At TrialSite, we have for months been chronicling the work of the Front Line COVID-19 Critical Care Alliance (FLCCC) doctors and their growing support for Ivermectin as both a prophylactic and early treatment for COVID-19. On January 6, MedPage Today published their own look at Ivermectin and the FLCCC, “What’s Behind the Ivermectin-for-COVID Buzz?” Arguing that the FLCCC is the main reason Ivermectin is big news, they note that the “group — led by three physicians with a knack for making headlines — posted its own review and meta-analysis of the global ivermectin literature on its website.” FLCCC doctors, after developing a meta-analysis of 18 randomized controlled trials from around the world, believe that ivermectin’s combination of antiviral and anti-inflammatory mechanisms makes it highly useful before or after infection. The group’s co-leader Paul Marik, MD, who is the chief of pulmonary and critical care medicine, Eastern Virginia Medical School in Norfolk, “co-authored the review and meta-analysis based mainly on studies from outside the U.S.” Dr. Marik notes that, “People are dying—-We treat patients at the bedside. We don’t have the ivory tower syndrome where you tell people what to do though you have no idea what you’re doing.” These front-line doctors “don’t see a need for more data” and also argue it would not be ethical to use a placebo in an RTC, “given the established safety of ivermectin.” Of course, these physicians have absolutely expressed the importance of adequate data, and as TrialSite just reported, they were recently invited to present to the National Institutes of Health (NIH) COVID-19 Protection Treatment Guidelines Panel.
The FLCCC was formed in March 2020 as a means for doctors to update each other on COVID-19 developments. The group members knew each other through previous work on vitamin C, according to Dr. Marik. The doctor is known for the “HAT” protocol for sepsis consisting of hydrocortisone, ascorbic acid, and thiamine. In a 2017 article in CHEST, his group’s observational study of HAT “garnered excitement,” yet later trials that focused on single elements of HAT were less positive. In the VITAMINS trial, the full protocol was tested using randomized patients in an open-label trial. Another study, VICTAS, has not yet reported any data. HAT was adapted for COVID-19 using a stronger steroid, an anticoagulant, and a vitamin and mineral cocktail under the name MATH+. Dr. Marik points out that his group was using steroids at a time when WHO and NIH were advising against them. “We said, we see that this works,” Marik said. “Then lo and behold, in June, the RECOVERY trial was published, and it showed that dexamethasone reduced the risk of dying in people with COVID in the hospital.”
From MATH+ to I-MASK+
The FLCCC recently published their experience with MATH+ at Marik’s hospital and also United Memorial Medical Center in Houston in the Journal of Intensive Care Medicine. “The average hospital mortality at these 2 centers in over 300 patients treated is 5.1%, which represents more than a 75% absolute risk reduction in mortality compared to the average published hospital mortality of 22.9% among COVID-19 patients,” the paper indicated. “Everyone in medicine will yell and scream that this paper is not a randomized controlled trial,” another FLCCC leader, Pierre Kory, MD, opined. “We didn’t believe in an RCT. We believe we’re supposed to doctor and use our expertise. If you’ve been doing this for decades, and you trust your assessment of the disease and your knowledge of medicine, it’s OK to doctor.” In the latest update of their protocols, I-MASK+, they focus on early treatment and prophylaxis using ivermectin as the focal point of treatment.
On the prophylaxis front, FLCCC doctors cite four RCTs and three observational studies as key data points. The RCT’s in Egypt, Argentina and Bangladesh had 100 to 300 patients each; they also cite the “natural experiments” in Latin America where Ivermectin was used widely with “large decreases in case counts…soon after distribution began.” Regarding use for mild illness, the FLCCC cites five RCT’s from Bangladesh, Iraq, Brazil and Spain with 24 to 722 patients each. Regarding use for hospitalized patients, they point to four RCTs in Egypt, Iran, India, and Bangladesh with 72 to 400 patients. In addition, they cite many observational studies in mild and severe COVID-19 cases. The one US study, a retrospective in CHEST of 280 hospitalized subjects in which 173 patients got ivermectin and 107 did not. “Most patients in both groups also received hydroxychloroquine, azithromycin, or both,” the study indicates.
Ethicist Calls for RCTs
As the corresponding author of the ivermectin review and meta-analysis, Dr. Kory notes he is frustrated by critics of the evidence. “If someone wants to discount those studies…and says they want to do an RCT with placebo, that’s problematic for me,” Kory noted. “I could not have a patient admitted to my care and give placebo knowing what I know about ivermectin.” Kory went on, noting FLCCC members “are firm believers in evidence-based medicine. But we disagree with how most practice evidence-based medicine. We think they are way too biased toward randomized controlled trials and completely dismiss evidence from anything but RCTs. We think that’s harmful and loses a lot of valuable data.” A critic, Steven Joffe, medical ethicist at the University of Pennsylvania, said he doesn’t think that clinicians “should be lowering our standards of evidence because we’re in a pandemic—-This group should be advocating strongly for a large, generalizable randomized trial if they believe so strongly in the efficacy of ivermectin,” Joffe offered. “If, in fact, it is effective, the only way to convince the clinical and scientific community and allow patients all over the world to benefit is to prove the case in such a trial.” He added that “With good data and safety monitoring, if the benefits are as overwhelming as they claim, the trial could be stopped early on the basis of interim data and the treatment rapidly instituted.”
First, if the FLCC were just some random group of physicians just in search of media attention, they certainly would not have been invited to the apex research agency Panel to present their findings. The FLCCC physicians are highly respected critical care doctors who have published many peer-reviewed articles. Second, they are not alone as the work of Andrew Hill, Ph.D., associated with the University of Liverpool in the UK, gains more attention across the Atlantic. Third, they are working in a more agile and lean manner, viewing data from the lens of a risk-based approach, much like the U.S. FDA embraced years ago for exploring regulatory risk. Perhaps Dr. Joffe introduces the “either-or” false dilemma to the equation?
Evidence “Very Low Grade”
Andrew Hill, Ph.D., has also presented his own meta-analysis of ivermectin data, which supports the FLCCC’s conclusions. Hill is a research fellow at the pharmacology department for Liverpool University in England. MedPage Today reported Zain Chagla, MD, infectious diseases physician at McMaster University in Hamilton, Ontario, looked at Hill’s review trials. He said the evidence was “very low-grade” and also expressed displeasure “that Hill disseminated it as a video.” Chagla notes, “We always want to see these things published, rather than me walking through a video, pulling these studies myself.” He also feels déjà vu from the HCQ episode, “We don’t want to come around a year later saying it didn’t help and it may have hurt.”
Of course, Hill didn’t disclose his work, but rather it was inadvertently leaked. That this Professor didn’t verify how the data was released indicates that other faulty assumptions may not be verified by such experts. Why is it when physicians want to take a more assertive stand to protect patients that their character is attacked?
Dr. Kory has suffered professionally from his advocacy; he resigned from the University of Wisconsin in May, saying, “he couldn’t stand by while patients were getting supportive care only.” At that time, he was concerned that patients should be getting steroids; his instinct on this was confirmed in the month of June. The doctor joined Aurora St. Luke’s but then left as “the hospital wanted to limit his freedom to speak.”
On December 4, Kory, Marik, and Varon held a press conference in order to raise awareness about ivermectin with the goal of getting WHO and NIH to change their current only-in-clinical-trials recommendation. A few days later, Kory testified at the US Senate, and political divisiveness reared its head as the ranking Democrat attacked the doctor as being ideologically motivated while Fox News favorably covered the testimony.
The FLCCC doctors are frustrated that they are pulled into any politics—they are completely apolitical. They have taken pains to distinguish themselves from American’s Frontline Doctors, a pro-HCQ and anti-lockdown group. “This is not a political issue and it should never be,” Marik offered. “We are driven by science and the data, not by politics or anything else.”
TrialSite Point of View
“Much of the rest of medicine” believes that RCTs are needed prior to the wide use of ivermectin. “The time is now to do a good clinical trial,” Chagla opined. “I don’t think the vaccine is going to eliminate COVID-19. It’s a disease we’re going to be dealing with. The vaccine rollout has been slow, we’re not going to see entire populations vaccinated. There are always going to be holes. To prove that this drug works is something that would be warranted.” And he noted, “the studies have to be done properly.” Of course, TrialSite agreed with Chagla as did the FLCCC physicians.
TrialSite months ago wrote a letter to the NIH imploring the need for public funding for such a trial to support just such a cause. We are happy to share. After TrialSite noted, now over $13 billion has been directed by the NIH’s ACTIV to just a handful of pharmaceutical companies to develop novel vaccines and monoclonal antibodies. The point here is to ask the question: why hasn’t the apex research agency even allocated a couple million dollars for an ivermectin study?
From TrialSite’s perspective, the MedPage Today piece has hints of bias on issues we have addressed. For one thing, the article implies that evidence from other nations is not legitimate for US-approval purposes. It also perpetuates the false dichotomy of RCTs versus real-world evidence: there is no reason that some doctors cannot continue with what is working while others get RCTs off the ground. MedPage Today plays it safe with advertisers and influencers, not delving deeper into meaningful interviews and engagement with the investigators in places such as India, Bangladesh, Peru and even Brazil, or for that matter, Mexico, Bulgaria or Argentina. TrialSite has done so and perhaps benefits from a broader and deeper perspective. Could it be that “first-world” doctors and researchers feel a sense of superiority over those peers in the “developing world” as well as low-and middle-income countries (LMICs)?
Regardless, TrialSite suggests to all those of influence that in such a brutal pandemic to keep an open mind to real-world and randomized studies in the developing world as well as in LMICs, in addition to activity in the developed world.
Many haven’t had the luxury to sit around and wait. In a way, the developing world and LMICs may be doing the developed world a favor—testing the drug ongoing in the form of randomized studies, observational studies and case series. In places like Uttar Pradesh, an Indian state that would be the fifth-largest nation in the world, local health authorities routinely prescribe ivermectin for ambulatory use. Why couldn’t health authorities here collaborate with those in that state to learn more about their real-world data?
The large public-funded studies as TrialSite has chronicled favor novel drug trials over practical repurposed existing drugs. Meanwhile, all of the waiting for a long term study outcome hasn’t been that beneficial to those of us who have lost loved ones in part because they had nothing to treat the virus early on—they were left at home for the SARS-CoV-2 virus to multiply.
While TrialSite applauds prominent companies such as Eli Lilly and UnitedHealth now bringing monoclonal antibody studies to the home; while we commend Lilly as well as NIAID for introducing mobile units to expand trials to at-risk, underrepresented communities and nursing homes—the quest for easy to access, economical and easy to administrate ambulatory care continues during this pandemic. The FLCCC is only attempting to contribute to the important national dialogue. Yet they are damned with faint praise.
To date, far too many people during this pandemic were left at home to fend for themselves, and by the time the symptoms of COVID-19 became too severe and consequently, patients made their way to hospitals, it was too late for far too many people.
As the numbers reveal, the world’s greatest economy and most sophisticated healthcare system worldwide has been most impacted, as recorded by total cases and deaths. Of course, as Dr. Anthony Fauci recently made clear at a Grand Rounds, the politicization of basic life-saving guidance, such as social distancing and mask, has severely worsened the situation. The fragmented and fractured American society of late didn’t help the fight against COVID-19—the people were not unified, and a universal threat faced all. That’s truly unfortunate but beyond the scope of this platform. TrialSite asks, could there, in fact, be a “third pathway to consider for potential treatments?” That is, a risk-based approach to evaluating off-label, repurposed drugs such as ivermectin and others in an accelerated manner?