the decision regarding other medicines that the kit contained. However, international organisations, such as the PAHO, did recommend against the use of some of these medicines (eg, hydroxychloroquine) early on in the pandemic when decisions about the distribution of COVID-19 kits were made in the region.56 This study also focused only on correlating the timelines of scientific publications with public announcements of policy decisions. Answering more detailed questions about why and how countries made decisions to provide ivermectin in the absence of publicly available evidence was not within the scope of this initial study. It would be expected that countries take into consideration a variety of information sources to make their decision on the distribution of COVID-19 kits. It can be reasonably argued that governments should take into consideration, among other factors, information from RCTs on the efficacy of ivermectin in preventing hospitalisations. More qualitative policy research is needed to examine how the decisions were made in individual countries. Furthermore, comparative studies would provide important insights about why some Latin American countries did not disseminate either ivermectin or kits more generally.

Despite the limitations, however, this study shows that in the absence of clinical evidence on the efficacy and safety to prevent hospitalisation eight countries in Latin America decided to distribute ivermectin. It also raises many important questions about different approaches to governmental decision-making when there is insufficient evidence and significant social pressures to act.