Searching for an effective Covid-19 treatment: promise and peril
By G. Caleb Alexander, Aaron S. Kesselheim and Thomas J. MooreApril 10, 2020
Scientists work in the VirPath university laboratory to find an effective treatment against the new coronavirus. JEFF PACHOUD/AFP via Getty Images
In response to the most serious global health threat in a century, the world's biomedical establishment is unleashing an unprecedented response to the Covid-19 pandemic, rapidly increasing resources aimed at finding safe and effective treatments for the disease. But without careful attention to the pitfalls that can befall biomedical research and regulatory decision-making during a time of crisis, a lot can go wrong.
On March 28, the FDA provided emergency use authorization for hydroxychloroquine — a medicine approved for treating malaria — for people hospitalized with Covid-19. It also however, told health providers that the optimal dose and duration of treatment were unknown. The authorization did not identify any clinical study on which this approval was based, and while hydroxychloroquine may affect viral replication and might ultimately prove beneficial, its impact on health outcomes among patients with Covid-19 is currently unclear.
Against this potentially worrisome action, the scope of the search for a new treatment to mitigate or cure Covid-19 is breathtaking. One recent listing identified more than 70 candidate molecules, including 15 antivirals, potent suppressants of the human immune system, and high-risk oncology treatments already approved by the FDA to treat other conditions.
The National Institutes of Health's ClinicalTrials.gov lists more than 100 clinical investigations focused on Covid-19 from around the world, with sponsors that include medical centers, pharmaceutical companies, and national research institutes. In time, it is likely we will see direct-acting antivirals tailored to the most vulnerable molecular targets on the SARS-CoV-2 virus.
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But this extraordinary effort is lacking international coordination, which may yield counterproductive competition among countries with biotechnology industries. The coronavirus does not respect national boundaries; neither can the development of new treatments, which are already being tested in more than 15 countries. As a first step, the biomedical community needs to insist on consistent use of central registries of clinical studies and on early sharing of complete details of both successful and failed studies, and not withhold important scientific evidence as proprietary information.
Acting against this effort is a growing industry fueled by fear and panic. Medical history has taught us that when people get sick and scared they will take practically anything. For centuries, worthless and sometimes harmful treatments, ranging from arsenic to swamp root, have been promoted by everyone from charlatans to well-meaning clinicians.
In an emergency situation such as this one, attention will naturally turn to repurposing already available products, which makes good sense. But we need to let scientists do their jobs. In too many past cases, drugs have been widely used off-label or based on a positive response in a narrow laboratory or clinical measure only to have independent analysis later show that the treatments do more harm than good or target the wrong patient population. For example, a family of anti-arrhythmic drugs that was effective in stopping asymptomatic irregular heartbeats was subsequently found to increase the risk of cardiac arrest when given to heart attack survivors.
The biomedical establishment must speak with a clear voice about the need to adequately test new drug treatments for Covid-19 and to subject that evidence to independent evaluation by the FDA.
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Other pitfalls await those too ready to embrace a new treatment. One is the power of the placebo effect. Among individuals participating in clinical trials, those unaware they are receiving an inactive placebo can show substantial improvement, sometimes equal to 80% of the apparent treatment effect of the active therapy. The placebo effect has been documented in clinical trials assessing health benefits that range from improvement in subjective psychiatric symptoms to objective laboratory results.
Who has not read media reports about an individual's miraculous recovery at the hands of a caring physician trying an entirely new approach to treatment? Independent investigation of the case confirms the striking improvement was real. But it turns out to be a dramatic example of idiosyncratic recoveries that can be neither explained nor duplicated in other patients.
The coming flood of research from trials now or soon to be underway should lead us toward realistic and objective measures of the two fundamental properties of every therapeutic drug: benefit and harm.
A drug that shows "disease activity" against SARS-CoV-2 could prove too toxic to give to Covid-19 patients with worsening pneumonia. A claim that a drug reduces "viral load" could be valid, but its health benefits or harms could depend on when in the cycle of infection it is used. A drug intended for those with mild-to-moderate symptoms but who are otherwise healthy must be of low toxicity because it will be given to many patients who might have otherwise recovered on their own, while it may be more acceptable to offer drugs with more severe toxicities to patients at higher risk of death.
Another fundamental aspect of all drug testing is encouraging when it comes to Covid-19 research. As the first antibiotics for pneumonia taught us in the 1930s, a dramatically effective treatment for an acute illness can be convincingly demonstrated in a small number of patients observed over a few weeks' time. The chances of discovering and documenting such a treatment grow if we also greatly increase the number of patients enrolled in clinical studies.
In the 1980s, during the HIV epidemic, patient advocacy groups not only helped shape the way clinical trials of the disease were conducted but served as a strong force for recruiting patients into trials of investigational drugs. A broad network of trial participants helped accelerate testing of drugs in the pipeline.
In the case of pediatric cancer, a collaborative professional network was established decades ago to ensure that all patients are enrolled in clinical trials at the time of initial diagnosis. These patients then get top-quality care and generate data to help future patients.
Supported by these forces, it is not surprising that both HIV and pediatric cancer have seen remarkable advances in care over the last 30 years.
It is a false choice to think that we can either have expeditious treatment options for SARS-CoV-2 or we can have rigorous testing of them. We can have both. Achieving that goal, however, will require avoiding missteps such as widely promoting unproven products so fearful people begin using them in inconsistent ways outside of the research enterprise. Instead, we will need international coordination of scientific goals, transparency of results, comprehensive participation in clinical research, and trials that evaluate meaningful outcomes. Doing that can ensure that any treatments that are developed do, in fact, benefit the patients who receive them.
G. Caleb Alexander, M.D., is a professor of epidemiology and medicine at the Johns Hopkins Bloomberg School of Public Health. Aaron S. Kesselheim, M.D., is a professor of medicine at Brigham and Women's Hospital and Harvard Medical School. Thomas J. Moore is a lecturer at George Washington University Milken Institute School of Public Health.
About the Authors	Reprints
G. Caleb Alexander
Aaron S. Kesselheim
@akesselheim
Dean W says:
The writers are obviously all academics / professors at funded institutions. I would prefer to hear from the researchers, but they are too busy doing th actual work in hard and fast research to find a cure. The notion of yet more hurdles so expectable with more burocracy won't do any good in this crisis.
Gord P says:
When contemplating global co-operation for Covid drug development (almost impossible due to natural competition and profits driven R & D), it is preposterous to only look at or consider the FDA for scrutiny. Unless this pooling-suggestion is only for American companies. It must be said that often while many countries (in EU, Asia) already have a drug approved, the FDA still requires trials in the US. The FDA is a singular sluggish machine that is NOT the ideal body to tackle Covid's crushing need for speed. Competition makes R & D healthy, innovative, and fast – also for Covid-19. If the intent of the pooling is global, then there should be multiple regulators also co-operating – not just the FDA. To adapt the laws in so many countries on researchers' operational and reporting requirements will take a century. We don't have time for that. So – let researchers do what they do best, in their own innovative and fast ways. This is how quote from the article) : "a dramatically effective treatment for an acute illness can be convincingly demonstrated in a small number of patients observed over a few weeks' time". So in the current crisis : cut the red tape overkill.
Gamaliel Isaac says:
How about this treatment? https://europepmc.org/article/med/1850209 Covid19 attacks surfactant producing cells in the lungs Why not restore the surfactant they way the scientists did in the above article for viral pneumonia.
Surfactant (soap) kills the virus an surfactant helps increase oxygen in the blood.
Ralf Harand says:
I am a former industry scientist, who has been working as project lead in drug development in the area of acute respiratory distress syndrom and acute lung failure until some years ago. I would like to inform you on a drug that has been in development as a life saving treatment for ARDS linked to pneumonia and aspiration of gastric content until 2008. The development was stopped after the originator company (Altana Pharma, Germany) was sold off to private equity fonds and some very unfortunate development mistakes happened in late clinical stage 3. The development was abandoned, according to my understanding not because the drug has been disproven but primarily because the patent shelf life had become to short to allow for a pay back of a repeated clinical phase III. The drug I am talking about, was an artificial lung surfactant preparation based on the recombinant surfactant protein C. It had the provisional trade name Venticute(TM) and it´s INN is Lusupultide. Clinical data from more than 500 patients had been available already before the last study – the majority from the US – and a highly sophisticated production facility had already been set up in Singen, Germany. I wonder, if someone from government site may have a look into finalizing this project. It dioes not prevent infections, but may be a chance to reduce mortality rates, shorten time on ventilator and such increasing the ICU capacity for this pandemy.
Kelly Hall says:
Hi Ralf,
I hope someone is following up with you! And thank you for sharing your work and experience with this research. It would be nothing short of incredible if this was one piece of the puzzle to help everyone who can collaborate on the breakthrough(s) that make the big difference FOR ALL. Also sorry to hear the profit motive led to the end of your very promising work. I hope you were able to find another opportunity to be a difference maker through science!
david James says:
Where does that now place the misleading, tendentious comments from Trump that " it is less serious than the flu which kills 6,000 annually in the USA" or " hydroxychlorquine is a cure" and "the USA will be coming out of the pandemic by Easter" but failed to nominate in which year. It seems to me his whole approach is one of deliberately misleading and criminal irresponsibility for the purpose of getting his own inaction and the parlous state of public health off the hook. Nothing to see here, stuff. What a turkey.
Jose Luiz M Garcia says:
Regarding your comments about the so called "placebo" effect, who cares if hydroxychloroquine is curing people in Brazil by hundreds. This attitude doesn't contribute at all for the solution of the problem and , as usual, reflects only another pandemic wich is the "cientificism" pandemic within the Medicine.
Artificial Intelligence Medicine Is going to get you all. Make a note of it.
Ejaz says:
The problem with COVID19 is that it is a new disease and we are trying to treat it like a well known old disease. It is not typical pneumonia, it is not typical ARDS, it is not SARS. Currently there is no therapeutic option available that will make sense in terms of what is known about the COVID19 infection. The limited data shows it does not cause significant viremia so any drugs that will work through the blood stream is most likely not going to be effective. It is well known the RNA virus can only survive in cells with nucleus, red blood cells where most of the chloroquine works, does not have a nucleus. The effects of chloroquine on lymphocytes(to work in lupus and arthritis) takes weeks and months to work. So why use a drug that makes no sense. If a drug make sense to use in any disease, a physician can use it on his discretion specially when there is no trials or data available. COVID19 does causes cytokine storm and any drug that help minimize or attenuate may be considered, however, that is not targeting the pathogen just the body response. Keep working on understanding the disease itself will help us come up with therapy.
John Chu says:
Are you suggesting or implying that people can be infected with coronavirus in the air from their ears? If it is true, then this is extremely alarming actually. Could you provide some links to this theory or hypothesis?
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