TrialSite recently went on the record that a major clinical program announced by the National Institutes of Health (NIH) for the “ACTIVE” program, while appreciated, was in many ways too late—this announcement should have occurred by last summer of 2020 at the latest. Instead, billions of taxpayer dollars were marshalled into the Accelerating COVID‑19 Therapeutic Interventions and Vaccines (ACTIV) public–private partnership, with an overwhelming focus on vaccines and novel therapeutics as TrialSite has been nearly alone in chronicling. But for nearly a year now, a growing numbers of front line physicians argue that care needed to happen in the clinic—and fast! While NIH director Francis Collins recently acknowledged that “While we’re doing a good job with treating hospitalized patients with severe disease, we don’t currently have an approved medication that can be self-administered to ease symptoms of people suffering from mild disease at home, and reduce the chance of their needing hospitalization,” it most certainly took a long time, and a lot of suffering to get to this point. That is, to acknowledge that the ACTIV program needed a major repurposed clinical drug research program targeting COVID-19. It’s ironic that just now, when the NIH via ACTIV announces a major, $155 million-backed clinical program for repurposed drugs targeting COVID-19—led by the National Center for Advancing Translational Sciences (NCATS), part of the NIH—that this organization’s director, a emphatic proponent of drug repurposing, simply resigned. That’s right; on April 15, the NCATS Director, Christopher P. Austin, a known advocate for repurposed drug research, formally called it a day. The departure was actually announced a month earlier by Director Collins. But it seemed odd that Austin would move on right at the time that a major repurposing program would be led by his organization. Why would he do this? What kinds of tensions underlie the nation’s biomedical research institute, one that’s so vital to the nation and world’s future? What’s behind the lack of progress in repurposing drug trials in the pandemic? What can we collectively learn to improve how we respond to pandemics?
On March 18th, the NIH Director, Dr. Francis Collins published a letter thanking Dr. Christopher Austin, Director of NCATS since 2011, for his service. A nice letter full of praises, one had to wonder why Dr. Austin for some reason expired at the institute? Why did this happen now, given just last year the drug repurposing advocate was making some noise, possibly deemed by some in the federal bureaucracy as too critical. His temporary replacement, acting NCATS director Joni Rutter, PhD, commenced April 15 while Dr. Austin shared she would be a fine replacement.
Advocate for Drug Repurposing
Dr. Christopher Austin has been an advocate for drug repurposing, notably in the pandemic. The former head of NCATS was known to publicly ponder what percentage of the 6,500 currently untreatable diseases could be somehow treated by a drug in the current pharmacopoeia that a patient could find over the counter in a drug store? Yet, perhaps, it was such questions that ultimately won fans but also enemies. One to publicly challenge himself and others, he not long ago (and during the pandemic) declared that if NCATS and the NIH couldn’t make sufficient progress in the movement to repurpose drugs then “shame on us!”
But Why So Few Repurposed Drugs?
Perhaps Austin is one of the top experts at this point in the field. He knows well, with certainty, why its so difficult to repurpose drugs for use against other indications. The COVID-19 pandemic offered a textbook case into his hypothesis as to the uncomfortable and inconvenient truth of it all.
But, given the departed NCATS director’s commitment to drug repurposing, one could rationally ask why there are so few off-patented drugs in use for other indications during his tenure? A prime example of off-label usage for COVID-19 has been ivermectin and to some extent fluvoxamine.
Dr. Austin has acknowledged that some nimble, yet well-capitalized non-profit drug development organizations, especially working in low-and middle-income countries (LMICs) have produced more results than America and other wealthy economies in this critical yet somehow struggling discipline. Why do high GDP economies such as the United States, or nations in Europe and Japan, for example, produce so few repurposed drugs? With aging populations and lots of wealth, the demand is there.
Ultimately, Austin struggled at the institute when it came to the topic of drug repurposing. They were able to develop a list of completed, non-redundant lists of repurposed drug candidates that’s been used by researchers in this field worldwide. An accomplishment that’s guided direction, it however is surely not sufficient in his own words.
Dr. Austin’s intentions have certainly been in the right place. His list of comprehensive repurposed drug targets started right with his arrival at NCATS in 2011, and in a way that list defines the drug repurposing mission at NCATS in the context of COVID-19—its on a piece of paper but not much elsewhere until the recent announcement of the major ACTIV-6 study, just days after his final Director’s Message.
Now this evolving list has most certainly had lots of influence, studied and used by many, in projects and myriad reports and studies, from the informal to the most formal of published manuscripts in peer review journals. But one could ask the question, how many of the drugs on that important list have actually been approved for other indications? Well, according to a 2020 presentation, Director Austin declared zero. That’s right: none of the drugs have been successfully authorized for new indications if that statement is 100 percent correct. But how could this be? What, with the immense resources, intellectual firepower and billions of dollars of funding within NIH, how could the answer be none?
The Problem is NOT Science
Director Austin knows that first and foremost the problem is not with the science or repurposing. Much like the ivermectin situation and COVID, where over 50 studies produce truly compelling data that in the aggregate, have led to meta-analyses from highly-respected experts in medicinal evidence: they argue the results clearly point to evidence.
Yet the so-called experts from academia, government, and industry are not convinced due to various technicalities in one study, to another. In fact, the authors of the ivermectin meta-analyses are viciously criticized and censored by social media such as Facebook, YouTube and Twitter. Dr. Austin’s been on the record that contrary to the experts and talking heads in the media that either ignore or find any excuse to poke scientific holes at candidates such as ivermectin or fluvoxamine, the science behind many repurposed drug candidates is not the problem.
Rather, he has shared that the countless drugs on his NCATS repurposed drug master list get stuck in a category where they sort of die in limbo, as they never make it for their turn at clinical trials.
Not an Agency for Repurposed Drugs
Perhaps Austin ruffled some feathers when on April 6, 2020 he went on the record in a workshop titled “Repurposing Off-Patent Drugs: Research & Regulatory Challenges” that in all reality, the NIH and its various institutes, including NCATS, does actually very little to support repurposed drug candidates. While acknowledging incredible team members, brilliant people and wonderful intentions clearly articulates that it’s actually partners and collaborators rather than the institute itself that drives most drug repurposing.
While this phenomena isn’t really noticeable in normal times (unless one has a disease that a repurposed medication could possibly help out with), it became strikingly noticeable during the pandemic, still ongoing. After all, as he made very clear, the NIH was more into sexy, innovative life science breakthroughs, from gene and cell therapy to precision, biomarker-driven treatments. These are exciting—TrialSite celebrates a breakthrough on nearly a daily basis. But just as important is exhausting all the potential existing approved therapies to target existing conditions. That ivermectin has demonstrated so much potential against COVID-19 is just one example.
Repurposed Drugs Die at the Vine
It’s difficult to develop drugs, taking lots of time and money, requiring significant expertise and involving considerable complexities. That’s why Austin himself has gone on the record that most repurposing exercises fail, the drug essentially dying on the vine. That’s because even the dedicated, committed non-profit drug research and development organizations ultimately find translating existing generic drugs to new indications. The great majority of these promising candidates never made it to authorization for new indication and ultimately to the bedside.
The Repurposing Business (or Lack Thereof)
Drug repurposing can imply many different things, activities or elements in a drug development program. But ultimately, Dr. Christopher Austin suggests that one should think about the process as involving three (3) essential categories, including 1) unapproved drugs that never made it to approval and are on the shelf, 2) approved drugs still on patent, and 3) drugs that are off patent and approved—these represent the great majority of cases.
While category number one dominates most repurposing activity, including any initiative at NCATS, it may not be truly as important as category three, which again would include those generics that are approved for at least one indication. It’s the vast majority of drugs on the NCATS repurposed drugs list that would fit into category number three.
Each and every year, this particular list just grows and, of course, ivermectin and fluvoxamine as examples would fall into this category for purposes of COVID-19 discussions. Again, the institute has an abysmal track record of successful translation to the bedside.
Off Patent Roadblocks
But there are some excuses. Drug development isn’t easy nor cheap. To actually develop off-patent, approved drugs for new indications necessitates a lot of intense activity and spend well known in drug development—from toxicology studies to GMP manufacturing of the API and the establishment of the dosage mode for the drug. Additionally, for older drugs, actual availability and adequacy can represent hindrances as can a whole range of practical challenges.
Yes, the breadth of challenges prevail in this sphere of activity. Now introduce the topic of clinical trials and the conversation becomes ever more complicated and costly. Then commercialization and dealing with regulators, payers (insurance companies and government health) and all of this leads to one real answer—the need for industry. And we must remind ourselves, industry must demonstrate return on investment. As TrialSite has articulated in the pharmaceutical company, if management fails to prioritize profit realization they’ll be ousted and replaced by those that do.
Not Sexy Science…No to Little Payment
Austin knew well that a systematic, comprehensive and impactful drug repurposing program presupposes myriad complicated and challenging activities and dynamics, all requiring lots of sophisticated talent, clinical infrastructure and lots of money. Now while the NIH actually spends about $41.7 billion per annum for the people’s research, Dr. Austin is on the record that the institute doesn’t like to pay for the nuts and bolts work necessary for repurposed drugs. But what about in a pandemic where the possibility of such research could save lives? No, as TrialSite has clearly documented over the last year that doesn’t matter: the profit motive is firmly in place right in the middle of a pandemic not because of some greedy cabal of corporations but rather, because of the laws of the market system itself, necessitate such adherence.
Consequently, its disruptive innovation, or ironically, perhaps an incremental “me too” that drives industry to fund research. Austin’s public stance makes this clear telling all that the NIH would much prefer to pay for what’s considered innovative science. In fact, this made him increasingly distressed by the fact that there was so much potential, so much need and so much already on the table in the sphere of repurposing drugs—especially in the context of the COVID-19 pandemic—yet little progress would ever be made because of the lack of wherewithal to transfer funds to what undoubtedly was considered blue collar and not sexy research.
Are Mice more Important than Men…& Women?
Yet the former NCATS director has pointed out that the NIH actually has paid lots of dough for these very nuts and bolts studies in the sphere of preclinical research (that is animal studies such as mice). There are lots of activities and spend at this stage. This is where Austin possibly lost all confidence in the system as we know it today. Dr. Austin is in fact on the record that he would engage in lots of arguments with the various funding institutes and agencies in the quest to push the repurposed research agenda. TrialSite suspects that Dr. Austin lost more arguments than he won.
Unfortunately, during this pandemic the mainstream press did little to ask any serious questions about repurposed drug candidates, such as ivermectin. There were exceptions, such as the CBS 60 Minutes show on fluvoxamine, but that’s probably thanks to a charismatic successful tech entrepreneur that’s been funding studies. That’s right: a private citizen had to step up and spend millions of dollars of his own money in a bid to advance the public good. But isn’t that what the NIH is supposed to do?
If more journalists were actually doing their job, there would have been a more lively public debate about this serious and deadly issue—under the assumption that it’s possible that certain repurposed drugs could have slowed down the progression of COVID-19 now hence keeping more people out of the hospitals and saving lives.
But there’s been little interest in the crux of the problem with bringing repurposed drugs to market. Clinical research is expensive, well beyond most non-profit organizations dedicated to research. And because NIH doesn’t like to fund human studies involving repurposed drugs (rather they like sexy new innovative science-based approaches), according to Austin this is exactly why the TrialSite continued to report on the billions of dollars going into brand new vaccines and novel therapeutics at the start of the pandemic while drugs that have evidenced tremendous promise, such as ivermectin, have gone literally nowhere with the NIH, as well as with other wealthy nation apex research institutes. As clinical trials can run from a handful of million to north of $50 million, only industry or government can sustainably manage such costs.
So given market economy dynamics, forces and pressures, industry (that is pharmaceutical companies) are not typically in a position to allocate capital to the development of repurposed drugs—even in a pandemic. Drugs are ultimately commercialized by corporations that must drive profits for their shareholders; TrialSite has argued a particular economic system in place that lacks the incentives for repurposed drugs such as ivermectin. University of California Hastings College of the Law professor Robin Feldman has written about the skewed bias and associated distorted incentive system in the world of drug development.
Director Austin Accomplishments
But despite the systemic challenges of bringing repurposed drugs to market Director Austin’s tenure accompanied a number of accomplishments. This should be noted and celebrated as his influence undoubtedly could lead to a reform movement within the NIH.
In his April 15th personalized “NCATS Director’s Message,” Director Austin wrote that this was in fact ‘the most difficult NCATS Director’s message I have ever had to write.” Austin certainly oversaw some progress sharing how translational sciences has progressed since 2011, the year of its founding (NCATS). He shared some of these accomplishments in his message, including:
- We led the establishment of the field of translational science and the communication of its potential and mission to get more treatments to more patients more quickly by transforming the development of treatments and cures from an inefficient empirical process into a productive predictive science.
- We fostered development of such breakthrough technologies as tissue chips, mechanisms for drug repurposing, technology platforms to efficiently identify new drugs, and informatics platforms that connect disparate information across disease. These technologies all address key roadblocks to the development of treatments and provide a road map for predictive identification of therapies ready for human testing.
- We have created and promulgated new ways to develop therapeutics of all modalities that are reaching uncharted biology and untreatable diseases with unprecedented efficiency.
- We have driven the evolution of unique national clinical translational platforms — including the Clinical and Translational Science Awards (CTSA) Program and Rare Diseases Clinical Research Network (RDCRN) into networked, science- and patient-driven innovation engines at the local, regional and national level. These platforms have demonstrated unmatched ability to solve such intransigent problems as multisite institutional review board review, recruitment of diverse clinical trial participants, more productive clinical trial designs, innovative clinical investigator training, and mobilization of electronic health records to drive discovery.
- We have shifted the scientific approach to rare diseases from one disease at a time to many diseases at a time and have transformed the scientific, medical and public perception of rare diseases from a curiosity to a major public health problem.
The outgoing director reminded all of the key ingredients to any success in this type of environment, including A) a culture of informed, persistent and patient focused questioning of how translation could be done better. Prioritizing teamwork over the individual research rock stars or super heroes, Austin emphasizes the necessity for diversity, which brings with it different perspectives, point of view and encompasses a path toward a more holistic quest for answers. Austin noted in his message that he will still be present, undertaking the work he likes to do—translational challenges while remaining “a relentless cheerleader for NCATS and translational science.”
The Big ACTIV-6
And again with Austin’s departure as director comes the largest COVID-19 pandemic clinical trial targeting repurposed drugs yet. Announced just days after the departure letter from the director, one has to wonder why these two events occurred at the same time. While TrialSite celebrates the fact that the NIH has finally decided to invest considerable public money in a large repurposed drug study, we believe unfortunately it’s announced very late in this horrific crisis: perhaps that’s one reason contributing to Austin’s decision?