The Ebola outbreak in the Democratic Republic of the Congo may end without the available experimental drugs having been tested, given the way transmission appears to have slowed. And some experts who have watched with frustration the snail’s pace progress of the efforts to study Ebola drugs during outbreaks are beginning to wonder if, with the advent of Ebola vaccines, the window for doing this kind of research may be closing for good.
There are now several experimental treatments vying to be tested, but each must be greenlit by national regulatory authorities whenever and wherever an outbreak occurs. There remain deeply divergent positions among scientists about how to design outbreak trials, specifically whether studies that don’t compare treatments to placebos can generate useful data. Add to that the fact that outbreaks are sporadic, and are often stopped after a few dozen cases.
The upshot: Ebola outbreaks are tough, tough circumstances in which to try to do badly needed research.
“These are always going to come up unpredictably, usually in gnarly parts of the world,” said Dr. Ross Upshur, who has served on a number of World Health Organization committees on conducting trials during disease outbreaks. “I’m less and less confident that we’re going to have any generally agreed upon therapy or the context in which to rigorously evaluate it.”
Paradoxically, the challenge of showing whether drugs like Mapp BioPharmaceutical’s ZMapp or Gilead’s Remdesivir actually help Ebola patients survive will likely be further complicated in future by an otherwise welcome development. There is now an experimental Ebola vaccine that can be used during outbreaks.
“We really have a good news, bad news situation right now with the control of Ebola virus infection in Africa. With the use of the vaccine and the rapid response, we should be able to hold cases to a minimum. And in that situation, it’s going to be very difficult to test the efficacy of these drugs,” said Michael Osterholm, director of the University of Minnesota’s Center for Infectious Diseases Research and Policy.
“The bad news is, if we don’t control it because it gets into a large urban metropolitan area, and we see hundreds and thousands of cases like we saw in West Africa, we might have a chance at detecting a real clinical impact with the drug — but at a hell of a cost to the residents of Africa.”
The experimental vaccine, made by Merck, is being used in a ring vaccination campaign designed to stop the Ebola virus from spreading by protecting the people who have been in contact with a case. If the vaccine arrives early in an outbreak and people agree to be vaccinated, there should be fewer infected people in future outbreaks.
For decades, the only tools Ebola response teams had were standard disease control practices. Isolate sick people and ensure the health workers caring for them are wearing the right protective garb. Monitor people who had been in contact with Ebola cases so that anyone who becomes ill can be quickly isolated.
These tools work. Time and again they have quelled Ebola outbreaks.
But during outbreaks, Ebola treatment units often come to be seen as places people go to die. Families sometimes hide sick loved ones to care for them at home — infecting themselves in the process. It’s long been hoped that if there were effective medicines to offer, people would seek care sooner, improving their chances of survival and lowering the infection risk for their families.
Research conducted over the past dozen years or so has led to the development of a number of possible therapies which look effective in animal testing. But generating the human efficacy data that regulatory agencies like the Food and Drug Administration look for has been almost impossible, even during the massive West African outbreak of 2013 to 2016.
“It’s clearly very difficult to evaluate efficacy of Ebola products in outbreaks — for obvious reasons,” said Vasee Moorthy, research coordinator in the World Health Organization’s department of research, ethics, and knowledge management.
Doctors Without Borders plays a de facto gatekeeper role when it comes to testing by virtue of the fact that they run Ebola treatment operations during outbreaks. The organization will not randomly assign patients to receive a placebo instead of an experimental medicine. So randomized controlled trials, the gold standard of biomedical research, aren’t an option.
MSF – the group goes by the acronym for its name in French — will conduct trials where some patients get one drug and some patients get another. But with as many as five therapies to test – the number approved for use this time by the DRC — one would need a lot of patients to be able to show that any one of those actually works, or works better than the other options.
The DRC government’s decision of what drugs to use has been guided by two committees it set up. Those panels — one studied the science, the other the ethics — considered if the drugs should be administered to Ebola patients, either under monitored compassionate use protocols or as part of a clinical trial. But that work took a couple of weeks to complete.
By that point, most of the cases had either died or recovered. At present, it’s believe there are only a few confirmed cases in care.
Some will see that as a missed opportunity, but Larry Zeitlin, president of Mapp, has another take. “Getting ZMapp data in human patients, that’s at the very, very bottom of my list. I’d much rather the outbreak is over before we get any data,” Zeitlin said.
Mapp has long assumed it will need to persuade the FDA to license ZMapp using what’s known as “the animal rule,” said Zeitlin. That’s an alternative regulatory pathway that relies on effectiveness data generated in animal studies coupled with human safety data. It was created for the licensure of therapeutics and vaccines that can’t be tested in standard ways.
“Prior to the 2013 to 2016 West African outbreak, I don’t think anybody was really thinking you’d ever really get clinical data for an Ebola therapeutic. It was really the scale of the 2013 outbreak that kind of changed the calculus there,” Zeitlin said.
After the West African outbreak, there was lots of discussion about the need to be ready to hit the ground running the next time there was an outbreak. Clinical trial protocols needed to be prepared in advance, experts insisted. When an outbreak is declared, they said, just fill in the name of the country, the principal investigator, and the drugs to be tested and then get started.
There have been two outbreaks in DRC since the West African outbreak. There are still no standard protocols.
Upshur recalled the discussions on the need to be ready to do clinical trials on the fly actually predate West Africa. There were meetings about what needed to be done after the 2009 H1N1 flu pandemic, he said.
“And we should have been on the ground with protocols for any of these agents that we thought had any promise in Ebola. And just gone right ahead into clinical trials,” said Upshur, a physician and ethicist who is scientific director of Toronto’s Bridgepoint Collaboratory for Research and Innovation.
Dr. Dan Bausch agreed. But Bausch, a veteran of many Ebola responses, understands why this hasn’t happened.
“No one’s job is solely dedicated to this,” said Bausch, who worked at WHO on Ebola therapeutics during and for a time after the West African outbreak. “There’s no Ebola department at WHO that people say: OK, I just work on Ebola.”
All the people who are laser focused on Ebola right now at the WHO were probably as immersed in Nigeria’s Lassa fever outbreak earlier this spring, said Bausch, who is director of the U.K. Public Health Rapid Support Team at Public Health England and a professor at the London School of Hygiene and Tropical Medicine.
“People come home from these outbreaks and we say: ‘OK, here’s what we need to do. We need to develop this protocol and be ready for the next one.’ And everyone agrees with that and it’s completely correct that we need to,” he said. “But it’s also true that people come home and … all the other things just take over.”
Bausch said the thinking now is that given the difficulty of generating data in any one outbreak, studies should be set up to collect data over multiple epidemics. Everyone knows Ebola will be back.
“Then you get 15 patients on this one and 22 on the next one and four on the next one and 35 on the next one. So after five years you have basically a multicenter longitudinal trial with systematic observations and a study design that allows for analysis,” he said.
“I do think that is possible and needs to be the approach that we take. No one of course wants to have enough cases to actually provide statistical power, but … if cases exist, we want to make sure that we take the opportunity and the obligation to learn from them.”
People involved in the planning have also concluded that this can’t be “somebody’s side job,” Bausch said, adding there are discussions underway about getting grant money to fund staff hired to get this work done.
Where others are frustrated, Bausch sees some progress, pointing to the fact that the Merck Ebola vaccine is being used now because it was tested and found to be protective in the West African outbreak. He thinks it’s still possible to gather outbreak data on the Ebola therapeutics.
“I go back to 20 years ago with Ebola outbreaks where there was just nothing to even think about testing,” Bausch said. “So, is there progress? Are we getting there? I think yes. Are we slower than we would like to be, and slower than we should be? I think yes, too.”
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