Magnevist was approved in 1988 by the FDA to “….facilitate the visualization of lesions and abnormal vascularity ….” The pharmaceutical was intended, in other words, for the diagnosis of cancer and stroke. Five years later, Harvard researcher Martin Prince published an article showing the effectiveness of this pharmaceutical for the diagnosis of atherosclerotic disease. The finding was replicated by other investigators and this use has become standard-of-care for the detection of atheroschlerotic disease. The adoption of this pharmaceutical for this purpose was never endorsed by the FDA or any other US governmental body. Clinicians simply learned from one another.
There are numerous instances of the process of drug repurposing. In some cases, the repurposing has been done with the explicit endorsement of the FDA. This is the case for the repurposing of Viagra pulmonary hypertension subsequent to its original approval for erectile dysfunction. Another case is that of Thalidomide that received its original approval for the treatment of leprosy but later received FDA approval for the treatment of multiple myeloma. Likewise, Amantadine was initially approved by the FDA for the treatment of influenza and later received approval for the treatment of Parkinsons disease.
In these cases though, FDA approval is not required. The only advantage of FDA approval is that marketing of a drug for a given indication requires FDA approval. The advantage of this model of drug development is that any physician with a modicum of scientific and regulatory expertise can contribute.
Into the mix comes COVID-19. In response to the pandemic, large-scale government-sponsored clinical trials were initiated. The goal, at least initially, has been drug repurposing for COVID-19. Notable successes of this model were validation of dexamethasone by the RECOVERY trial and budesonide in the PRINCIPLE trial. Limitations of this approach have also been apparent. To date the NIH ACTIV initiative and the WHO SOLIDARITY trial have both failed to produce effective COVID-19 therapies. In the case of the NIH ACTIV initiative, it has failed to even evaluate a single therapy.
Another governmental response to COVID-19 was the COVID-19 Treatment Guidelines. The Guidelines are produced by a panel of 46 medical experts and community advocates. The Guidelines identify promising therapies and provide a recommendation for or against the use of the therapy in COVID-19. In some cases, the Guidelines indicate that there is insufficient evidence to even make a recommendation.
Recommendations from the Guidelines are not enforceable:
“… it is important to stress that the rated treatment recommendations in these Guidelines should not be considered mandates.”
On the other hand, the Guidelines are quite influential. The recommendation process does not explicitly require evidence based on monolithic clinical trials. In fact, other types of evidence are explicitly recognized including “nonrandomized trials”, “observational cohort studies” and even “expert opinion”. However, the standard that is embedded in the Guidelines recommendation is highly dependent on the quality of the clinical trials:
“Results from adequately powered, well-designed, and well-conducted clinical trials are needed to provide more specific, evidence-based guidance on the role of ivermectin in the treatment of COVID-19.”
That brings us to ivermectin. On August 27, 2020, the Panel updated its Guidelines with the inclusion of ivermectin; an off-patent drug that has been repurposed with extraordinary success. It was originally approved by the FDA to treat river blindness (1987). It has since been approved by the FDA for the treatment of head lice under the trade name of Sklice (2020), for the treatment of rosacea under the trade name of Soolantra (2014) and for the treatment of intestinal strongyloidiasis under the trade name of Stromectal (1998). Use of ivermectin in the treatment of scabies has been endorsed by the World Health Organization but is not FDA-approved.
In its initial review of ivermectin the Guidelines recommended against the use of ivermectin in COVID-19 except in the a clinical trial. However, on January 14, 2021 the Guidelines lifted its recommendation against the use of ivermectin in COVID-19 but also noted the lack of good evidence for its use:
“There are insufficient data for the COVID-19 Treatment Guidelines Panel (the Panel) to recommend either for or against the use of ivermectin for the treatment of COVID-19. ”
Other leading medical authorities including the FDA, the European Medical Agency (EMA), and the World Health Organization (WHO) have followed with recommendations against the use of ivermectin in COVID-19 except in clinical trials.
A flash point in the growing conflict over the use of ivermectin in COVID-19 is a recent article in the Journal of the American Medical Association (JAMA). The clinical trial described in the article was physician-initiated. The trial showed improvement in the resolution of symptoms in COVID-19 patients but the trial result failed to reach statistical significance. Notably, the trial also involved profound ethical violations. In spite of that, the study has been cited by both the EMA and the WHO to justify their recommendation against the use of ivermectin in COVID-19 except in clinical trials. This conclusion has been challenged in an open letter to JAMA by a group of over 100 physicians who wrote:
“We oppose this fixation on randomized controlled trials at the expense of other clinical and scientific evidence and urge medical policymakers to restore balance to the practice of medicine.”
As drug repurposing has come under more control from the medical authorities, there is a correspondingly greater need for transparency of those authorities. As has been reported earlier, the COVID-19 Treatment Guidelines Panel has been less than transparent. A particularly concerning issue is whether votes have been held to endorse recommendations. As strange as it may seem, the NIH has not been able to confirm that a vote was held on the latest recommendation on ivermectin. That has now led, unfortunately to a legal confrontation under the Freedom of Information Act that entitles journalists and others access to federal government records.
In summary, the process for drug repurposing has undergone a subtle but important change in response to the pandemic. The physician-centric model has been displaced, in the US, by a more centralized, governmental model. Choices of medications for COVID-19 are now strongly influenced by the views of the members of the COVID-19 Treatment Guidelines Panel. At the very least, this medical authority has a responsibility to follow the absolute best practices for transparency. The public must be confident that their decisions are based purely on science and the public interest.