Ivermectin Fact Check—An Independent TrialSite Breakdown

Ivermectin Fact Check—An Independent TrialSite Breakdown

While a growing body of research indicates the potential of ivermectin as a possible treatment targeting COVID-19, much of the mainstream press of late has either focused on a few studies that failed to show any statistical benefit or warnings against the use of the veterinary drug. Presently, the drug is under study by prominent groups such as the University of Minnesota (in partnership with UnitedHealthcare’s Optum), the National Institutes of Health (NIH) via its Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) “ACTIV-6” study led by Duke University, and at least 43 active clinical trials as documented in Clinicaltrials.gov. The drug was first identified as a possible inhibitor of SARS-CoV-2 due to lab experiments at Australia’s Monash University Biomedicine Discovery Institute (BDI) in partnership with Peter Doherty Institute of Infection and Immunity

That’s when TrialSite first started tracking this drug and its applicability to COVID-19. While the doses in the initial lab experiments were much higher, what ensued was a combination case series, observational studies, randomized controlled trials, and real-world, off-label usage. Since April 2020, TrialSite has tracked dozens of studies and interviewed nearly one hundred doctors, researchers, and health professionals from almost 20 nations. The drug is used around the world off-label, targeting COVID-19 except in a few countries where the health authorities either directly authorized its provisional use or indicated its acceptance of off-label use. Indian included the drug in its national COVID-19 guideline for a handful of months.

What’s the ivermectin story?

This drug has been called a “wonder drug,” given its safety profile and contribution to eradicating certain parasitic diseases. Approved by the U.S. Food and Drug Administration (FDA), ivermectin is used to treat certain parasite-based medical conditions in the United States and much of the world.

In fact, billions of drug doses have been administered—hundreds of millions every year—as part of a global effort to eradicate diseases such as river blindness. A centerpiece of this effort is Merck’s Mectizan program, which helped dramatically eliminate the parasite-born, tropical disease in Africa, Latin America, and Yemen. The discoverers of ivermectin went on to win the Nobel Prize, including Merck’s Dr. William Campbell and Satoshi Ömura of Japan.

As TrialSite describes below, a preclinical in vitro study in Australia early on during the pandemic revealed powerful inhibitory forces against SARS-CoV-2. Conducted in a lab, translating those findings via clinical trials and the standard lengthy process of medicine development was constrained by pandemic conditions and several low-and-middle-income countries (LMICs) that sought imminent off-label approaches. As TrialSite will discuss below, 63 studies have been completed, and nearly 50 active studies are ongoing. TrialSite produced a documentary in Peru investigating why that nation accepted the drug so early on.

Is the drug safe?

Ivermectin’s general safety profile cannot be challenged. However, like any drug, if used in the wrong way, it can be harmful. According to ivermectin experts at Spain’s IS Global (Barcelona Institute for Global Health), “When used for the current indications, at the currently approved doses, ivermectin is a very safe drug.” The Spanish group shares, “To date, more than three billion treatments have been distributed in the context of the Mectizan Donation Program alone with an excellent safety profile. Most adverse reactions are mild, transitory and associated with parasite death rather than the drug itself.”

Edenbridge Pharmaceuticals develops ivermectin in the United States—the U.S. FDA approves their product, and their label is included here

But what about for COVID-19?

It depends on who one listens to. Organizations such as the Front Line COVID-19 Critical Care Alliance (FLCCC) have developed protocols for the use of ivermectin that have treated many thousands already with no reported problems. Dr. Jacques Rajter, Broward Health, conducted a case series study (ICON) that led to peer-reviewed published findings that the drug could become a safe tool in the war against COVID-19. TrialSite has interviewed many dozens of physicians worldwide using the drug in research or in care who report it’s very safe.

Yet alternatively, there is concern that if the drug isn’t recommended by the NIH or approved by the FDA, it’s inherently risky and could be misused off label. That’s because drugs are heavily regulated.

Moreover, authorities grow increasingly concerned with self-medicating with the veterinary version. Ultimately the FDA is the administrative branch agency that enforces food and drug laws in the United States, and recently, they have grown concerned during the pandemic with self-medication using the animal variety. No one should self-medicate with any prescription-based drug. And no one should inappropriately access and consume an animal drug.

Does the FDA represent the “Gold Standard” of national drug regulatory agencies?

Yes. The FDA regulates all drugs in the United States. The FDA was created over a century ago to protect consumers from unhealthy to dangerous treatments put into the stream of commerce in the late 1800s into the early 1900s. The 1906 enactment of the Pure Food and Drug Act led to the new agency. It’s long been considered the leader of food and drug regulatory agencies, a Gold Standard agency. 

What’s the FDA’s position on off-label prescribing?

The FDA declares that generally, “…healthcare providers…may prescribe the drug for an unapproved use when they judge that it is medically appropriate for their patient.”

Why are there growing media accounts of warnings involving ivermectin?

Typically, this involves the use of ivermectin for animal use. Physicians may not prescribe off-label animal ivermectin. There is growing concern that people may be obtaining animal ivermectin and self-medicating, as recently reported by the New York Times.

In the U.S., only the human version of the drug can only be prescribed off-label. That is at the discretion of the doctor and consenting patient, per the FDA. The media generally has evidenced bias against ivermectin, not mentioning many of the positive data points from around the world, but rather centering attention on negatives. An example of another drug is remdesivir. The World Health Organization (WHO) Solidarity trial established that remdesivir doesn’t help treat COVID-19 at all. Yet in America, remdesivir is embraced by the FDA, NIH, and market with $3 billion in sales during the first nine months of the pandemic. Much of the U.S. media focused on those successes, not other material data points from elsewhere.

Is ivermectin a cure for COVID-19?

No. There is no cure for COVID-19.  

What about a Silver Bullet?

No. There are no silver bullet therapies for COVID-19. Rather, ivermectin used off-label in the U.S. (e.g. physician assessing risk-benefit with consenting patient) is a potential tool, along with other possible treatments, for early care used by some physicians combined with safe and effective vaccines and other precautionary measures from social distancing to other sanitary practices. Notably, in America and most jurisdictions in other countries, ivermectin isn’t recognized as a COVID-19 treatment and, therefore, would only be legally usable off-label if allowed in any particular nation. Some countries have formally authorized its use, but it’s not a “silver bullet.”

How many studies in the context of COVID-19?

Presently, the drug has been used in 63 completed studies involving 613 scientists and 26,398 patients. 31 of those studies are actually randomized controlled trials. A few meta-analyses from accomplished physicians/researchers indicate significant promise. See Bryant et al. and Kory et al., while another one led by Dr. Andrew Hill reveals promise but calls for more clinical trials data.

What is the critique of most ivermectin studies?

The NIH, FDA, and numerous academicians don’t buy into the positive results thus far. They believe that the studies are either too small (lack of statistical power), have methodical limitations, or have too much variability in dosage or study outcome measures. These institutions call for more numerous, extensive studies for more dependable data. In some cases, TrialSite completely agrees with the NIH. In other cases, we question some of their points of view.

What does research detect about mechanisms of action?

Again, the interest in ivermectin as a possible treatment for COVID-19 resulted from an in vitro study in Australia with published results here

One recent evidence-based review article published in the Journal of Antibiotics suggests numerous mechanisms of action targeting SARS-CoV-2, including a description of proposed cellular and biomedical interactions between the drug, host cell, and novel coronavirus pathogenesis. Other suggested mechanisms of action are proposed in “Repurposing Ivermectin for COVID-19: Molecular Aspects and Therapeutic Possibilities.” Researchers out of India probe mechanisms of action in “Ivermectin as a potential drug treatment for COVID-19; an in-sync review with clinical and computational elements.” Several other studies and papers cover the topic, as do YouTube videos such as Whiteboard Doctor and Drbeen Medical Lectures.

What’s the position of health-related authorities in the U.S.?

The U.S. FDA cautions against the use of the drug in the context of COVID-19 because, first and foremost, the Gold Standard agency hasn’t authorized the drug for the indication of SARS-CoV-2, the virus behind COVID-19. TrialSite has issued critiques of some of the agency’s statements, and that can be read here. As SARS-CoV-2 is a new pathogen, the FDA has concerns about off-label use, but it is allowed under the law.

The National Institutes of Health (NIH) updated its treatment guidelines after meeting with the authors of two of the meta-analysis studies back in January 2021. Specifically, the NIH’s COVID-19 Treatment Guideline Panel changed its statement on the ivermectin topic from recommending only for clinical trials to a more neutral position, declaring a lack of sufficient data to declare for or against. Of course, this position is subject to change. Individuals in the NIH, such as Dr. Anthony Fauci, have been on the record that they don’t recommend use until more substantial clinical trial data is available.

Can doctors prescribe ivermectin off-label in the United States?

Yes. As mentioned previously, the FDA supports this within various legal boundaries. There are many doctors now prescribing ivermectin for COVID-19. Prominent among them is the Front Line COVID-19 Critical Care Alliance (FLCCC). 

Why are there a growing number of lawsuits involving patients/families that are denied access to ivermectin?

Suppose a COVID-19 patient is in a hospital or health system. In that case, most often, the policies of the particular institution will preclude the use of ivermectin off-label because it’s not on the NIH panel’s recommendation list as an example. Attorney Ralph Lorigo has been involved with dozens of cases involving patients’ family members pleading with hospitals for access to their dying parents or other family members. TrialSite has reported on a few of these lawsuits and interviewed Mr. Lorigo.

Is there absolute proof that ivermectin can consistently treat early-stage COVID-19 patients?

No. Some researchers and physicians point to studies and real-world data that indicate the drug has a positive impact if used early on at symptom onset. Others, in fact, a majority of influential health authorities, research institutes, and the like, declare that there isn’t enough evidence based on the current data. The medical world is highly influenced by regulatory agencies (e.g., FDA), medical societies and boards, and the like. At least some of these institutions would need to embrace the data for a more confidential declaration of affirmative proof. Otherwise, it’s a niche off-label use case, but that doesn’t equal a more universally accepted norm.

Has the Delta variant impacted the use of ivermectin?

Yes. TrialSite reported that the FLCCC updated its protocol as the Delta variant has a much stronger viral load. If variants get stronger, it could be that the purported effect of this generic drug could diminish further.

What are some prominent initiatives TrialSite investigated?

large population health study in Mexico City, widespread use in various Indian states, including the Uttar Pradesh battle against Delta, and prominent studies in Bangladesh, parts of Brazil, Latin America, and Eastern Europe, and Africa.

Did India authorize ivermectin use at the national level?

Yes, for at least a handful of months. An Indian biotech was even issued a license to produce the drug, TrialSite reported. There was a split at the national level, and the DGHS issued a statement that ivermectin would be dropped from the national list as the Delta surge declined there.

Was ivermectin involved with the state of Uttar Pradesh’s dramatic turnaround in COVID-19 cases?

Yes. TrialSite monitored this closely. See “Unprecedented Turnaround in Uttar Pradesh with Dramatic Decline in Cases..” However, because there was no systematic real-world evidence-based study, there is probably not a way to prove that ivermectin was a factor or not. Yes, the drug was involved, but was a causal relationship proven? Not one that can be proven. That would require study conditions, rigorous registry documentation, or some combination thereof.

Does ivermectin compete in the early onset COVID-19 home care market?

Possibly in a minimal way. The drug is not approved for this use by the FDA, so that will fundamentally limit its reach. Right now, there are no approved drugs for the early care COVID-19 space, a market that is potentially massive given that about 90% or more of COVID-19 cases are mild-to-moderate in nature. 

Presently, a handful of pharmaceutical companies are working on antiviral, orally administered antiviral drugs to target this space, including Merck (Molnupiravir), Roche (AT-527), and Pfizer (PF-07321332).

In other parts of the world, a drug called Favipiravir is used. TrialSite has reported extensively on this antiviral, while U.S. media rarely mentions it, if at all. This antiviral could have some modest positive impact on the observational studies, but it doesn’t appear to be a game-changer.

What other therapies look promising as prophylactic or early care?

While AstraZeneca’s long-acting antibody therapy (AZD4772) is designed in the same class based on recent preliminary trial results, the investigational product shows promise as a prophylaxis—but only time and data will tell. Recent preliminary data was highlighted by TrialSite.

Do ivermectin & other potential early care treatments compete with vaccines?

No. If ivermectin is used off-label in the U.S. for early-onset COVID-19, this would be in alignment with what multiple pharmaceutical companies are working on in the clinical pipeline. In fact, it’s been known by the pharma industry and government research institutes like the NIH that the use of antivirals as a tool to help treat COVID-19 will be indispensable. That’s why, for example, the U.S. government awarded $356 million to Merck and $486 million to AstraZeneca (not an antiviral but cocktail antibody). The latter’s recently announced clinical trial for a prophylactic use case, for example, isn’t considered competitive to vaccines but an alternative approach for select cases. The U.S. NIH is on record as to the importance of antivirals (or similar) medicines to treat COVID-19 early on.

Is there an industry, government, or WHO-led effort to block the use of ivermectin around the world?

TrialSite cannot say for certain, but there are some questionable data points. For example, ivermectin was used extensively in Uttar Pradesh to combat the Delta variant-driven surge there as part of a proactive public health initiative using home medical kits. The World Health Organization (WHO) praised the Indian state’s public health effort but omitted the fact that they were using ivermectin.

TrialSite now has several data points that the WHO or elements within appear hostile to countries that formally embrace the use of the drug other than for clinical trials. Sources have informed that if a nation’s public health or comparable group formally embraces the drug for use targeting COVID-19 at this point, it’s not looked upon well. That has implications as WHO’s budget of nearly $5 billion is allocated to various nations for health efforts. TrialSite is aware of one case where a government is afraid of announcing that it’s accepted the drug in national guidelines.

Merck, a producer of ivermectin, went on the aggressive against ivermectin’s use for COVID-19, even questioning the drug’s safety profile. As TrialSite reported, Merck received $356 million from taxpayer-originated sources to develop a pharmaceutical antiviral targeting COVID-19. Recently, under the Biden administration, they secured a guaranteed contract worth $1.2 billion should the drug get authorized on an emergency basis or approved.

No conspiracy theories here! Often a confluence of interests may align on a particular paradigm or point of view. What looks to be an orchestrated coordinated set of actions is merely various groups conducting business in similar ways, based on shared understanding and shared values and perceptions. Of course, active lobbying by industry can help shape interests. One only needs to look at the opioid crisis as an example. And TrialSite reminds all “history is just a series of coincidences.”

Does TrialSite recommend ivermectin?

No, that’s not TrialSite’s place. That should be a topic between a patient and their physician. TrialSite is a rapidly growing online media and social network platform centering on transparent, accessible biomedical and health-related research, emphasizing awareness building, information exchange, and hopefully empowerment. Generally pro-pharma, pro-free markets with sensible regulatory oversight, we are committed to driving more transparency, accessibility, and openness while providing more informative awareness about potential breakthrough medicines that can save human life.  

Does the drug development system in the U.S. favor branded, new drugs versus cheap repurposed drugs?

Generally yes. There is much literature on this topic. See “Drugs Money and Secret Handshakes: the unstoppable growth of prescription drug prices” by Robin Feldman, for example. Developing pharmaceuticals is a high-risk, high-cost affair, and investors seek considerable returns. Thus market forces drive companies to find high-value medicines that address unmet needs, for example. See TrialSite’s Is the Departure of NCATS Director Indicative of NIH’s Repurposing Track Record” to learn more.