Watchers of COVID-19 repurposed drug trials are abuzz with the news that a sizable Egyptian trial sponsored by Benha University in Egypt is actually problematic. Why? It looks like a confluence of factors, from laziness and plagiarism to more than likely lack of resources and what appears to be a fraudulent misrepresentation of data, taint a widely cited study known as Elgazzar et al. TrialSite celebrates this moment. This is what this platform is all about—transparency is key, and one of the fundamental criticisms of some of the apex players in research evidence, from the U.S. National Institutes of Health (NIH) to the World Health Organization (WHO), have called out that a considerable number of the many dozen randomized controlled trials from around the world have the potential to reveal design problems, data inconsistency, etc. Their criticism includes some correct points in that the potential is there and, in this case, a sharp “medical student” did a great job finding them. That’s to be applauded. But there’s more to this story. As it turns out, the author, positioned as a humble medical student, turns out to be a disinformation buster in partnership with some sort of blogging network. Moreover, according to reports from the study author(s) from Egypt, they were not given a proper chance to respond to the allegations. TrialSite’s position herein is that while this is not a good look and most certainly heightens the overall risk premium perhaps applied to a bundle of studies conducted in low-and middle-income countries (LMICs), the accumulation of data based on feedback from other ivermectin meta-analyses authors evidences real potential as a public health tool in the COVID-19 pandemic—especially in poor countries that won’t see the majority of their populations vaccinated anytime soon. How do we know? Why else would the U.S. government spend $155 million on ACTIV-6 unless, in part, to study ivermectin? Why would the University of Oxford, even if begrudgingly—finally announce conclusively that they will include the antiparasitic tablets in the PRINCIPLE trial? Why would one of America’s largest health insurance companies, UnitedHealthcare, fund the COVID-OUT study, led by the University of Minnesota, featuring same-day shipment of ivermectin for early-onset COVID-19 patients for at-home care? These institutions wouldn’t make such investments of money, time, resources, and effort unless there was considerable potential. And to provide a different point of view, this Egypt-based study was but one out of 62 total studies to date, plus dozens of real-world care initiatives involving millions of people TrialSite has tracked from Mexico City and Bangladesh to Uttar Pradesh, India, that when aggregated continue to be at least a compelling unfolding story of potential.
Money, Drugs & Power
Whether this group that uncovered glaring issues in the Egyptian-based study (NCT04668469) was part of a campaign to dig up problems with ivermectin studies, doesn’t really matter to us at TrialSite. That comes with the territory. The authors claimed to have given the professor time to respond yet the word from speaking with others in touch with the authors is that they didn’t afford the Egyptian investigational team, led by Benha University’s Ahmed G. Elgazzar, a chance to respond. Who is correct? That answer will come forth.
To explain the hypocrisy of the mainstream media, regulators, and industry, and a corresponding age of crony capitalism in medicine, one only needs to look at some of the episodes and articles in TrialSite’s Drugs, Politics, and Power. They go hand and hand with money and most recently, an unconstitutional lust for control.
After all, how else can one explain the remdesivir situation? The World Health Organization (WHO) declared, based on findings in the Solidarity Trial, that remdesivir (the drug for which Dr. Anthony Fauci and NIAID changed the pivotal clinical trial endpoint to ensure acceptance by regulators) wasn’t effective for COVID-19 patients as TrialSite reported. WHO also declared remdesivir shouldn’t be recommended under any circumstances.
Yet American and many other national regulatory bodies ignored those findings as most mainstream media, and Gilead continues to generate billions of dollars. No mainstream press made much of a stink of that. Float that on Facebook now and a White House censorship squad will censor—despite the fact that it’s true. They tend to beat up on the little, generic underdog like an underfunded Egyptian professor. But if it’s bad, it must be called out—hence TrialSite called it wrong before. That happens, and we own it.
What follows is a breakdown of what appears to be a rotten ivermectin study and an argument as to why the ivermectin train has left the station, regardless of what Melissa Davey at the Guardian touts.
Underlying Critique of Ivermectin Studies
Drug development is a high-stakes, incredibly risky, expensive, time-consuming, and not to mention highly regulated affair. That’s because of the risks to health and human safety—that is, the regulatory oversight necessary to ensure high-quality clinical outcomes. That’s the reality of the pharmaceutical clinical development world, and that’s why the apex research and regulatory agencies are skeptical of many of the ivermectin trials particularly in LMICs, where there may not be the resources, capital, sufficient levels of talent, or the appropriate controls to produce quality data. They are not incorrect at least some of the time—that’s a reality. And the rooting out of plagiarism, misrepresented data, and other misconduct leading to the potential for scientific fraud is a good thing.
The Foundation of Clinical Quality
Those critics of underlying ivermectin studies, especially ones in LMICs, concern themselves particularly in areas of study design, process controls, data integrity, uniformity, and the like. The NIH, World Health Organization, FDA, and various other agencies are correct in theory for sure.
That’s because, fundamentally, to achieve quality, one must be ever mindful of a principle known as “ALCOA-C.” That is, Good Clinical Practices (GcP) necessitate rigorous process controls, training combined with stellar talent—that is what is known as “vocational certainty.” The byproduct of such confluence of clinical quality comes data that is:
- Attributable
- Legible
- Contemporaneous
- Original
- Accurate
- Complete
Attributable informs with transparency into who documented or did what on the study as all material data and documents need to be traceable to a responsible person, date, and subject visit. Legible shows that the clinical record is easy to read with signatures identifiable; fundamental to the clinical quality of data is the concept of Contemporaneous, that is that the study information at the site level should, in fact, be documented as the study occurs, not after the fact. If a study observation isn’t practical to document at the moment, it should be recorded as part of the study’s chronology. Any delays from the time of activity to documentation need to be defined and justified by the study team. And the clinical quality assurance must ensure all signatures attesting to such “late entry,” for instance, are attached to a date indicating when such signatures were affixed to the document. Additionally, study records must be the Original: the investigator at the trial site maintains the original source in the regulatory binder while the drug sponsor (or university’s investigator, such as is the case with the Benha University case) maintains a primary record or certified copy of each study record artifact. Whether study data is Accurate gets to the heart of the matter. That is, the particular information or data on the document or in the database is accurate, consistent, and represents an actual representation of the facts. Finally, the clinical records are Complete, that is, after the study, a holistic and comprehensive picture emerges, backed up by the who, what, when, where, why, and how.
ALCOA-C elements apply to both paper and the digital world—that is, electronic source data and the systems and software applications that maintain such records. The net summary here is that such aggregation of source documentation depicts the comprehensive story of the study—an accurate and truthful one.
The Findings: A Bad Study & A Shady Investigation?
Jack Lawrence, positioned by the Guardian’s Melissa Davey as a humble London-based medical student, actually is “a journalist and disinformation researcher.” He also founded Grftr News and runs the @TimPoolClips Twitter project, according to his own website. He may also be a medical student but Mr. Lawrence was probably looking for dirt on ivermectin. We start to wonder if someone paid him but that doesn’t really matter. It’s his right, and he did find real trouble, we believe. But Ms. Davey should have disclosed the full apparent operation.
First diving into Benha University’s findings, Jack Lawrence’s initial work ultimately led to the retraction of the non-peer-reviewed document. Apparently, part of the “medical student’s master’s degree assignment” according to Davey, upon first reviewing the study documents he found the authors took the liberty to simply undertake wholesale “cut and copy” plagiarism throughout. Lawrence undoubtedly knew that this initial observation would lead to more critical problems associated with data—that is, problems underlying the data and records would violate ALCOA-C principles.
Lawrence shares that the study authors went through a total of four versions of the document, evidencing plenty of time to either do the right thing or do a lot of the wrong things, which in this case was the latter. In a key blow to any ALCOA-C principle, Lawrence stated:
“When opening what the authors claim is their original data the first thing that any reader notices is that it’s remarkably complete. In many columns data for all patients are fully listed. The second thing the reader will likely notice is that the original data do not match the author’s public results. In three of the four study arms measuring patient death as an outcome, the numbers between the paper and original data differ.”
This, of course, is a cardinal sin in the world of clinical trials. Lawrence found numerous other problems that can be read in detail in his own Grftr News. This blog requested the involvement of Nick Brown, a scientific fraud expert involved in the study reviews. Mr. Brown has since analyzed the Benha University-sponsored ivermectin study in detail in his blog.
Brown breaks down the various analyses of the study with Lawrence, focusing on various topics from plagiarism to questionable activity associated with each version to an article by Gideon Meyerowitz which focuses on the overall “…implications of this study for the whole Ivermectin-for-Covid literature” and an article for the masses, one that’s partially a hit piece, according to TrialSite, authored by Melissa Davey. Note that Lawrence works with Gideon Meyerowitz frequently, indicating perhaps this was more than just an innocent school assignment.
But back to Mr. Brown, who is apparently one of the top experts out there in the field of investigating inconsistencies in clinical trials data: his analysis centers on those important data and documentation that are supposed to be reflected in ALCOA-C principles.
Brown made available the Elgazzar et al. data and found that it appeared the authors were still buzzing around, working on the study results by December 12, 2020, despite the fact that two versions of study results were already uploaded to the preprint site by November 16. This provides clear evidence that something was not right—that is, based on ALCOA-C principles, one wouldn’t see authors working on data and documents that should have already been locked down and completed. Brown does a decent job of breaking down the study data findings here.
An Article for the Masses with the Appropriate ‘Hit’
The Guardian’s recent piece made a big splash with the title, “Huge-study supporting ivermectin as covid-treatment withdrawn over ethical concerns.” Part accurate popular journalism, part ‘hit piece’ for the masses, the author, Ms. Davey attempts to kill two birds with one stone:
“The efficacy of a drug being promoted by rightwing figures worldwide for treating COVID-19 is in serious doubt after a major study suggesting the treatment is effective against the virus was withdrawn due to ethical concerns.”
This is a prime example of sensationalism for the multitudes—that is, using the mass media to both 1) politicize the matter of ivermectin (e.g. rightwing) while 2) imply that all of the good research gets thrown out because of this one study.
That’s frankly not good journalism but it’s what sells, unfortunately, and more than likely helps a muckraking place like the Guardian pay its bills. Such tone and banter insults so many in poorer countries that have benefited from the use of the treatment and evidences a First World, entitled contempt of others below—indicating a false sense of superiority.
What this bad study does, however, is most certainly raise questions about the quality (e.g. ALCOA-C) principles of the other ivermectin studies in many a skeptic’s mind. Should other key studies be further scrutinized for quality data and integrity? Why not? But we must also remember for many studies in the Third World—or emerging world—with limited resources, time, and money, not to mention in the midst of a pandemic, nothing will be perfect. I think we can say the same about the biggest most capitalized pharma studies—there are plenty of problems and certainly an inclination by some to manipulate the situation for wealth accumulation. And post-authorization? An entire industry got much of America hooked on opiates, for example. That’s reality.
Doesn’t Make Much Difference
The reality is, after communicating with people like Dr. Pierre Kory from the Front Line Critical Care Alliance (FLCCC), authors of a meta-analysis or Tess Lawrie, co-author of Bryant et al., even the disqualification of this study doesn’t discredit their respective meta-analyses. They are as confident as ever. According to Dr. Lawrie, whose team conducted a post Lawrence analysis: “take out Elgazzar and the confidence interval is widened but the overall conclusions remain the same.”
The FLCCC and the British Ivermectin Recommendation Development Group issued a joint press release in response to the retraction of early research on ivermectin. That can be reviewed here.
The prominent Dr. Andrew Hill from the University of Liverpool, a highly respected contributor to the WHO’s ongoing review of ivermectin, tweeted after the findings published in the Guardian:
“After removal of the Elgazzar trial from ivermectin meta-analysis, borderline significant effects are still seen for hospitalization and survival, but small number of endpoints. More evidence still needed from a large ongoing randomized trial—must be continued.”
Dr. Hill certainly isn’t ready to listen to Ms. Davey and throw in the proverbial towel on the potential of a low-cost way to treat at-risk people in LMICs with little access to safe and effective vaccines. It’s absolutely irresponsible of Davey to make such declarations with so much looming danger in this pandemic, especially in the LMIC world where people don’t have the luxury for vaccines anytime soon. Moreover, did Davey do responsible journalism and check into the authors from the pro-ivermectin meta-analyses for their opinion—of course not!
TrialSite is still bullish about the prospects of this drug—the media platform’s team has chronicled clinical trials, observational studies, and case series around the globe. We have also interviewed many dozens of doctors and researchers in nearly two dozen countries. The confidence level is considerable in that there is some efficacy—how much, in exactly what dose and duration still is open for interpretation and debate. But clearly, clinical trials continue, and you don’t cast aside a sizable body of research and real-world data because of one funky study.
But researchers and the media shouldn’t be playing information war games like Ms. Davey’s employer does. When they introduce the medical student, they should also introduce the other position the chap holds. They should also not just declare that the drug’s days are numbered because of this one study. Says who? The Guardian? Moreover, to remain objective and ethical, they should ensure that they provide the Egyptian professors sufficient time to provide their side of the story. Ditto for the ivermectin-focused meta-analyses.
And to the fact that the Guardian’s writer starts the piece by positioning ivermectin as a “Rightwing” drug? Hogwash. Those tracking ivermectin studies in the developed and developing world aren’t some kind of right-wing movement. It’s a humanistic movement! These are scientists, researchers, public health professionals, and a myriad of other interests. In many cases, they swing way to the Left.
The interest behind ivermectin is diverse, multifaceted, and spans the rainbow of ethnicity, economic level, political leaning, and socio-cultural background. This is an example of the media taking one piece of news to tear at the heart of something disliked, or feared. A classical tactic by today’s media, often making money on advertisers from the same industry they cannot critique. Try even reporting on an ivermectin fact, and FaceBook or YouTube immediately censor—now at the command of the White House. That sounds fundamentally flawed, particularly in America.
But at the same time, even if we disagree with Lawrence, et al.’s motives and Davey’s sensationalism, the fact is that they found problems; and that’s important in the research and scientific endeavor. The quest for continuous improvement across the biomedical research enterprise and, for that matter, all facets of material life, is what makes everything over time better. Hence why TrialSite celebrates the uncovering of problems in this or any study.