When American relief workers Kent Brantly and Nancy Writebol were offered and took an experimental treatment for Ebola last month, the event triggered a seismic shift in the largely behind-the-scenes debate over whether untested drugs should be used in the spreading outbreak in West Africa.
Until then, many experts felt it would be unethical to offer African Ebola patients drugs that had never been given to people, let alone tested for safety. (Related: "Promising Ebola Drugs Stuck in Lab Limbo as Outbreak Rages in Africa.")
The mere idea evoked memories of pharma giant Pfizer's disastrous clinical trial of a new antibiotic, trovafloxacin (Trovan), during a 1996 meningitis outbreak in northern Nigeria, or the plot of John le Carré's novel, The Constant Gardener, in which Kenyans are used as guinea pigs to test what turns out to be an unsafe tuberculosis drug.
But when news broke that two infected Americans had been given a therapy that had previously been tested only in primates and, further, that they were holding their own, the flip side of the ethical coin was revealed.
Suddenly the question was no longer "How could one use untested drugs in Africa?'' but "Why Americans and not Africans?" Why was the therapy flown to Liberia for Brantly and Writebol not also offered to Sheik Umar Khan, who had died a few days earlier in Sierra Leone, where he was his country's only virologist and leading Ebola expert?
Questions like these will shape discussions during a World Health Organization (WHO) meeting on the ethics of using experimental Ebola drugs in the current outbreak. The meeting, held today by teleconference, involves ethicists, the affected countries, and representatives of civil society.
Treatments Scarce, Untested
Nothing is easy about the issues, starting with the fact that supplies of the various experimental therapies and vaccines are so limited that recommending their use would be largely symbolic for the next few months at least.
"I think that one of the main showstoppers in all of this—again, I can't speak for every product—is the paucity of availability of any product at all," says Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, part of the U.S. National Institutes of Health.
There is only enough ZMapp—the product the Americans took—to treat a handful of people, Fauci says. The U.S. Department of Health and Human Services' Biomedical Advanced Research and Development Authority, which recently conducted an assessment of the various experimental products in the pipeline, says it could take three to four months to produce another small batch of the therapy.
The remaining doses of ZMapp have been distributed, LeafBio, the company commercializing the product, said in a brief statement posted to its website Monday afternoon. It indicated remaining doses had been provided to Spain for treatment of an infected missionary and to an unnamed West African country for two medical doctors. By Monday evening, the statement was removed from the website.
Sarepta Therapeutics, which shelved an Ebola drug it was developing when it lost U.S. government support for the work, has indicated it would be willing to allow use of its remaining supply—enough to treat a few dozen people, CEO Chris Garabedian told the financial news publication Barron's.
Tekmira Pharmaceuticals, the only company to have done some preliminary safety testing of an Ebola therapy in people, says it would allow its drug to be used by infected individuals. In early July the U.S. Food and Drug Administration placed the drug on a clinical hold because of safety concerns about giving it in high doses, but last week revised its status to allow for compassionate use. Tekmira will not say how much of the product it has or how long it takes to make.
Even therapies and vaccines that have been tried on infected primates have been used only in small numbers of animals. Is it ethical to offer these? Is it safe?
After all, not all drugs that are safe in primates turn out to be safe in people. In 2006, for instance, six healthy volunteers were given an experimental drug called TGN1412, a synthetic antibody under development for leukemia and arthritis. All six nearly died.
"Is there a threshold of what they should have demonstrated in animal models? In nonhuman primates? Is there a threshold also on toxicity?" asks Marie-Paule Kieny, the WHO's assistant director general for health systems and innovation.
On the other side of the deliberation scale is the crushing need for therapies, not just to treat the ill but also to gain their trust. As is often seen in Ebola outbreaks, hostility and suspicion have plagued efforts to halt the spread of the disease.
People who fear they may be sick resist efforts by medical teams to isolate them. And communities often hide the sick, leading to more infections. With no cure and a high death rate, rumors fly that the medical teams are spreading the illness or killing people for their organs.
Aid workers believe that if effective therapies were available, the resistance problem would eventually evaporate. (Related: "Ebola's Deadly Spread in Africa Driven by Public Health Failures, Cultural Beliefs.")
Who Gets Scarce Drugs?
But what would the impact be if affected communities learn that a very small number of people are being offered treatments, but most are not? Would that make medical teams from groups such as Médecins Sans Frontières (Doctors Without Borders) more welcome in these villages? Would it endanger the aid workers?
If the few doses available are going to be used, one ethicist suggests they should be given to health care workers, who have made up an alarming proportion of the Ebola cases in this outbreak. (Related: "Q&A: American Virus Expert in Africa's Ebola Zone: 'This is Like War.'")
"If we have a limited amount of medication to use, it makes sense to use it first on those who are in there trying to treat everyone who has this disease. Because if we allow the people who are treating it to be wiped out, there's no one left to treat it," says Kevin Donovan, director of the Pellegrino Center for Clinical Bioethics at Georgetown University Medical Center. Donovan is not a member of the WHO panel.
He and others suggest that if the experimental treatments are deployed, they should be used in a way that helps scientists determine what actually works against Ebola and why, so that the world is better armed for the next outbreak.
Says Donovan: "This is why I think the rush to say, 'We just have to throw whatever's available at people,' and not do it in a careful way to find out if it really is effective and if it really will be safe, is misplaced goodwill. And it's supported by this great anxiety that the infection epidemic causes."
Given the conditions on the ground, using Ebola drugs in a clinical trial-type approach would be challenging—but not impossible, says Frederick Hayden, an expert on antiviral drugs at the University of Virginia, Charlottesville, and a consultant to the WHO.
Still, Hayden is talking about several months down the road. "Because obviously there are a lot of things that have to get put into place. It's not just having the [drug]. You have to have the protocol, the ethics review, the regulatory piece in place, the import licence. These things all have to fall into place."
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