What can medical research deliver — and when?
The medical research community is collaborating in unprecedented ways, and working overtime, to fight COVID-19. Academics, public health agencies, biotech, and big pharma are working together to repurpose existing drugs, develop new therapies and protect us with new vaccines. What can we expect them to deliver — and when?
Here is a glimpse of the “pandemic pipeline”:
1) Repurposed drugs
The nearest term option to help patients with severe cases of COVID-19 lies in thoughtful use of our existing toolkit — the drugs that we already have. Physicians around the world, desperate to save their dying patients, are leading the charge in experimenting with the use of existing drugs to fight COVID-19 ( “off label” use).
The top COVID-19 candidates target either the virus (e.g, Remesdivir, Lopinavir / Ritonavir (Kaletra), or Chloroquine / Hydroxychloroquine — an anti-malarial) or the immune system response (e.g. Tocilizumab, an anti-inflammatory). The latter strategy stems from the observation that some patients experience harmful immune system over-reactions (e.g. “cytokine storm syndrome”).
To truly understand both the efficacy and the safety, of these investigational COVID-19 drugs, rigorous clinical trials are needed — ideally, the gold-standard (large, randomized, placebo-controlled). Many such trials are already underway around the world, and will give us results in the next few months.
The largest of these is the a global mega-trial run by the World Health Organization, known as the SOLIDARITY trial. The trial will compare four candidate treatments against standard of care: (1) Remdesivir; (2) Lopinavir/Ritonavir; (3) Lopinavir/Ritonavir plus interferon beta; (4) chloroquine.
While hopeful, we must bear in mind that these treatments are still unproven. Their promise stems from anecdotal uses (case studies) and small, uncontrolled, or poorly controlled clinical trials. Experimental use can not only be dangerous but can also impact drug availability for those who need them for proven uses (e.g. chloroquinone for SLE).
The message to healthcare professionals — and the public — is clear: these drugs should not be used outside of the context of a clinical trial (e.g. US Centers for Disease Control guidance)
Read more about investigational COVID-19 treatments: BMJ best practice
2) Convalescent serum
Just as breast milk offers protection to babies through the antibodies it contains, plasma (blood) from patients who fought off COVID-19 may offer short term antibody-mediated protection to the disease to others. Antibodies bind to and “neutralize” pathogens, like cops putting shackles on a villain.
This approach, which involves collecting plasma (blood) from past patients, has been employed in past outbreaks including 2009–2010 H1N1 influenza virus pandemic, 2003 SARS-CoV-1 epidemic, and the 2012 MERS-CoV epidemic, and Ebola with mixed results.
As with other experimental therapies, clinical trials are needed to assess the value of convalescent serum in the context of COVID-19. Such trials are already underway (e.g. this small trial in China, slated to close in July, 2020). In addition, the US FDA is facilitating clinical testing by allowing an emergency IND path, for licensed physicians (they don’t provide the actual plasma!). Even if it’s proven to be both safe and effective, widespread adoption of convalescent serum would mean overcoming important logistical hurdles.
3) Novel therapies
There are at least twenty five potential new therapies for COVID-19 under development, spearheaded by from nearly as many biotech companies (and a handful of academic-led efforts). The majority of these candidate therapies employ the tried and true antibody strategy; the remainder span a range of novel approaches, including siRNA (small interfering RNA), nanoparticles, and recombinant proteins.
It takes many years to bring a new drug to market, even once a strong candidate molecule is ready to test in humans (timeline estimates hover around 5–7 years, including precision oncology) at a cost of hundreds of millions of dollars. Figures for novel technologies are far, far slower (more than a decade from technology initiation).
This long timelines reflects the many hurdles that a drug must pass, from Phase 1 human safety trials (dose-finding), to small Phase 2 proof of concept (clinical efficacy) trials to large Phase 3 trials. It’s only in this last phase that we can truly begin to understand efficacy in target populations through randomized, placebo-controlled trials. In parallel, drug developers must develop the means to scale up production without compromising drug purity and safety.
While regulatory bodies sometimes allow accelerated approval for breakthrough drugs that can treat life threatening conditions, even accelerated timelines mean “few” years rather than “many” years. For example, this 2017 report looked at 10 cancer drugs, of which half received accelerated approval, and reported an average development time of 7.3 years (5.8–15.2 years). All said, even 2021 is a very optimistic timeframe for new therapies to come online (outside of clinical trials).
4) Protective vaccines
A protective vaccine challenges the host’s immune system in a way that enhances its response to future encounters. You essentially develop military reserves, ready to mobilize (and proliferate) at the sight of the pathogen. An effective vaccine, when widely deployed, stops viral spread by providing “dead-end” hosts.
Incredibly, in the few short months since COVID-19 sprang onto the world stage, there are already over sixty potential vaccines under development. These vaccines are being pursued by nearly as many biotech companies around the world, often working with leading academics. These potential vaccines exploit a wide range of mechanisms ranging from attenuated live viruses, to adenovirus-based, to recombinant proteins, to free DNA or RNA.
The pace of vaccine development is hampered by many of the same hurdles as drug development — extensive safety and efficacy testing, and challenges in scaling up production — and augmented by the fact that multiple (spaced) doses are often required. Thus, despite the fact that patients are already being recruited for some phase 1 safety trials, we can’t realistically expect widely available vaccines until early 2021 — if things go well.
Will the fruits of this COVID-19 research be too late?
While the medical research being conducted today will be too late for many victims of COVID-19, there is still great value to be had.
Repurposed drugs offer the greatest promise of near term improvements to standard of care — if production can meet demand. This could happen in a few short months.
Novel therapies and vaccines may be available as soon as 2021. These tools will be critical for preventing subsequent waves of COVID-19, either the original strain or new mutations that crop up. Furthermore, they can help us fight off new pathogens that arise in the future, just as we now repurposing existing tools using to fight COVID-19 (SARS-Cov-2), including some developed to combat past pandemics.
The Bottom Line
The massive, collaborative investment being made by biotech, pharma, and academics around the world is remarkable, inspiring and hopeful, but the timelines are sobering.
Good science takes time. Even when we push harder than we ever though possible, there is only so much we can do. With time, we can understand how to make the most of existing drugs, develop new treatments, and protect ourselves with vaccines. We can do all of this safely, and effectively.
While some of the barriers in the pace of medical research are immovable, others can be overcome with breakthrough technological — and regulatory — innovations, and the funding to make this possible. When this pandemic subsides, my greatest hope is that the global community redirects the remarkable effort and investments being made to fight COVID-19 into radically improving our global preparedness.
In 2015, on the heels of the Ebola outbreak, Bill Gates gave a TED Talk: “The Next Outbreak, We’re Not Ready”. The skyrocketing views of his talk (19 million and counting, on March 26) tells me that we are ready to listen. Are we ready to act? Are we ready to invest? If we don’t want to be part of a sequel to the COVID-19 nightmare, we must. The next outbreak is only a matter of time.
Last but not least, please don’t underestimate the role that you can play in mitigating this pandemic. The toll that COVID-19 takes on our society lies as much in your hands as in the hand of science. Please do your part to flatten the curve: practice physical distancing (2m from others), wash your hands often and well, avoid touching your face, and seek testing if you think you may be infected.
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