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On July 30, the National Emergency Medicine List Committee released its third update of the initial Rapid Review Report of 25 January 2021 in which the research question ‘Should Ivermectin be used for the management of Covid-19?’ was addressed. The NEMLC Covid-19 sub-committee’s recommendation suggested that Ivermectin not be used in the management of Covid-19, except in the context of a clinical trial. The rationale behind this recommendation was that ‘the current evidence for the use of Ivermectin in Covid-19 does not suggest any clear benefits in either 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 potential harm caused by the controversial drug. The Report’s conclusion further provided that; ‘All domains were assessed as being of low or very low quality evidence.’ The NEMLC’s recommendation is conditional upon ‘new high quality evidence of a clinically relevant benefit.’ In other words, and as provided in this article by Professor Colleen Aldous, the regulatory authorities are waiting for a single large double-blind, randomised control trial (DBRCT) to provide absolute proof of Ivermectin’s impact.
To aid the understanding of the compelling argument put forth in this article, DBRCTs – considered the “gold standard” study design for assessing the efficacy and safety of new medicines – are frequently conducted for the purpose of obtaining data to support regulatory approvals. Aldous, a full Professor and Health Care Scientist at UKZN’s medical school, argues that the demand for this “gold standard” of proof is inappropriate in a pandemic, particularly in respect of Ivermectin.
In contrast with traditional efficacy DBRCTs, randomised controlled trials (RCTs) relate to pragmatic effectiveness as they are designed to evaluate medicines in the “real-world” setting across a broad patient population. RCTs furthermore offer the opportunity to address issues faced by patients and healthcare professionals on a daily basis. Ironically, these advantages that are unique to RCTs – especially when the myriad variables relating to Covid-19 are taken into account – are the same reasons upon which the NEMLC based its recommendation.
A video exploring the null hypothesis that Ivermectin does not have any effect on Covid-19 is embedded below this article. The video provides further information in support of Aldous’ argument. – Nadya Swart
Ivermectin: Why scientific evidence demanded by regulatory authorities is inappropriate in a pandemic
By Professor Colleen Aldous*
Regulatory authorities have routinely recommended that Ivermectin should not be rolled out regardless of whether it has the potential to save lives, reduce illness, and hospitalisation and cause no harm. They are disregarding all current scientific evidence and are waiting for a single large double-blind, randomised control trial (DBRCT) to provide absolute proof of Ivermectin’s impact.
This narrow focus flies in the face of evidence-based medicine (ebm) which was defined, by the father of ebm David Sackett1, as “the conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients.”
One problem with a large DBRCT is that if this is going to be the only proof that regulatory authorities use to base a decision on, we could lose the potential of Ivermectin completely. If a study – such as the Together Trial and the Principle trial currently being carried out at Oxford University – is unable to show statistical significance because too low a dose of Ivermectin was used on the Delta strain which responds better to higher doses, the regulatory authorities will throw the baby out with the bathwater and Ivermectin will be off the table.
Another problem with a single large DBRCT being the deciding study is that the heterogeneity of the disease does not allow for only one study. A definitive DBRCT is not likely. There is variation in co-morbidities, stage of disease, dosing, variants. A comparator group would have to be huge. Standard care versus standard care plus Ivermectin will be difficult to set up since care is non-standardised based on disease progression. End points are variable.
As David Ogilvie states in an article by Helen Pearson in Nature3 in May this year, “In the standard paradigm of ebm, researchers collect evidence on therapy from RCTs until it gets a green or red light. But in many situations such trials are unethical, impractical or unfeasible.”
The NEMLC is once again giving the red light. On the 18 June, the NEMLC presented their update suggesting that Ivermectin not be used routinely in the management of COVID-19, except in the context of a clinical trial.
The Nuremberg Code precludes such a trial in their point no.5 where they state that if death or disability is a possibility, the research should not be carried out. The time it takes to set up a large DBRCT in a fast-moving pandemic and the competition for research participants with other novel therapeutics makes it impractical. The costs of a large DBRCT are prohibitive and funds are allocated for such work where the outcomes could lead to profits to recoup these costs. The smaller RCTs that have been published have been clinician-driven studies in their own settings and have been published to share experience as quickly as possible to stem the impacts of the pandemic. They make up the current body of evidence that is spurned as “insufficient.”
A clear rationale for avoiding the narrow view of evidence-based medicines was published in the BMJ by Smith and Pell4. In their paper titled ‘Parachute use to prevent death and major trauma related to gravitational challenge: systematic review of randomised controlled trials’ they came to the following conclusion:
‘As with many interventions intended to prevent ill health, the effectiveness of parachutes has not been subjected to rigorous evaluation by using randomised controlled trials. Advocates of evidence-based medicine [RCTs] have criticised the adoption of interventions evaluated by using only observational data. We think that everyone might benefit if the most radical protagonists of evidence-based medicine [RCTs] organised and participated in a double blind, randomised, placebo-controlled, crossover trial of the parachute.’
In essence they are saying that if the observational trials for parachutes are not enough to adopt parachutes, then those requiring RCTs should participate in the trial. But the crossover trial ensures that those who were in the intervention arm (supplied with parachutes) in the first round get to be controls in the next (no parachute).
RCTs are not the only form of evidence that informs ebm. Research on Ivermectin use in Covid-19 is filling all the research levels of evidence in the evidence-based medicine pyramid. Although the lowest level of confidence publication is an opinion piece, a growing number of opinions pointing in the same direction alerts one to possibilities. As at the beginning of August, we have over 20 published opinion pieces in our bibliography. Case studies, case series, and cohort studies are small descriptive studies outlining patient outcomes. These studies, by their nature, are not controlled for bias but continue to show signals worth following. We have 25 in our bibliography.
But the most important studies that are being neglected are the mechanism of action papers and safety data and the other laboratory-based research. The NEMLC’s statement that “What evidence does exist does not suggest any clinical or virological benefits” implies that they have not engaged with this body of literature. The signals coming from these studies all point to the fact that we understand how Ivermectin works in Covid-19, that its already established safety profile continues to exhibit itself and that animal studies are confirming what we already know.
Going back to Ogilvie3, his insights as a public health specialist at the MRC Epidemiology Unit at the University of Cambridge suggest that we need to be pragmatic and assess a range of evidence and “mosaic them together to give a picture of whether something is worthwhile.” Then you need to constantly evaluate practice and keep up with emerging research.
As a scientist in medical research, I do not believe Ivermectin should be given the green light yet. We need more pharmacokinetic and pharmacodynamic studies across the spectrum of co-morbidities, age groups and variants. But there has been enough practice on the ground, and enough research evidence for the orange light. Which means that the use of Ivermectin by doctors who have educated themselves on the drug, and who are currently getting positive results on the frontline, should not be actively discouraged from using it.
The NEMCL reiteration of their previous statements has also caused misunderstanding with some doctors being under the impression that Ivermectin may not be prescribed outside of clinical trials. This is indeed false, because off-label use continues under the court order, as does the SAHPRA Controlled Compassionate Use Program. Many doctors have changed medical insurance providers after some introduced measures to curtail Ivermectin prescription.
- Sackett, David L., et al. “Evidence based medicine: what it is and what it isn’t.” (1996): 71-72.
- Cohen K, De Waal R, Gray A, Kredo T, Maartens G, Nel J, Parrish A, Rees H, Reubenson G. NEMLC THERAPEUTIC GUIDELINES SUB-COMMITTEE RECOMMENDATION.
- Pearson H. How COVID broke the evidence pipeline. Nature. 2021:182-5.
- Smith GC, Pell JP. Parachute use to prevent death and major trauma related to gravitational challenge: systematic review of randomised controlled trials. BMJ. 2003 Dec 18;327(7429):1459-61.
- Prof Colleen Aldous has a doctorate and is a full Professor and Health Care Scientist at UKZN’s medical school where she runs the doctoral academy at the College of Health Sciences. She has published over 130 peer-reviewed articles in rated journals.
- SA health regulator gives Ivermectin the red light … again! – Professor Aldous and Dr Mdladla interrogate
- Ivermectin: facts and science are in its favour – Dr Rapiti
- Ivermectin: Are we trusting a handful of experts at the potential cost of human life?
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