Special report: Ebola's thin harvest

                 By Jon Cohen and  Martin Enserink

Since 29 November, not a single new Ebola case has been reported in Guinea, Sierra Leone, or Liberia. If no new cases pop up, the world will be able to declare on 14 January that the 2-year Ebola epidemic has ended at last, after more than 28,600 cases and 11,300 deaths.

Victory would also mean the end of an unprecedented era in Ebola research. The tragedy offered a unique opportunity: Never before had the disease affected enough people to allow researchers to test Ebola drugs and vaccines in a real-world setting. As the number of cases exploded in mid-2014, they set in motion a vast research program that operated at breakneck speed.
But the harvest of that massive effort is thin.
The biggest success so far is a vaccine produced by Merck. A 31 July report in The Lancet  documented remarkable effectiveness in a real-world trial in Guinea. But all other results have yet to appear in the scientific literature. And a careful examination of the data so far—supported by dozens of interviews with the leaders of the studies and other Ebola experts—makes it clear that almost every other trial seems destined to end in questionable results or outright failure. Findings from those that have ended are proving difficult to publish in top-tier journals.
The reasons are varied and complicated. Even under the best circumstances, clinical trials don’t always deliver satisfying results. In this case, many studies started too late, when the epidemic was already declining, and ran out of patients. Others had designs that from the outset had little chance of providing a clear answer. A pharmaceutical company aborted a trial for reasons it never clarified, and the fate of another trial remains obscure even to the World Health Organization.

G. GRULLON/SCIENCE

(Click on image to expand.)
“Thin harvest” explains where the clinical Ebola trials carried out in Guinea, Sierra Leone, and Liberia stand today, and what they're most likely to yield.

• Brincidofovir: A trial ends without an explanation
  
• TKM-Ebola: Negative results prove difficult to publish
• Favipiravir: A big study fails to give solid answers
  
• Interferon: A trial that few believed in
  
• ZMapp: A front-runner fades
  
• Survivors’ blood: A trial whose fate is unclear
  
• Plasma: Cloudy results from filtered blood
  
• Vaccines: The only real success story so far
  

For more of Science's news and research coverage of the Ebola epidemic, visit our collection "The Ebola Files." For more coverage, see the 1 January issue of Science.
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Brincidofovir
A trial ends without an explanation

BIDNESSETC

Chimerix, the maker of brincidofovir, didn't become a superhero defeating Ebola, as this 2014 cartoon suggested.

On 30 January, Chimerix of Durham, North Carolina, pulled the plug on a clinical trial of its experimental drug brincidofovir in Ebola patients. The drug, which mimics a DNA building block, is active against many viruses in test tube experiments and is in human studies to treat cytomegalovirus and adenovirus infections. But the Ebola test, started on 1 January by researchers working with Doctors Without Borders (MSF) at an Ebola clinic in Monrovia, was canceled after it had enrolled just four patients.
The announcement surprised even the scientists running the trial. “The press knew about it before I did,” says Stephen Kennedy, a Liberian investigator on the study. Lead researcher Peter Horby of the University of Oxford in the United Kingdom says Chimerix never told him the reasons either; in a press release the company simply noted that the number of new cases in Liberia had "decreased significantly."
Horby says he doubts the decision was related to how the drug performed in the first four patients. Instead, he believes Chimerix decided that it didn’t want to pursue bringing brincidofovir to market for Ebola after discussions with the U.S. Food and Drug Administration (FDA) raised questions about the interpretation of animal studies. FDA’s acting chief scientist, Luciana Borio in Silver Spring, Maryland, says she can't comment. “We’ve asked the company to disclose the facts surrounding the trial and we were not allowed to.” (FDA did not oversee the Liberian trial itself.)
"Someone should call Chimerix and ask them," says Marie-Paule Kieny of the World Health Organization in Geneva, Switzerland, who has coordinated the international research effort for Ebola. Science did that but a spokesperson for the company declined to comment.
Whatever the motivation, “it was frustrating," Horby says. “We invested a huge amount of resources, time, effort, in very difficult circumstances, as did MSF. It should not have been stopped unless it was for a very good reason.” With so few patients enrolled, results from the study are "uninterpretable," says Horby, who nonetheless still hopes to publish a paper about it.