Why the “gold standard” of proof required to give the green light to ivermectin is inappropriate – Prof Colleen Aldous
On July 30, the National Emergency Drug Listing Committee released its third update to the initial rapid review report of January 25, 2021 in which the research question “Should ivermectin be used for treatment?” management of Covid-19? Has been discussed. The recommendation of the NEMLC Covid-19 subcommittee suggested not to use ivermectin in the management of Covid-19, except as part of a clinical trial. The rationale for this recommendation was that “the current evidence for the use of ivermectin in Covid-19 does not suggest any clear benefit in inpatients or outpatients with respect to mortality, clinical improvement, or viral clearance” .
Of particular interest is the fact that this very comprehensive review report makes no mention of the potential harm caused by the controversial drug. The conclusion of the report further provided that; “All of the areas were rated as low or very low quality. The NEMLC recommendation is conditional on “new, high-quality evidence of clinically relevant benefit”. In other words, and as noted in this article by Professor Colleen Aldous, regulatory authorities are waiting for a single large, double-blind randomized controlled trial (DBRCT) to provide absolute proof of the impact of ivermectin.
To facilitate the understanding of the convincing argument advanced in this article, the DBRCT – considered the gold standard study design for evaluating the efficacy and safety of new drugs – are frequently conducted in order to obtain data to support regulatory approvals. Aldou, a full professor and healthcare scientist at UKZN medical school, argues that demand for this “gold standard” of evidence is inappropriate in a pandemic, especially when it comes to ivermectin.
In contrast to Traditional Efficacy DBRCTs, Randomized Controlled Trials (RCTs) relate to pragmatic efficacy because they are designed to evaluate drugs in the “real world” on a large patient population. RCTs also provide the opportunity to address issues faced by patients and healthcare professionals on a daily basis. Ironically, these advantages unique to RCTs – especially when the myriad of Covid-19 variables are taken into account – are the same reasons the NEMLC based its recommendation on.
A video exploring the null hypothesis that ivermectin has no effect on Covid-19 is incorporated under this article. The video provides further information to support Aldous’ argument. – Nadya Swart
Ivermectin: why the scientific evidence required by regulatory authorities is inappropriate in the event of a pandemic
By Professor Colleen Aldous *
Regulatory authorities have consistently recommended that ivermectin not be deployed, have the potential to save lives, reduce illness and hospitalizations, and not cause harm. They ignore all current scientific evidence and are waiting for a single large, double-blind randomized controlled trial (DBRCT) to provide absolute proof of the impact of ivermectin.
This narrow focus goes against the evidence-based medicine (ebm) that was defined, by ebm’s father David Sackett1, as “the conscientious, explicit and judicious use of the best current evidence in making decisions about the care of each patient”.
One problem with a large DBRCT is that if this is to be the only evidence that regulators rely on to make a decision, we could completely lose the potential of ivermectin. If a study – such as the Together trial and the Principle trial currently underway at the University of Oxford – is unable to show statistical significance because too low a dose of ivermectin was used on the strain Delta responds better to higher doses, the regulatory authorities will throw out the baby with the bathwater and the ivermectin will be off the table.
Another problem with a single large DBRCT being the landmark study is that the heterogeneity of the disease does not allow a single study. A definitive DBRCT is not likely. There are variations in comorbidities, stage of disease, dosage, and variants. A comparison group should be huge. Standard care versus standard care plus Ivermectin will be difficult to implement because care is not standardized according to the progression of the disease. End points are variable.
As David Ogilvie states in an article by Helen Pearson in Nature3 in May of this year, “In the standard ebm paradigm, researchers collect evidence on therapy from RCTs until it gets a green or red light. But in many situations, such testing is unethical, impractical or impractical. “
The NEMLC once again gives the red light. On June 18, the NEMLC presented its update suggesting that ivermectin should not be used routinely in the management of COVID-19, except in a clinical trial.
The Nuremberg Code prohibits such a trial in their point # 5 where they state that if death or disability is a possibility, research should not be carried out. The time it takes to set up a large DBRCT in a rapidly evolving pandemic and the competition for research participants with other new therapies make it impractical. The costs of a large DBRCT are prohibitive and funds are allocated for such work the results of which could lead to profits to recover these costs. The smaller RCTs that have been published are studies conducted by clinicians in their own settings and were published to share the experience as quickly as possible in order to stem the impacts of the pandemic. They constitute the current body of evidence which is dismissed as “insufficient”.
A clear rationale for avoiding the narrow view of evidence-based drugs was published in the BMJ by Smith and Pell4. In their article titled ‘Use of parachutes to prevent death and major trauma associated with gravitational challenge: a systematic review of randomized controlled trials ” they came to the following conclusion:
“As with many interventions aimed at preventing health problems, the effectiveness of parachutes has not been subjected to rigorous evaluation using randomized controlled trials. Advocates of Evidence-Based Medicine [RCTs] criticized the adoption of interventions evaluated using only observational data. We believe that everyone could benefit if evidence-based medicine’s most radical protagonists [RCTs] organized and participated in a double-blind, randomized, placebo-controlled crossover trial of the parachute. ‘
Essentially, they’re saying that if the observational trials for parachutes are not enough to adopt parachutes, then those that require RCTs should join the trial. But the cross-test ensures that those who were in the intervention arm (supplied with parachutes) in the first round get to be checked in the next (no parachute).
RCTs are not the only form of evidence that informs ebm. Research into the use of ivermectin in Covid-19 meets all levels of research evidence in the evidence-based medicine pyramid. Although the lowest trust post is an opinion piece, an increasing number of opinions pointing in the same direction are warning the possibilities. At the beginning of August, we have over 20 opinion pieces published in our bibliography. Case studies, case series, and cohort studies are small, descriptive studies that describe patient outcomes. These studies, by their nature, are not controlled for bias but continue to show signals that are worth following. We have 25 in our bibliography.
But the most important studies that are overlooked are the mechanism of action documents and the safety data and other laboratory research. The NEMLC statement that “existing evidence does not suggest any clinical or virological benefit” implies that they did not engage in this body of literature. Signals from these studies all indicate that we understand how ivermectin works in Covid-19, that its already established safety profile continues to show up, and that animal studies confirm what we already know.
Back to Ogilvie3, his ideas as a public health specialist in the MRC Epidemiology Unit at Cambridge University suggest that we need to be pragmatic and assess a range of evidence and “mosaic it together to give a picture of if any. something is worth it “. Then you need to constantly evaluate the practice and keep abreast of emerging research.
As a medical research scientist, I don’t think ivermectin should be given the green light yet. We need more pharmacokinetic and pharmacodynamic studies on the range of comorbidities, age groups and variants. But there has been enough practice in the field and enough research evidence for the orange light. This means that the use of ivermectin by physicians who have educated themselves about the drug and are currently seeing positive first-line results, should not be actively discouraged.
The reiteration of their previous statements by the NEMCL has also caused misunderstanding, with some doctors feeling that ivermectin cannot be prescribed outside of clinical trials. This is indeed false, as the off-label use is continuing under a court order, as is SAHPRA’s Controlled Compassionate Use Program. Many physicians changed health insurance providers after the introduction of measures to reduce the prescription of ivermectin.
- Sackett, David L., et al. “Evidence-Based Medicine: What It Is and What It Is Not” (1996): 71-72.
- Cohen K, De Waal R, Gray A, Kredo T, Maartens G, Nel J, Parrish A, Rees H, Reubenson G. RECOMMENDATION OF THE NEMLC THERAPEUTIC GUIDELINES SUB-COMMITTEE.
- Pearson H. How COVID Broke the Evidence Pipeline. Nature. 2021: 182-5.
- Smith GC, Pell JP. Use of parachutes to prevent death and major trauma associated with a gravitational challenge: systematic review of randomized controlled trials. BMJ. 2003 Dec 18; 327 (7429): 1459-61.
- Professor Colleen Aldous holds a PhD and is a Full Professor and Healthcare Scientist at UKZN School of Medicine, where she heads the Doctoral Academy at the College of Health Sciences. She has published over 130 peer-reviewed articles in peer-reviewed journals.
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