FDA’s New and Irrational Aversion Towards Granting Emergency Use Authorization for Generic Drugs in the Midst of the COVID-19 Pandemic
Dr. Hooman Noorchashm is an American cellular immunologist and thoracic surgeon with expertise in transplantation immunology and autoimmunity. Since March 2020, he has been advocating for testing and deployment of cyclosporine for blockade of COVID-19 disease progression to critical illness. Photo credit: stock image SS21381246, source www.ScienceDirect.com
On April 27, 2020 the United States Food and Drug Administration, rejected an Emergency Use Authorization (EUA) application submitted by a group of clinicians and scientists from Philadelphia, PA, USA.
This EUA application sought FDA authorization to quickly test the generic immunomodulatory drug, cyclosporine, to block progression of the hyperimmune syndrome caused by SARS-CoV-2 virus. Using FDA's own "Real World Evidence" (RWE) mechanism, this EUA asked FDA for authorization to formally test the drug in a limited number of patients "with unremitting COVID-19 disease.
Rejection of the cyclosporine EUA is, sadly, emblematic of the haphazard response of the United States federal government to the COVID-19 pandemic – one which has cost nearly 100,000 lives as of this writing. As it became clear that FDA’s buckling to non-expert US presidential demand to grant an EUA to the anti-malarial drug, Hydroxychloroquine, was an error, the agency seems to have oscillated to the other extreme. Now, even scientifically and clinically cogent EUA proposals involving generic drugs whose safety profile are well known are resisted by FDA - in the midst of a deadly global viral pandemic.
I’m not writing this opinion piece as a critique of the choice of Hydroxychloroquine for treatment of COVID-19 disease – though the debacle speaks for itself to most reasonable physicians and observers. Rather, I am suggesting that two wrongs don’t make a right. If FDA’s leading experts caved to the presidential bully pulpit in granting an EUA to Hydroxychloroquine, they ought not compound that error by unreasonably heightening their threshold for approving other scientifically and clinically legitimate EUA requests using nimble legal testing pathways, like RWE. To do so, literally blocks efficient deployment of potentially life-saving drugs – especially ones like, cyclosporine, for which large commercial revenue interests are not vying.
A word or two about the rationale presented to FDA for emergency testing of cyclosporine in treatment of COVID-19 disease. It is becoming clear that progression to critical illness in COVID-19 patients is related to a hyperimmune reaction mounted by T-cells and Macrophages. In some patients, this hyperimmunity morphs into a cytokine storm syndrome akin to that seen in the disease entity known as Hemophagocytic lymphohistiocytosis (HLH). Though the treatment of cytokine storm syndromes and HLH enjoys a diversity of clinical approaches, cyclosporine is a main staple - particularly in cases refractory to corticosteroids. Not to mention that literally millions of ambulatory patients on the planet are taking this relatively inexpensive drug daily, to dampen a variety of T-cell and macrophage mediated hyperimmune diseases – anything from Inflammatory Bowel Disease, to Ulcerative Colitis, to Psoriasis, to organ transplants.
Three main mechanistic characteristics of cyclosporine make it particularly attractive as a candidate to block progression of COVID-19 hyperimmunity: 1) by virtue of inhibiting the Calcineurin Pathway, it is a highly specific dampener of T-cell and macrophage activation, which is the likely root of COVID-19 disease pathogenesis, 2) it spares activated B-cells and Antibody Secreting Cells (ASCs), responsible for producing neutralizing antibodies, and 3) it’s been shown to inhibit replication of coronaviruses in vitro.
Additionally, by virtue of being a vastly utilized generic and relatively inexpensive nonbiologic, cyclosporine is globally scalable – particularly in the developing world.
As of this writing in May 2020, FDA has yet to approve even a traditional “Investigational New Drug” (IND) application for a phase 1 trial of cyclosporine in COVID-19 patients at a prominent US medical center – submitted by a well-known team of clinicians and cellular immunologists. This process promises to take at least another several months – with thousands dying every day and millions of lives still at risk in America and abroad. In this regard, our colleagues in Spain appear to be ahead of the curve with a clinical trial of cyclosporine already underway. I highly suspect that the Spanish results will be of extreme importance to interruption of COVID-19 disease globally.
As an American physician-scientist, it is quite tragic to witness the real-time decline of American leadership in medicine with the world confronting its gravest existential medical challenge in living memory. Not only is the US medical and public health establishment being guided lethargically by nonexperts, like the President of the United States himself, overriding clinical expertise and science with foolish bombast, but our regulatory drug approval framework at FDA is failing too: It is arcane, it is unadaptable and it is guided, dominantly, by political or money interests in big Pharma – and not by practical and nimble translational science or reason.
With a potential vaccine against SARS-CoV-2 on the distant horizon, if that, and with the current American leadership vaccum in place, it is incumbent on every nation in the world to act well instead. Any and all scientifically feasible and scalable drug options ought to be efficiently tested to block progression of COVID-19 disease to critical illness. Chief among these, cyclosporine ought not be ignored.