Disputes emerge over African Ebola drug trials

THE Ebola crisis is winding down in West Africa, but the effort to develop drugs to treat the virus hasn’t lost its urgency, dividing scientists over whether it is ethical to test treatments on patients without rigorous research controls.

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Ebola. Picture: REUTERS/BAZ RATNER  “We couldn’t do this in the US, and you couldn’t do it in the UK, so why do you think you can you do it in Africa?” Andre Kalil, a leading Ebola doctor from the University of Nebraska Medical Centre, said as he confronted the University of Oxford’s Jake Dunning, who has helped run Ebola drug trials in Liberia and Sierra Leone, at a World Health Organisation (WHO) meeting in April.

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Leading US and European doctors are meeting again this week in Geneva to assess the progress and ethics of African Ebola trials.

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At issue is the way doctors from Oxford, Doctors Without Borders and other European groups are evaluating experimental Ebola drugs without using a comparison group of patients given a placebo — just as Doctors Without borders has done with vaccines. Randomly assigning patients to drugs or a placebo is the gold standard for testing whether drugs work and aren’t causing harm. With the outbreak waning — the WHO just declared Liberia free of the virus — it now appears likely scientists won’t gather enough evidence to show which Ebola drugs work.

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Dr Dunning said in an interview that the Europeans believe “nonrandomised trials are ethical and valid. To do a randomised (placebo-) controlled trial would be unethical.

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Yet this means not only doling out unproven medicines, but also the likelihood that the drugs’ effectiveness would never be proven.

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“It’s going to be hard to come up with conclusive answers outside of a randomised, controlled trial,” said H Clifford Lane, deputy director of the US National Institutes of Health’s National Institute of Allergy and Infectious Diseases.

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“It has thus far not been possible to demonstrate the efficacy of any experimental intervention.”

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Ebola, which causes severe diarrhoea, vomiting and haemorrhaging, isn’t an automatic death sentence. Providing fluids is by far the most helpful form of supportive care, meaning what doctors do when they have no real proven therapy. In more high-tech settings, doctors also use mechanical ventilation and organ-protective steps like dialysis.

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Overall, the death rate is 41%, according to WHO data, down from an earlier figure of about 55%. But doctors say it varies greatly from village to village, and over time.

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With those odds, US officials, and some in Europe, believe experimental drugs and vaccines should be given in West Africa only as part of a randomised, controlled and double-blind trial. This means patients would be randomly assigned to receive the experimental drug or a placebo, and that neither doctors nor patients would know who got what. This method generally produces the fastest, most compelling answers and avoids the possibility doctors could overlook dangers of the experimental drugs.

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“We recognise the need for compassion and quick access to effective drugs for those in need,” said Nicole Lurie, US Health and Human Services assistant secretary for preparedness and response, “but history has taught that the best approach is to conduct rigorous controlled trials to determine both safety and effectiveness.”

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One study involved an experimental Chimerix drug called brincidofovir given to patients without any control group. The study was shut down at the end of January after the first four patients died, said people familiar with the details.

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The company said the trial was stopped for lack of Ebola patients.

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Guinea’s national health ministry has decided that an antiviral drug called favipiravir is now the standard of care for treating Ebola, said Dr Lane.

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And yet the testing of that drug is at best “not sufficient to draw any conclusions,” said one doctor participating in the favipiravir study.

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A Guinean health official didn’t respond to e-mailed requests for comment.

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The NIH is conducting the only placebo-controlled Ebola drug trial, evaluating Mapp Biopharmaceutical’s ZMapp in Liberia, Sierra Leone and possibly Guinea.

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The trial, which follows a successful test on 21 Ebola-infected macaque monkeys — all survived — may yet produce results, but the number of patients is dwindling.

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The doctors from Oxford, Doctors Without Borders and Britain’s Wellcome Trust are using a different methodology. Oxford doctors, for example, are conducting a second trial of a drug from Tekmira Pharmaceuticals, TKM-Ebola-Guinea, by comparing outcomes for patients who are given the drug with historical results.

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That approach — historical controls, not placebo controls — is widely viewed with great scepticism in medicine. That is especially so with Ebola, where the death rate varies greatly from week to week and village to village.

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Peter Horby of Oxford, a doctor who is leading the TKM research, said, “The methods of study Oxford uses have been approved by all the required ethical and regulatory committees.”

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When the Oxford study in Liberia of the antiviral medicine brincidofovir was stopped, the maker, Chimerix, said at the end of January it did so after less than a month because not enough people were getting Ebola; the WHO statistics reported on January 28 showed there were 20 Ebola cases in Liberia in the previous three weeks.

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Armand Sprecher of Doctors Without Borders said four deaths in four patients is difficult to interpret, and the doctor acknowledged that “placebo control would help.”

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A third study, from the French national health institute Inserm and Doctors Without Borders, has a similar protocol, studying the drug favipiravir against historical results.

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Doctors Without Borders in a February news release said that of the first 80 patients, the drug showed “absence of efficacy” in the sickest patients and that 93% of them died. In less sick patients with lower levels of virus, the group said 15% of patients died, compared with 30% among previous Ebola patients.

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Martin Friede of the WHO, however, said historical data are “iffy, and were not constant from one centre to another and one country to another.” The drug “should not be standard of care,” he said.

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“The data that we’ve seen do not show evidence of efficacy of the drug.”

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Disagreements over testing turned confrontational at the WHO meeting in Rome in late April.

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Dr Kalil said he isn’t allowed to discuss the meeting, but two attendees confirmed what happened.

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Dr Kalil from the University of Nebraska Medical Centre — one of three US hospitals designated to receive patients from Africa — gave a presentation about the need for randomised, controlled studies.

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Introducing himself, he jokingly posted slides of people like Fred Astaire, Marlon Brando and Warren Buffett and asked what they had in common. The answer: they are all from Nebraska.

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The next morning, Dr Dunning, in describing Oxford’s so-called single-arm study, showed slides of famous Oxford graduates, observing, “None of them are from Nebraska.”

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Dr Kalil shot back: “Jake, with all these famous people from Oxford, all you could come up with was a second uncontrolled, single-arm study?”