Two prominent researchers affiliated with Emory University, including a Professor of Medicine and Dean of the School of Medicine and Chief Academic Officer of this preeminent university, remind readers recently in Health Affairs that although COVID-19 cases are now on the decline, 3,000 Americans die every day while more contagious and possibly dangerous mutant strains circulate around North America now, again keeping health systems on the precipice. While the authors express overall confidence in the global drug and vaccine development imperative, they warn that mass vaccination impact won’t evidence palpable positive results until at least mid-2021. Moreover, they are mindful that these vaccines are still experimental (under emergency authorization) and many outstanding questions remain unanswered—such as how long they are impactful. Vikas Sukhatme and Vidula Sukhatme boldly declare more must be done, and now. That is, a plan to potentially save up to 150,000 lives over the next few months. Listen to their proposal—use repurposed drugs in a national decentralized real-world program, while monitoring the ongoing real world data. Only an easy to administer, affordable, scalable, and of course safe and efficacious therapy can work. Yet multiple drugs can possibly serve this interim strategy, suggest the academic researchers. With established safety records and evidence of treatment in the hundreds of millions, the risk profile is low, and off-label treatment should be considered—now. These drugs include ivermectin, fluvoxamine, colchicine, famotidine and nitazoxanide in conjunction with monoclonal antibodies for higher risk patients and of course ongoing vaccination efforts. The authors posit such an approach could markedly lower the number of patients necessitating hospitalization in the short run.
TrialSite breaks down the authors case for this very different approach. Think of it as the Operation Warp Speed for rapid recovery from COVID-19. Who will pay for it? The authors here become a little less daring but TrialSite helps them out.
Why do the authors suggest decentralized studies over traditional randomized controlled studies for this emergency action?
Well, it’s pretty simple. Traditional randomized controlled trials are complex, time consuming and expensive. Firms involved with off-patent drugs have little financial incentive to repurpose for another use. The time, effort and capital necessary will often not outweigh the return on investment. Investigator-initiated trials have limitations, including the time it takes to enroll participants.
However, a decentralized trial could be used to enroll participants nationally, in a way mirroring the COLCORONA study that involved a patient-centered remote model. Via telehealth, smart phone apps and home delivery, a compelling regional or national initiative would take vision and leadership but is very doable.
Why doesn’t government agencies issue temporary guidance encouraging repurposing of off-label drugs targeting COVID-19?
That’s a great question. The two authors smartly suggest such a move by the National Institutes of Health, Centers for Disease Control and Prevention or the U.S. Food and Drug Administration (FDA). This guidance could spell out the inclusion and exclusion criteria, dosing, monitoring requirements and a standardized informed consent form.
The authors suggest that once this infrastructure was in place, any physician and doctor regardless of location could immediately participate, facilitating rapid enrollment, participation and ultimately generation of real world data. After all, the National Institutes of Allergy and Infectious Diseases (NIAID) went to great lengths to consolidate their trial site and investigational networks to form the COVID-19 Prevention Network to test primarily novel, investigational products. Why couldn’t they consider the great idea by these authors to help save lives?
TrialSite has been on the record for several months now that a global ivermectin registry was needed—unfortunately, not enough funders materialized.
Is the author’s idea the same as an Emergency Use Authorization?
While similar in concept to the EUA, this approach differs in that they propose a program that includes data collection, monitoring and evaluation ongoing of real world data for safety and efficacy.
How would the data be tracked, according to the Emory-based author?
Coupled with the temporary guidance issued by government agency, a tool such as the FDA-sponsored CURE ID app could be used. They suggest that government funds could be pooled to offer a “small stipend to incentivize physicians to report their real-world patient data” as well as fund an analytics team for monitoring real-world data, including safety events.
Does the author’s approach have a comparable program out there?
Yes, possibly the Temporary Recommendation for Use classification in France. They quote: “regulatory instrument which aims to allow, on a temporary basis, the use of a medicinal product to allow its effectiveness to be evaluated on the basis of its use.” The Emory-based authors continue that this approach would offer “patients immediate options otherwise not available combined with infrastructure to help “…transform real-world data into real-world evidence.”
Why is there advantages to this proposal?
With a federal authority guidance combined with standardized data collection, informed consent and monitoring as well as rapid enrollment of substantial numbers of patients from diverse background, this study could possibly mitigate the challenges raised about the lack of randomization. The authors rightly point out that often well-designed and controlled studies do not always stimulate real world reality yet they are accepted by medical authorities. Moreover, much like is done with NIH and WHO so-called platform studies, this approach could involve simultaneous assessment of multiple repurposed therapies. They suggest an emerging front runner could be transitioned to big, randomized study if merited.
What are some drawbacks?
According to the authors, this proposed approach is optimized for use of “Oral drugs with few well-characterized drug-drug interactions and known minimal toxicities.” Drugs that aren’t well known in clinical practice may pose more of a challenge for physicians.
Moreover, this approach could expose a greater number of patients to adverse effects but this is mitigated by known safety profiles of most of these proposed drugs and two dedicated central analytics team tracking incoming data for signals.
Would this approach compete with existing clinical trials?
While the authors conjure a politically correct answer referencing the hydroxychloroquine debacle—that is, they won’t compete with existing studies, the reality is probably different. The authors fail to address the power and money connections to what is probably approaching at least $20 billion in public money transfers alone to just a handful of drug development firms. These novel therapeutics are in need of patients and in fact when a health system signs up to do a monoclonal antibody study, for example, they may in fact sign an agreement that precludes them from doing something deemed competitive.
How would this centralized, federal level study be paid for?
Here the authors again lose some of their audacity. Suggesting that if payers don’t buy in to cover, that a “fund” could be raised—but they don’t spell out where that money comes from. Suggesting if Medicare/Medicaid agreed then insurance could follow; howver, the authors neglect to look at existing funding mechanisms associated with the U.S. government involving tax payer money—The NIH Foundation’s ACTIV; HHS BARDA, Department of Defense (JPEO-CBRND) and others are pouring hundreds of millions to billions into COVID research now. Why couldn’t they help pay—its ultimately taxpayer money. For a breakdown of how NIH’s ACTIV allocates (or makes recommendations) to spend money, see the TrialSite piece. For a different sort of introduction to ACTIV, see the link.
What agency could champion this cause?
The authors introduce the FDA’s collaboration with the National Center for Advancing Translational Studies (NCATS) and their Cure Drug Repurposing Collaboratory or “CDRC” as a possible champion for such an endeavor. This group could in theory promote tools, such as CURE ID for the data collection, analytics and evaluation in conjunction with testing of “financial orphans” as an example supporting repurposed drugs with no financial backing.
What if the government moves too slow? What else can be done?
How about a few major health systems taking the lead? They could not only issue temporary use guidance but also encourage provider and specialist networks “…to prescribe off-label treatments in a standardized manner, ideally with an informed consent.” This program could also involve the careful, select and proper use of clinical records following HIPAA and the like. Like TrialSite has called out for, a patient registry can be set up and monitored.
Again, the same federal bodies that have allocated billions to drug and vaccine developers could also incentivize health systems to get this program started.
Who are the Authors?
Call to Action: Follow the link to Health Affairs to read this entire fascinating and what some might consider provocative opinion piece. What are your thoughts? You matter!