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SAHPRA’s Ivermectin decision shows wilful blindness to totality of evidence – Professor Aldous
This week, the South African Health Products Regulatory Authority (SAHPRA) announced that: “Given that there is currently no credible evidence to support a therapeutic role for Ivermectin in Covid-19, SAHPRA has decided to terminate the controlled compassionate programme with immediate effect.” SAHPRA enabled the programme in response to the demand for access to Ivermectin for human use, which was initiated at the beginning of 2021, after the country had been under lockdown for almost an entire year and was desperate for alternative therapies to treat Covid-19. Prior to the onset of Covid-19, Ivermectin had been used in humans for 35 years and over four billion doses had been administered. In 2015, the two individuals who developed Ivermectin were awarded a Nobel Prize for medicine. However, when Covid-19 came along, Ivermectin was a thorn in the side of the official narrative. Professor Colleen Aldous, a healthcare scientist at UKZN’s College of Health Sciences, has valiantly challenged the establishment’s resistance to Ivermectin throughout the pandemic. After SAHPRA’s decision this week, Aldous penned the following article dissecting Ivermectin trials, which credibly evidence the benefits of Ivermectin. Aldous asserts that SAHPRA is “wilfully blinded to the totality of the evidence [and] follow only what is fed to them by other ‘reputable’ national and international bodies”. As always, each reader can decide for themselves. – Nadya Swart
Pondering SAHPRA’s Ivermectin decision
By Professor Colleen Aldous*
On 30 May 2022, SAHPRA shut down their Controlled Compassionate Use Programme for Ivermectin, which they put in place at the end of January 2021. It is not the fact that they have terminated the programme that worries me as much as their reasons for doing so. The compassionate use programme was never going to be permanent, and good housekeeping would require a formal termination. Had their reasons been because “no new applications for importation of unregistered Ivermectin products have been received since August 2021. A marked decline in the number of health facilities applying for permission to hold bulk stock was noted after August 2021. No individual named patient applications have been approved since December 2021, and a lack of reporting by the treating healthcare providers of the outcomes achieved was also noted”, I would not raise an eyebrow.
But they have said that the latest developments have led to their decision. Let’s unpack these from their press release and ponder the scientific integrity of their rationale:
“The studies that suggested potential efficacy of Ivermectin in the prevention and treatment of Covid-19 and which motivated the adoption of the programme have since been retracted.”
On 25 May 2022, I did a snapshot search on PubMed for all papers published on ‘Ivermectin’ and ‘Covid-19’ or ‘SARS’. PubMed is the go-to database for published literature in the medical sciences. My search rendered 317 articles. Of these, 41 studies were carried out in a clinical setting, and two were retracted with retraction notices published. Reading between the lines, I think SAHPRA was referring to the Elgazzar trial, which was included in initial reviews from several authors. Elgazzar has not been heard of again since his study, which was never published beyond preprint format, and had received enormous criticism through the press worldwide, so his work has to be rejected. Nevertheless, most of the meta-analyses that had already been carried out excluded this study, and the results still showed efficacy for various measures of morbidity and mortality.
Another paper that was retracted was Andrew Hill’s meta-analysis. In January last year, the world was waiting for the promises from Hill’s work. It was apparently also the Elgazzar study that SAHPRA suggests in their statement, “This was due to serious ethical concerns regarding a study on which the meta-analysis heavily relied.” At the same time, however, others were also carrying our meta-analyses. The Bryant et al. meta-analysis showed efficacy for Ivermectin even after removing the Elgazzar data but has been ignored. The science of review and meta-analysis has shown me the creeping subjectivism that has come into what is meant to be a very high standard in evidence-based medicine. Right now, I believe the only meta-analysis I can take as truth will be one I am involved in doing.
SAHPRA refers to two 2021 clinical trials that “do not support the use of Ivermectin for patients with COVID-19”. These are the Malaysian I-Tech study and the TOGETHER trial. Ironically, SAHPRA representatives criticised the literature available in January 2021 as not being credible, yet they base their decisions on these two trials which have been shown to be flawed.
The I-Tech trial was underpowered. Their primary outcome measure was progression to severe disease, a soft outcome that can be subjectively applied. In the study, 52 of 241 patients in the ivermectin arm and 43 of 249 patients (17.3%) in the control group progressed to severe disease. Nevertheless, for other outcomes, Ivermectin clearly showed a trend towards benefit with only four patients on Ivermectin requiring mechanical ventilation occurred vs 10 on placebo, six on Ivermectin requiring intensive care unit admission in vs eight, and three on Ivermectin vs 10 for 28-day in-hospital death.
Whilst their conclusion, “the study findings do not support the use of Ivermectin for patients with Covid-19”, is true only because a p value of 0.05 was not achieved for the primary outcome, it is misleading as it implies strong evidence against the use. Their Ivermectin arm has an advantage for mortality with a p = 0.09. This means that you can be 91% certain that Ivermectin was effective in preventing mortality in their study. The p value has not done medicine any favour when studies are judged only on this number and not on clinical context.
The TOGETHER trial was designed as a coup de gras to crush the Ivermectin debate. Weeks before its publication, there were press releases internationally stating that the trial found Ivermectin to be ineffective. Since its publication at the end of March, there have been scientists and medical professionals from across the globe who have challenged this trial on grounds of poor design, poor execution and poor reporting of results. Whilst I share the concerns of my colleagues, there is one particular statistic reported in this trial that worries me and that is of the mortality calculated in the placebo group.
Let me explain. There were 679 patients enrolled in the ivermectin and placebo arms respectively. The numbers dropped to 624 and 288 respectively. In the Ivermectin arm, 21 people died out of the 624 who completed the study, and 24 people died out of an unknown number of patients. The researchers clearly did not use the 288 placebo participants who completed the study in the control arm. It appears they may have borrowed placebo participants from other study arms in the broader TOGETHER trial. Why would they do this?
I wrote to the senior author asking the following question for clarity: “The placebo group mortality is 24. When I work out the RRR I get the same answer as offered in the paper if I use the ITT (679) number. However, it is not clear to me where the 24 deaths actually come from. How many of the 24 reported deaths in the placebo group occurred among the 288 patients who stayed per-protocol? It is reported how many of the placebo group’s hospitalisations occurred in the per-protocol group but not the mortality.”
The response from Doctor Edward Mills: “I’m not interested in this question as it’s not the correct way to interpret the outcome.”
Many scientists from across the globe are incorrectly interpreting the outcome then. In research as we know it, one would work out the mortality in the intervention and the placebo arm, i.e. the 624 and 288. If this was so, then there is a clear survival advantage in the Ivermectin arm with 21/624 and 24/288 deaths in each arm respectively. Clearly there is a new way of calculating mortality in this trial which Dr Mills feels he cannot explain.
On 4 April 2022, Mills wrote to a colleague: “I don’t understand the psychology of the Ivermectin advocates. They fail to see the positive in this study and just focus on it not being overwhelmingly positive. I actually think it is quite positive. I presented this a couple weeks ago at the NIH Collaboratory Rounds and, if they listened, I advocate that actually, there is a clear signal that IVM works in Covid-19 patients, just that our study didn’t achieve significance. In particular, there was a 17% reduction in hospitalisations that would be significant if more patients were added. I really don’t view our study as negative and, also in that talk, you will hear me retract previous statements where I had been previously negative. I think if we had continued randomising a few hundred more patients, it would have likely been significant.”
There are calls for the TOGETHER trial to be retracted. However, it comes from the New England Journal of Medicine, which appears to be beyond reproach. Ignoring calls for retraction is within their authority. It was also stated that after publication, the data would be made available. Several colleagues have requested the data through the correct channels and have been stonewalled.
The TOGETHER trial has had some success as a coup de grace. SAHPRA refers to the NEMLC and the NICD not supporting Ivermectin. They usually follow what the USA NIH does. The NIH COVID-19 guidelines panel, misled by the TOGETHER trial’s claims, had no credible scientific basis for its 29 April 2022 changed recommendation on IVM from neutral to negative. Do we have to copycat the West? 47 African nations stood up together in the WHO on 30 May and firmly stated that they would not support WHO ‘reforms’. We should be standing up together more frequently against centralised control that may not necessarily have our interests as Africans as primary goals.
In my snapshot analysis of the literature last week, I found lots of data on the safety and efficacy of Ivermectin. Dosages have been worked out based on Merck’s own research from the early 2000s. Drug interactions are well known, particularly with Warfarin, side-effects are well documented as being relatively mild and transient. VigiAccess shows 6,558 adverse reactions and 25 deaths for Ivermectin in its decades of use and Remdesiver has 8,763 adverse reactions and 652 deaths since it was introduced three years ago. I will leave the reader to decide how safe or dangerous Ivermectin is.
Yes, it is SAHPRA’s obligation to consider all published data, but do they? They make reference only to the two trials and the one meta-analysis from 2021. They are not considering the totality of data. They have ignored all the laboratory and modelling studies that support the use of Ivermectin. They have ignored all the other published meta-analyses that do not fit their argument. And their guiding ‘reputable’ authorities from the developed world do not always make decisions that are appropriate for us in Africa, so should not be followed without question and depth of thought. Again, I draw attention to our continent standing up against the WHO reforms on 30 May.
The vaccines are not a replacement for Ivermectin, nor vice versa. Ivermectin’s role is mainly in the early treatment of Covid-19 to prevent progression to severe illness. Colleagues from the USA, SA and Zimbabwe have just had a paper accepted for publication. We show that after Ivermectin is given to a sick patient, their oxygen saturations improve dramatically within 12 hours without oxygen being provided. Having been involved in this research has convinced me of the efficacy and safety of Ivermectin in certain patients at specific times under certain conditions. No large randomised control trial has yet been carried out with appropriate dosages, over the appropriate length of time, and with meals and zinc because Ivermectin is a zinc ionophore.
SAHPRA has a very narrow definition of credible evidence. They are wilfully blinded to the totality of the evidence. They follow only what is fed to them by other ‘reputable’ national and international bodies. Do they do any research monitoring themselves? They say they “will continue to monitor the peer-reviewed, scientific literature regarding the safety and efficacy of Ivermectin”. As the public, we should ask them for the evidence that they have started!
- Professor Colleen Aldous is a healthcare scientist at UKZN’s College of Health Sciences where she runs the Doctoral Academy. She is a member of the Academy of Science of South Africa. She has a PHD and has published over 140 peer-reviewed articles in rated journals.
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