- Coronavirus research is falling into the same pitfalls that set back efforts to develop an Ebola drug.
- A frenzy of research is underway, but most early studies are small and limited. The first few months of this crisis have brought few clear findings on treatments and plenty of confusion.
- Many ongoing COVID-19 trials don’t have placebo arms. Some have argued it’s unethical to withhold a treatment that could help patients.
- That same argument was used in the 2014 Ebola outbreak. It played out poorly, with research taking several years to find drugs that worked against the virus. A drug that drew massive attention after seemingly curing one Ebola patient turned out to be largely ineffective.
- There are a handful of high-quality trials that have seen success in recruiting patients. They could set a path forward for research.
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Dr. Kent Brantly was on what he figured to be his deathbed. With his health rapidly deteriorating from an Ebola infection he got working in Liberia, he called his wife to say goodbye.
But on the last night of July 2014, Brantly received an infusion of an experimental drug called ZMapp. The first American to be infected with Ebola then started to recover. Within days he was able to walk and continued to improve.
ZMapp looked like a miracle cure for this deadly outbreak. Brantly’s compelling recovery led to a flurry of media attention, both for him and for ZMapp. A few months later, he was on the cover of Time, embodying “The Ebola Fighters” as the magazine’s person of the year.
The years that followed were much more humbling in the fight against Ebola. ZMapp, dubbed the “secret serum” for Ebola, turned out to not be a breakthrough or even an effective treatment. But it took five years to generate quality data that showed other drugs were better.
In the months following Brantly’s recovery, researchers argued about how to design studies, while the virus continued to wreak havoc. By the time global health groups agreed on a testing strategy, the epidemic had waned. There weren’t enough people to test.
It took a second major outbreak of Ebola, in 2018, to finish the research, with a trial starting within a few months to test several treatment options. It found two other drugs were much better at preventing death than ZMapp.
As the world now shelters in place with millions infected from the novel coronavirus, the question is, did we learn enough from Ebola to do better this time around?
While it’s early in the outbreak, initial signs aren’t hopeful. There’s a slew of ongoing research, but most studies lack the rigour to tell if a medicine helps patients. That’s led to a void of quality data about which coronavirus treatments work.
“We’re not going to learn enough from this one either,” Derek Lowe, a veteran drug researcher, said. “We’re human beings, so we’re going to do this over and over and over.”
How ZMapp demonstrated the need for randomised controlled trials
Shortly after Brantly recovered, in 2014, a debate ensued over the next steps for ZMapp.
Researchers pondered whether it was ethical to run a study comparing ZMapp to a placebo during an epidemic. Was it fair to withhold a potential cure from some critically ill patients? Advocates said that was the only way to know if the drug actually worked.
It was far from the fringes of the research world arguing against placebos. Top infectious-disease researchers, including Peter Piot, who helped discover Ebola, and David Heymann, now an adviser to the World Health Organisation, argued a trial where some patients wouldn’t get ZMapp would be unethical.
Researchers shouldn’t be “doggedly insisting on gold standards that were developed for different settings and purposes,” they wrote along with more than a dozen other experts in a letter published in The Lancet, a top medical journal.
The debate slogged on, even as Ebola cases began to fall. By February 2015, half a year after Brantly’s recovery, the US National Institutes of Health had started a randomised controlled trial of ZMapp in the US and Liberia.
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Even then, prominent groups resisted. Doctors Without Borders “balked” at participating in the trial, since only half the participants received ZMapp. The NIH prematurely stopped the study in late 2015, enrolling less than half the targeted 200 participants as the outbreak waned. The results were inconclusive.
When Ebola reemerged in 2018, researchers ran a trial testing four drugs, including ZMapp. While no one got a placebo, the design allowed scientists to compare the drugs to each other. It found a clear result: Researchers recommended dropping ZMapp, finding two other treatments to be better than the so-called secret serum.
‘The bottom line is, we have no reliable data’
COVID-19 drug research is hitting some of the same stumbling blocks that hindered early progress in finding a treatment for Ebola.
It’s been about four months since the world saw the first cases of COVID-19, the disease caused by the coronavirus. And a swarm of research activity has so far led to almost no meaningful findings on a treatment.
“The bottom line is, we have no reliable data,” Martin Landray, a University of Oxford professor now leading COVID-19 research in the UK, said in a recent webinar. “Many people have opinions, but no one has knowledge, at least at present.”
That’s not for a lack of trying. There are 1,200 ongoing COVID-19 trials around the world and more than 260 drugs in development, according to Informa Pharma Intelligence. Yet the designs of most of these studies practically ensure they won’t tell us anything meaningful about whether or not a particular treatment is actually helping patients.
Scientists know what it takes to run a high-quality drug trial. The trial needs to include enough patients so that its conclusions are meaningful. Patients need to be randomly assigned to get either the treatments being tested or a placebo. And doctors and patients shouldn’t know which one they’re getting.
Most coronavirus drug trials fall short of this level of rigour. About 20% of studies that have finished or are now signing up patients meet this bar, as do 40% of trials planned to start soon, Ann Meeker-O’Connell, a vice president at Vertex Pharmaceuticals, said in a recent webinar.
Rigorous trials can take several months to set up, a time frame that is a major drawback in a pandemic. They can be hindered by complex rules, procedures, and data-collection processes that govern a highly regulated space. Yet, even with these difficulties, they remain the most efficient path to quality data.
“We need large, randomised, well-controlled clinical trials,” said Fergus Sweeney, a leader of the European Medicines Agency, Europe’s equivalent of the US FDA. “They are essential to provide us with the evidence to progress the development of COVID-19 medicines.”
The need to run randomised controlled trials during outbreaks was supposed to be a hard lesson learned from Ebola. While that’s the type of study Landray is running in the UK, it’s an exception rather than the rule for COVID-19 research.
Low-quality studies are recruiting large numbers of patients and competing with one another
Edward Cox, a longtime senior official at the FDA, led the argument that trials comparing Ebola drugs to placebos were “essential” to getting answers in 2014.
Cox is now a vice president at the biotech company Regeneron, where he’s making the same argument for COVID-19: If we want to figure out which drugs work, and avoid wasting time, money, and effort on those that don’t, we have to set up properly designed studies.
“Consistent with this goal is avoiding the use of large quantities of investigational drugs in a manner that does not allow us to learn and understand whether the drug provided benefit, had no effect, or harm,” Cox said. “It’s critical that we sort this out.”
Some of the largest coronavirus treatment studies will fail to produce definitive results because of the way that they’re designed.
Gilead Sciences, one of the biggest biotechs in the world, designed two trials to test remdesivir, an experimental antiviral drug.
One of the studies, for patients with moderate COVID-19 cases, will compare remdesivir to standard care for the coronavirus. But it’s open-label, meaning patients and doctors know whether or not they’re receiving remdesivir. This increases the potential for biased results.
Gilead’s second study, in severely ill patients, doesn’t have a control arm. Everyone will receive remdesivir. And the biotech has massively boosted the enrollment goal for that study, from 400 patients to 6,000.
“Sorry if you are developing a therapeutic and actually wanted to test for efficacy in a controlled fashion,” wroteBaird biotech analyst Brian Skorney, “Gilead will now be taking your patients.”
In a statement, Gilead said it decided not to compare remdesivir to a placebo in its trials because other trials doing so were already underway, and because it had limited capacity to manufacture the placebo. The company said it expanded the trial to collect more data on remdesivir and to give more people access to the experimental treatment.
While Gilead’s studies of remdesivir have drawbacks, the NIH is running a trial with a better design. It should yield data in late May that can tell us if remdesivir helps patients.
Walid Gellad, director of the Centre for Pharmaceutical Policy and Prescribing at the University of Pittsburgh, said it’s a legitimate worry that the torrent of studies will compete for the same pool of patients, making it harder to find enough people to test all the drugs.
And even if it’s unlikely we run out of COVID-19 patients anytime soon, a top FDA official warned there is a risk of running out of researchers and time.
In perhaps the closest parallel to ZMapp, hydroxychloroquine has been transformed from an obscure generic drug to a household name. President Donald Trump has touted its potential to be a game-changer in the coronavirus fight. Already approved to treat malaria, lupus, and arthritis, it can prescribed for other reasons as well, if they believe it will help the patient. But these patients won’t generate any data, leaving a vacuum of evidence.
Researchers plans to enroll 200,000 people in more than 100 studies testing these malaria pills, Wall Street Journal reporter Jared Hopkins reported. These researchers have to compete with each other to enroll patients.
It can be a tough challenge to persuade patients to sign up for a study if there’s a risk they won’t get the drug.
Dr. David Boulware is now facing that challenge. The infectious-disease physician is running two placebo-controlled studies of hydroxychloroquine at the University of Minnesota. For weeks, he has been struggling to recruit patients, with trial enrollment plateauing.
He says many people have already made up their minds about the drug: Either they believe it works and his trials are therefore unethical, or they think it’s too dangerous, reaching the same conclusion on his studies.
Enrolling the first 200 patients took four days. The most recent 200 volunteers took three weeks.
There are reasons to hope that COVID-19 will go better than Ebola
Still, there are reasons to be hopeful after the first months of coronavirus research.
Collaboration is happening in unprecedented ways among drug companies that typically view each other as rivals. The NIH has launched a sweeping partnership with government agencies, nonprofits, and 16 top drug companies working together to expedite research on treatments and vaccines.
The Bill & Melinda Gates Foundation is working with pharma companies to open up their labs and share internal resources. A bunch of data-crunching specialists are building a shared research database that will include health records, medical claims, and demographic info from COVID-19 patients.
And while the majority of ongoing studies won’t produce quality data, there are a handful that will.
And the UK is running one of the most promising early research efforts, a trial called Recovery. In about a month, the study has enrolled 7,000 patients and has well over 150 hospitals working together. Participants are randomised to test one of five potential medicines – all of which share the same control group to compare results against.
“This is demonstrating that it is possible to deliver really large-scale, randomised trials with a control group in the context of a pandemic,” said Landray, the Oxford researcher helping run the trial.
He said it would “generate the evidence that patients, doctors, and the health service so desperately need.”
In the middle of a pandemic that has the world’s attention, everyone wants a treatment as soon as possible. But no one wants to end up with another ZMapp.
The 1,000-plus ongoing trials will produce a torrent of data in the comings weeks and months. Some, like the NIH’s trial of remdesivir and the UK’s Recovery study, will give quality results that can guide a sensible path forward.
Others will be uninterpretable, lacking the rigour to determine whether or not a medicine helps patients. The challenge will be separating the meaningful from the noise.