An Urgent Probabilistic Framework For Treatment of Outpatient COVID-19 Disease Using Cyclosporine: A Lesson From Medical Devices’ 510(k) Process.

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Cyclosporine is a widely available, inexpensive and generic anti-inflammatory drug that is highly likely to block progression of COVID-19 inflammation and would very likely prevent hospitalizations and critical illness in a majority of patients, if used.

It is November 2020. We do not have ANY effective, or reasonably effective, standard therapy for treatment of COVID-19 outpatients with worsening symptoms, who ultimately become hospitalized, or critically ill.

The United States is now out of time to perform the traditional pre-COVID randomized controlled clinical studies at pre-COVID speed.

We are out of time to generate data in traditional Phase 1, 2 and 3 clinical trials for use of generic anti-inflammatory agents against unremitting COVID-19 disease.

America’s public health leaders have wasted precious time, mainly focused on developing anti-viral agents, neutralizing antibodies and a vaccine — while ignoring COVID-19’s “kill mechanism”: T-cell and Macrophage Mediated Inflammation!

Specifically, despite serious efforts on all fronts, since March 2020, we are out of time to properly test the T-cell and Macrophage specific anti-inflammatory drug, cyclosporine, for treatment of COVID-19 disease.

The easily anticipated Fall/Winter 2020 COVID-19 upsurge is currently underway.

Our nation wasted precious time tinkering with complex, novel, expensive and non-scaleable, but profitable therapies. Therapies, which are unlikely to be available to the vast majority of people, being catastrophically affected by COVID-19 disease right now.

But it’s not too late.

Ironically, I find myself in a position of visiting other paradigms of rapid innovation within the FDA policy framework for examples of how we might justify unleashing cyclosporine from its surreal generic drug silo — during a pandemic time, where a coronavirus is causing the type of deadly inflammatory disease this drug is highly likely to specifically block or ameliorate.

By virtue of my own personal history, I cannot help but know, well, the medical device space’s 510(k) framework for market clearance of medical devices by the FDA.

It is ironic, because I’ve spent the better part of the last decade critiquing 510(k). Because, as a matter of routine, it does expose patients to too many safety problems in the medical technology space - a catastrophic one of which, I lost my own wife to, back in 2017.

Full disclosure, I am NOT a fan of 510(k), because I know that it has a severe deficit in capturing unsafe medical devices. Those who know me well, have followed and read my specific critique of this regulatory framework for medical products. So, I hope, the fact that I am invoking the 510(k) example to convince policymakers and physicians of its potential utility during the COVID-19 pandemic might resonate with my friends in government.

To be clear, in the 510(k) framework, no Randomized Controlled Trial (RCT) is required for clearing a new medical device into the marketplace. Literally millions of Americans are annually treated, some in highly invasive manners, by medical devices that were cleared by FDA for use following the 510(k) process.

So, how does this 510(k) work?

510(k) increases the speed of medical product entry to market by requiring only: 1) a reasonable assurance of safety and 2) a substantial equivalency to a prior effective device.

In other words, the vast majority of the millions of medical devices in the US are cleared for marketing and use in patients, not with the traditional evidence-based methods required on the drug side of FDA (i.e., the RCT), but using a probabilistic approach to getting technological advances to market FAST.

The main ethical rationale for the 510(k) process is that this mechanism allows for efficient innovation and delivery of novel “life-saving” products into the healthcare space — quickly.

Of course, as I said, using this probabilistic 510(k) approach has created its share of disasters in the medical device space, which I know only too well. And I remain convinced that the Center for Devices and Radiological Health at FDA needs to reform this process to ensure that faulty medical devices do not get through the safety cracks — the one that killed my own wife being a prominent example (i.e., the Laparoscopic Power Morcellator).

BUT, in truth, there are times when the probabilistic approach built into 510(k) is the ONLY way to achieve enough speed to target on a systemic level. I believe an out of control pandemic is exactly such an instance.

So, I am certain that Operation Warp Speed and FDA need to work quickly towards adopting the principles guiding the existing 510(k) model in the medical device space in thinking about cyclosporine’s (or any other generics’) utility against COVID-19 inflammation.

Specifically, by asking the following questions:

1) Is there a “reasonable assurance of safety” in the use of this drug against unremitting COVID-19 disease? Built into the answer to the “reasonable safety assurance” are prior precedents for cyclosporine use during infections, emerging anecdotal/observational evidence, and A RISK-BENEFIT trade-off considering the mortality/socioeconomic cost of COVID-19 disease itself vs. any potential harm from transient use of this drug. In other words, does one expect that any catastrophic complications associated with a 7 day course of cyclosporine will be any more catastrophic than the 2–5% mortality COVID-19 disease, itself, imposes on the population? I am certain not!

2) Is there a “reasonable assurance of efficacy” in the use of this drug against unremitting COVID-19 disease? Built into the answer to the “reasonable efficacy assurance” are the mechanistic scientific rationale for cyclosporine’s use to block inflammation, any anecdotal/observational studies available pointing to an efficacy signal, and clinical precedent for treatment of similar diseases with this cyclosporine.

At this late hour we can, with certainty, state that the slope of rise in COVID-19 cases is not being captured by the slope of progress in our traditional clinical trials of anti-inflammatory generic drugs. So, it is inescapable that we need to rely on a probabilistic model for target drug identification — if we are to stand a chance at protecting lives, and our hospitals, in a meaningful way.

The “reasonable assurance of safety/efficacy” paradigm built in to FDA’s 510(k) mechanism, used for clearance of the vast majority of medical devices space, has thus far primarily served an entrepreneurial objective in the healthcare marketplace — at times with disastrous consequences. But, in fact, this flawed but living policy paradigm may be the blueprint for the reasonable and ethical deployment of generic drugs like cyclosporine against COVID-19 disease in this raging pandemic.

In fact, I would go as far as to state that not thinking and acting probabilistically about potentially effective anti-inflammatory drugs during this pandemic assault on our nation, would be negligent of us all — simply given the sheer number of lives at risk of mortality within the next several weeks to months across the US and the world.

I have attempted to convince the FDA and its leadership using two separate Emergency Use Authorization (EUA) applications to adopt a “reasonable assurance of safety” approach in thinking about cyclosporine. These EUA applications were both rejected in the Spring and Summer of 2020. The basis for the rejection was that FDA’s Center for Drug Evaluation and Research (CDER) is restricted to traditional Phase 1 trial data to provide EUA approval for the use of any drug for novel indications.

But, of course, despite some very serious scientists and clinicians initiating exactly this type of Phase 1 trial for cyclosporine, led by professor Carl June at the University of Pennsylvania, ONLY 4 patients have been enrolled so far. YES, 4!

Cyclosporine is simply not sexy or lucrative enough for any organized entity to lobby FDA or our executive branch for its rapid testing and deployment. Certainly, the drug has been at a disadvantage at some very high level academic medical centers, because it is not deemed cutting-edge enough!

So, short of a systemic or federal willingness to use the “reasonable assurance of safety” metric to trigger wide scale observational use of cyclosporine to block COVID-19 disease progression, we are left with only one option: off-label use by individual physicians in appropriate consenting patients.

At this late hour as the pandemic undeniably begins to surge, I have no problem personally prescribing this generic anti-inflammatory drug, cyclosporine, to any appropriate patient who is informed and willing to be treated. I certainly hope that my colleagues and friends might understand the rationale for my doing so and follow suit.

Our pre-COVID algorithms for innovation in the drug space are failing us catastrophically during this pandemic. Primarily because for the past 9 months these algorithms have been deployed dominantly by money interests and professional prejudices — not by fully balanced science. In this lop-sidedness, inflammation, which is the main cause of COVID-19 morbidity and deaths, has been well ignored.

And, as of today, America’s public health leaders are still ignoring a viable and clinically cogent therapy specifically directed at COVID-19 inflammation: cyclosporine!

I am left knowing that the only choice now, is careful “off-label” use to block inflammatory disease progression!

Hooman Noorchashm MD, PhD is a physician-scientist. He is an advocate for ethics, patient safety and women’s health. He and his 6 children live in Pennsylvania.

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