Ivermectin: A Popular Science Story

Important efforts are now being made, which we fully support, to help the public become more knowledgeable about and involved with science. It is increasingly clear that misinformation spreads easily among people who are not fluent with the way science works and nearly everyone agrees that a scientifically literate public will help us overcome the alarming spread of mis- and disinformation about health and science we now face.

         Perhaps the most successful example of public advocacy for scientific research we have seen occurred in the 1980s and 1990s when a sluggish research system was pressured to take action to find the causes and treatments for the human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS). That advocacy effort undoubtedly convinced politicians to put more money into HIV research and energized researchers to enter the HIV research field, resulting in the discovery of effective treatments that have made the illness manageable and far less deadly than it was when the AIDS epidemic began.

         Yet we have not come to grips with how to handle the situation when a popular notion about some health topic grips people’s attention even though it may be wrong. The situation with the medication ivermectin is an example of the dilemma between wanting people to become involved in the scientific process and trying to prevent recommendations for actual medical interventions to be made before there is adequate scientific justification for them.

Ivermectin Is An Approved Drug

         Ivermectin can be prescribed in different forms by physicians and veterinarians. The U.S. Food and Drug Administration (FDA) approved ivermectin for the treatment of two parasitic infections in humans, one called strongyloidiasis and the other called onchocerciasis (or river blindness).  It’s discoverers even won the Nobel Prize for their work. It can also be prescribed to people in a topical form for some skin conditions. Veterinarians prescribe it to prevent heartworms and other parasitic infections in animals.       

Ivermectin is an FDA-approved medication for the treatment of parasites in humans and animals. It is unclear at this moment whether it has any role in preventing or treating COVID-19 or any other viral disease.

         It turns out that ivermectin kills viruses in test tubes, including the virus that causes COVID-19, called SARS-CoV-2. That information made some scientists call for tests of the drug in animal models of COVID-19 and in people with the illness to see if the “in vitro” or test tube results might translate into benefit for humans. Almost immediately, however, scientists noted that the concentration of ivermectin needed to kill SARS-CoV-2 in test tubes was far higher than what is typically administered to people with the parasitic infections for which the drug is FDA approved. This raised the possibility that ivermectin could only work in people to treat COVID-19 if it were given in much higher doses than currently approved and that further raised multiple safety concerns.

         Finding that ivermectin does have in vitro antiviral activity does justify carefully studying the drug in humans to see if it could be a treatment for COVID-19, and studies have both been completed and are ongoing. An early clinical trial that was released as a pre-print before peer review showed that ivermectin dramatically reduced mortality rates, but the paper was withdrawn because of reported irregularities. Preliminary results from the large outpatient TOGETHER trial showed no benefits of ivermectin over placebo. Right now, there is a clear consensus among experts that there is insufficient evidence to warrant using ivermectin to prevent or treat COVID-19 in any of its manifestations. The FDA has warned the public against taking it for COVID-19.

Ivermectin and Public Discourse

Somehow, however, ivermectin has emerged into the popular media as a potential “cure” for COVID-19, even prompting legal action to force doctors to administer it. Social media commentators advise that ivermectin does work for COVID-19, either citing anecdotes or cherry-picking studies or both. Some have advanced a kind of conspiracy theory in which pharmaceutical companies are suppressing data that would support ivermectin because it is an inexpensive drug in order to promote the more expensive vaccines instead. The result is that patients with COVID-19 are requesting that their doctors prescribe ivermectin and some people have even resorted to taking veterinary ivermectin, apparently resulting in numerous instances of toxic reactions and calls to poison control centers.

         Physicians, perhaps chastened from their experience with hydroxychloroquine, another “miracle” cure for COVID-19 that achieved immense popular support but has proven ineffective against the illness in clinical trials, are understandably reluctant to prescribe ivermectin to patients regardless of their level of illness severity. Some have taken to making adamant statements that ivermectin categorically does not work for COVID-19.

         That absolute stance is also premature because there are a bevy of clinical trials of ivermectin for COVID-19 now in progress, some with results not expected for months. It is still possible that one or more of them will show a benefit for the drug. Remember that drugs can be tested to prevent the acquisition of COVID-19 or its treatment; they can be tested against mild, moderate, or severe disease; and they can be tested for multiple different types of outcomes, such as whether people with mild symptoms get worse or not or whether the drug decreases the rate of hospitalization or death. A drug might work in only one of these scenarios and still be deemed useful, so there is much yet to be learned about ivermectin.

Rigorous Clinical Trials Still Needed

As with almost all medications that work for something, ivermectin is not without adverse side effects. Doctors are right not to prescribe a drug for which there is no clear evidence of benefit and the possibility of harm. Yet some people seem determined to take ivermectin now, unwilling to wait for the clinical trials that hopefully will resolve the question.

         As scientists, including those who work at pharmaceutical companies, know all to well, many things that work in test tubes do not turn out to work in humans. Hence, merely finding that ivermectin kills viruses in the laboratory, while an important clue, hardly guarantees clinical effectiveness. One could argue that the pandemic is an emergency situation, and we should be extra careful not to withhold potentially useful medications. But even the vaccines, which were given emergency use authorization before full FDA approval, were subjected to rigorously conducted clinical trials before they were released to the public.

         After laboratory confirmation that a drug might have activity against any disease, it must always be tested in rigorously conducted, randomized clinical trials or RCTs, the gold standard for scientific proof that a medication works and is safe. In an RCT, a relatively large number of patients are randomly assigned to receive either the drug under study or a comparator, usually either a placebo or an intervention already known to work. Patients and investigators generally do not know which study participants are receiving the study drug and which are receiving the comparison intervention in order to minimize biased assessments of whether the study drug is working. These trials are usually expensive and time-consuming.

Before committing to doing an RCT, it is often the case that investigators will conduct less expensive but also less rigorous studies of a drug in order to get some early answers about its potential. For example, let’s say a drug works in the laboratory but only at a very high concentration. Before conducting large-scale RCTs of the drug on humans, scientists might do a study in which they administer escalating doses of the drug to people to see if it is tolerated and safe at higher doses. Or scientists might give the study drug to a small number of people without a comparator arm to the study, a relatively inexpensive and more rapid way to get some early information about the drug. If the study drug doesn’t work under those circumstances, it is unlikely to work in a larger study and a lot of time and money can be saved by not proceeding to an RCT. But if it does seem to work in a “quick and dirty” study like that,  it could be due to assessment bias and a full RCT is still required. Unfortunately, as in the case of ivermectin, it is possible to “cherry-pick” such lower quality studies and reach the premature conclusion that a drug works. Once again, scientists are all too familiar with the many instances in which a bunch of low-quality studies suggest an intervention works for some illness, only to be followed by higher quality RCTs that don’t pan out. There are some shortcuts to making the decision that a drug doesn’t work; unfortunately, there are few shortcuts to concluding a new drug is effective, safe, and ready to be prescribed.

How do we balance, then, our desire to support and promote “citizen” science while at the same time ensuring that only rigorously collected evidence properly evaluated by experts is used to make critical health decisions? In fact, we want people to say “hey, what about hydroxychloroquine? What about ivermectin? What about vitamin D?” just as we now recognize that the advocates for more HIV research were crucial in turning the tide against AIDS. But at the same time, we don’t want people to actually take unproven and potentially harmful medications.

We need to find better ways for scientists and concerned citizens to talk with each other about the state of evidence. Citizens need to stay informed and to advocate for research. Scientists need to evaluate the data and push back against premature conclusions. Citizens need to refrain from trying to take unproven treatments. Scientists need to listen to citizen advocates and heed their calls for more research attention to the things that concern them.

Once again, then, we’ll point out that there is insufficient high-quality data to justify prescribing ivermectin for the prevention or treatment of COVID-19. It is possible that studies now being conducted will change that verdict. Physicians should suspend judgement about ivermectin until more data are available, neither prescribing it now nor making blanket statements that it doesn’t work. In the meantime, concerned citizens should carefully monitor research progress, advocate for sufficient research funding to continue to test emerging potential interventions for COVID-19, educate themselves about what constitutes high-quality evidence, and resist falling into the trip of listening to pundits with a political agenda rather than to experts with genuine scientific credentials. We want the public to be involved in science, but not harmed by misinterpreting it.

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