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Feature Infectious Diseases

Ebola: an opportunity for a clinical trial?

BMJ 2014; 349 doi: (Published 06 August 2014) Cite this as: BMJ 2014;349:g4997
  1. Sophie Arie, freelance journalist, London
  1. sarie{at}

As the largest outbreak of Ebola virus has forced hitherto neglected tropical diseases on to the public agenda, debate is growing over whether affected patients should have the chance to try experimental drugs. Sophie Arie reports

A few weeks ago, most people worldwide had probably never heard of Ebola disease. Outbreaks were rare and usually quickly contained. Before the current epidemic, the disease had killed only 1590 people in total, most of them in remote parts of Uganda and what is now the Democratic Republic of Congo, since it was discovered in 1976 (box 1).1

Box 1 Ebola timeline1

  • 1 August: Two infected US citizens are flown home from Liberia where they had been working with Ebola patients. One of them was reportedly given an unnamed experimental serum to treat the disease. Another infected colleague reportedly took a serum of antibodies taken from a survivor. At the time of publication, their condition was not known

  • 31 July: WHO announces $100m to upscale the effort to contain the disease, and secretary general Margaret Chan warns of “catastrophic numbers of dead” if the disease is not brought under control. WHO staff and aid agencies on the ground say there are signs in some areas that numbers of new infections are beginning to fall. In total, 729 people are confirmed dead. The same day, the US announces the bringing forward of a clinical trial of a possible vaccine

  • 25 July: Sierra Leone’s top Ebola doctor, Sheik Umar Khan. succumbs to the disease. More than 100 medical workers are known to be among the dead

  • 23 June: Médecins Sans Frontières (MSF) declares that the outbreak is “out of control,” with more than 60 hotspots where the cases have been reported. 337 people were confirmed dead at that stage

  • 20 July: A man arrives at Nigeria’s Lagos airport with Ebola symptoms, triggering concern worldwide that the disease could spread internationally by plane

  • May: Ebola reported in Sierra Leone

  • March: Ebola virus outbreak confirmed in Guinea. Subsequent tracing shows that the disease had first struck in December 2013. It is thought to have been carried to Guinea from Gabon. Ebola reported in Liberia at the end of the month

  • Several studies for possible treatments and vaccines show promising results in primates and mice

  • The US and other countries begin investing in research towards developing treatments and vaccines for Ebola and other so called neglected tropical diseases as part of the post-9/11 bioterrorism campaign

  • 24 outbreaks of Ebola are reported—five in Uganda, six in DR Congo, four in Congo-Brazzaville, three in Sudan, four in Gabon, one in Ivory Coast, and one in South Africa. The largest was in Uganda in 2000 when 425 people died. Little funding is available for research, and the basic facts about the origin of the disease and its behaviour are not discovered. It is thought to be transmitted to humans from fruit bats

  • Ebola first appears in two simultaneous outbreaks, in Nzara, Sudan, and in Yambuku, Democratic Republic of Congo (called Zaire at the time). The latter was in a village situated near the Ebola River, from which the disease takes its name

Now, Ebola has spread across three densely populated countries in west Africa in less than six months, killing 887 people, and—despite their best efforts to contain it—the World Health Organization and aid agencies have warned that the outbreak is out of control. “If the situation continues to deteriorate, the consequences can be catastrophic in terms of lost lives but also severe socioeconomic disruption and a high risk of spread to other countries,” said Margaret Chan, the director general of WHO on 31 July.2

Because of fears that air travel could spread the virus almost anywhere, alarm bells are suddenly ringing worldwide. Borders and airports in the affected countries have been closed, and in the West headlines about a pandemic threat have appeared, with calls for a vaccine and a cure.

A possible turning point?

Will this extraordinary Ebola epidemic prove to be a turning point in terms of the world’s attitude towards this—and other—deadly but hitherto neglected tropical diseases? “There’s an opportunity here. Whether or not it will be seized remains to be seen,” Peter Walsh, an Ebola specialist at Cambridge University, told The BMJ. “Several experimental vaccines have been highly successful in animals. They should be used now to save lives and to carry out a clinical trial.”

“The odds are that these vaccines are safe,” says Walsh, who has worked on one experimental vaccine. “When probable benefits outweigh probable risks, there’s obviously a net benefit.” Yet people fighting the outbreak on the ground, where tensions are high amid fear and mistrust of foreign doctors, say it would be unwise to start experimenting with new drugs now.

Ebola haemorrhagic fever is a horrific disease that first involves flu-like symptoms, diarrhoea, and vomiting but can rapidly cause internal and external bleeding and organ failure. It is only transmitted through contact with bodily fluids during the final stages of the disease, however, which means that in the past containment has always been possible through simple techniques, involving isolation of infected people, contact tracing, and good hygiene.

WHO, which is leading the effort to support the affected countries, has acknowledged that because of the unique conditions in west Africa the virus is still “moving faster than we are.” The region has never experienced Ebola before, so the virus was able to circulate for more than three months before it was identified.3 This is a densely populated region, where the infrastructure is better than elsewhere in Africa and the population is highly mobile. But Guinea, Liberia, and Sierra Leone are among the poorest countries in the world4; health services are very basic (some places have no running water) and the least equipped to cope. Fear, lack of understanding of the disease, and burial traditions mean that the public have not avoided contact with people who have been infected, and many people have been too afraid to seek medical help. Some even believe that doctors are spreading the disease.5

Recognising the scale of the challenge, WHO has just announced that it will spend $100m (£59m; €75m) on deploying many more experts and vast quantities of equipment. The World Bank has also pledged $200m. International aid agencies MSF and the International Committee of the Red Cross both expressed hope in late July that with far greater resources the disease can be contained by the end of the year. No one is willing to estimate how many people may have died by then. Although there are signs that the virus has peaked in Guinea, where the outbreak started in March, a second case of Ebola has now been reported in Nigeria.

Can experimental drugs be used?

Although WHO and international aid agencies would like to be able to offer both vaccines and therapeutic treatments to the affected population, they insist that for ethical and practical reasons, the drugs must be tested on humans first. “As doctors, trying an untested drug on patients is a very difficult choice since our first priority is to do no harm and we would not be sure that the experimental treatment would not do more harm than good,” Bart Janssens, MSF’s director of operations, told The BMJ.

In an atmosphere of growing panic—with schools closed in affected areas, government workers sent on compulsory leave for a month, and people fleeing—the idea of Western doctors injecting African people with experimental drugs seems potentially disastrous. If the drugs worked, there could be a sudden clamour for them to be given to millions of people when only limited numbers of samples are currently available. If the drugs failed, there could be a huge backlash against the doctors who administered them.

“The experimental vaccines and treatments that are most promising in animal studies work best when given in the earliest stages of infection,” said Heinz Feldmann, an Ebola expert who heads the laboratory of virology at the US National Institute of Allergy and Infectious Diseases’ Rocky Mountain Laboratories in Hamilton, Montana. “In west Africa right now, people are turning to doctors only when the symptoms are already very advanced. At that stage, no experimental drug can save them.”

The governments battling the outbreak have not called for experimental drugs to be made available, Feldmann points out, and securing informed consent for trials in the population would be a huge problem. The time and cost of manufacturing sufficient volumes of a new drug for human use are another consideration. Until now, that investment has simply not made economic sense for either drug companies or governments, because the disease affects only relatively small numbers of people in poor countries.

The US government has invested more than any other country in researching neglected tropical diseases since the 9/11 terrorist attacks raised fears about possible bioterror attacks.6 That investment had led to several experimental treatments and vaccines having shown potential during laboratory testing (box 2).

Box 2 Experimental treatments and vaccines

  • Tekmira pharmaceuticals, a British Columbia based company, has developed a treatment based on so called RNA interference, which works to block DNA making proteins and stop the virus replicating. The drug was in phase I trials, but the US Food and Drug Administration (FDA) halted them in 2012 to investigate the process, which would involve a “heavy dosing regimen.”

  • A North Carolina company, BioCryst Pharmaceuticals, has used the same technique to develop a drug, with a working name of BCX4430, which has proven effective in animal studies in preventing deaths from the Marburg virus, which is similar to Ebola.

  • Another promising approach, based on creating a cocktail of antibodies taken from survivors of the disease, has also proven highly successful in animal trials. Results are expected to be published in the coming months.

  • The most promising vaccine is made from a microbe called vesicular stomatitis virus (VSV).

Clinical trials for safety are expensive, however, and efficacy trials can be conducted only during an outbreak. The FDA halted two safety trials on experimental Ebola drugs in recent years, one as a result of funding problems; only in 2012, experts were saying that developing these drugs might never be possible.7

So will the scale of the current outbreak change that? “It would be great if this could be a wake-up call for this issue,” says Peter Hotez, director of the Sabin Vaccine Institute in Washington. “But I don’t know if this [outbreak] will be enough of a game changer because it’s not big enough. Malaria kills as many people each day as this outbreak has killed so far. We must try to keep things in perspective.”

Anthony Fauci, director of America’s National Institute of Allergy and Infectious Diseases, has just announced that a phase I clinical trial of a promising Ebola vaccine will be brought forward to start this September. Results should be ready by January; if they show that the vaccine is safe for healthy people and effective in terms of prompting the development of antibodies, the vaccine could be manufactured for human use later next year, Fauci said. It could then be given to health workers who are both at high risk of infection and so called “superspreaders” of the disease because of the physical contact they have with patients. Because of their professional expertise, they would also be best placed to give informed consent to participate in a trial. The only positive development to come from the epidemic is that it has attracted long needed attention from drug makers, Fauci said.

Under FDA regulations, in an emergency the “two animal rule” can be applied so that as long as a drug has shown efficacy in two different animals and has proven not to have serious side effects in healthy humans, it can be made available on compassionate grounds.8 But even the US’s efforts to fast track the approval of experimental drugs in this way will prove too late for the victims of the current outbreak.

Walsh says that if $10-20m had been found to fast track experimental drugs in March—only a fraction of what is now being spent to contain this outbreak—a vaccine and a treatment would be available by now, the outbreak would be under control, and drugs could be stockpiled for any future outbreaks or bioterrorist attacks.

“Plague vaccines were developed by testing experimental treatments on victims,” he says. Because of concerns about the ethics of experimenting on African patients, however, nobody is brave enough to start testing drugs that have not gone through the rigorous Western approval process. Whereas Westerners might immediately consent to trying an experimental drug faced with the 56% chance of death in the current epidemic, in Africa there is a deep seated mistrust around drug trials conducted by foreign organisations.”

Walsh believes, however, that if small numbers of medical professionals were seen to be cured or immunised against the disease by experimental drugs, the affected population and their governments would rapidly be won round. “There has to be a change in the policy elite about what is the right thing to do,” he says. “It’s in everybody’s interests.”

Who should take responsibility?

Walsh suggests that the UN and international organisations are hamstrung by bureaucracy and an aversion to risk taking. Drug companies are not willing to take on the legal responsibility. “What’s needed is insurgents from outside to come and change the culture.”

Jeremy Farrar, director of the Wellcome Trust and a professor of tropical medicine, might prove to be just that. He has called for a major rethink in the current approach. “Not a single individual has been offered anything beyond tepid sponging and ‘we’ll bury you nicely,’” he said in early July. “It’s just unacceptable.”

Despite recent efforts to improve the way the world works together against potential global health threats,9 resistance to testing new treatments during outbreaks, wherever they are, has to be overcome, Farrar says. “We need to work with at-risk communities and national governments to discuss potential new treatments and how they might work within ethical, logistical, and assessment frameworks, and we need them to be ready to go within days,” he argues.10 “We also have to work out how to ethically, and practically, undertake the essential clinical research in an emergency that is critical to save lives and reduce disease transmission.”

The Wellcome Trust has proposed that it could potentially fund and organise such trials, in the hope that experimental drugs will be stockpiled so that next time Ebola—or another neglected tropical disease—strikes, the victims might have a chance to try them.


Cite this as: BMJ 2014;349:g4997


  • Competing interests: None declared.

  • Provenance and peer review: Commissioned; not externally peer reviewed.

  • No Holds Barred: Courage is treating patients with Ebola (BMJ 2014;349:g4987, doi:10.1136/bmj.g4987)


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